Novel amino acid salts, compositions and methods for treating skin, regulating skin and detecting

Abstract

Substituted lysine and branched chain amino acid salts are selected, compositions comprising them, and their use in treating undesirable physiological effects of various diseases, especially skin diseases, mitigating the effects of aging and environmental factors on the skin, and improving and glowing the skin.

Description

[0001] Related applications This application claims the benefit of prior U.S. Provisional Patent Application No. 63 / 527,483, filed July 18, 2023, entitled "Novel Amino Acid Based HistoneDeacetylase Modulators for Treating Skin," and prior U.S. Provisional Patent Application No. 63 / 621,598, filed January 17, 2024, entitled "Compositions and Methods for Regulating Malanogenesis," the entire contents of which are incorporated herein by reference. Technical Field

[0002] This disclosure describes specific lysine and branched-chain amino acid salts, their analogues, tautomers, stereoisomers, polymorphs, and hydrates, as well as their pharmaceutically and cosmetically acceptable divalent metal salts, compositions, metabolites, and prodrugs. These compounds have been found to inhibit or activate a variety of enzymes (depending on the compound type), including histone deacetylases (HDACs); maintain stemness; prolong telomeres; and promote collagen regeneration. They can also be used as therapeutic or ameliorative agents for: preventing and / or reversing signs of skin aging; improving wound healing; improving barrier function and repair and skin hydration; controlling pigmentation, inflammation, and immunosenescence; and mitigating, reversing, and / or preventing various skin diseases and adverse effects of physiological and environmental factors on the skin. Background Technology

[0003] Histones are among the most abundant proteins in the human body. They are highly basic proteins rich in lysine and arginine residues and are found in the nucleus of eukaryotic cells. They act like spools, helping to compress DNA and allow our vast genome to fit within the limited space of the cell nucleus. Each spool consists of eight histones, surrounded by only 147 base pairs out of the more than 3 billion base pairs in the human genome, meaning that each cell requires more than 163 million histones to hold the base pairs together. Remarkably, despite the tight folding of DNA, this compression allows it to be easily accessed by numerous enzymes within the cell, which replicate, repair, or utilize its genes to produce proteins. B Alberts et al., Molecular Biology of the Cell. 4th Edition, New York: Garland Science, 2002 ].

[0004] Of all known histone modifications, acetylation has the highest chromatin unfolding induction potential because it neutralizes the electrostatic interaction between histones and negatively charged DNA, thus making them more accessible to the transcription apparatus. H Zentner, Regulation of nucleosome dynamics by histone modification, Nat Struc Mol Biol, 20:259 - 266, 2013In normal cells, there exists a delicate balance between histone acetylation and deacetylation. E Roperto, The role of histone deacetylases in human cancers, Mol Oncol, 1:19 - 25, 2007 This balance is primarily controlled by HDAC and histone acetyltransferase (HAT). Gong et al., Acetylation readers protein: linking acetylation signaling to genome maintenance and cancer, PLoS Genet, 12, e1006273, 2016; Shen et al., Histone acetylation enzymes coordinate metabolism and gene expression, Trends Plan Sci, 20:614 - 621 2015 ] 。 HAT catalyzes the transfer of the acetyl moiety from acetyl-CoA to the ε-amino group of a histone lysine residue, thereby neutralizing the positive charge at the histone tail. This results in a more open chromatin state, making DNA more accessible to transcription factors. Conversely, HDAC catalyzes the removal of the acetyl group from the lysine residue at the histone tail, forming a more compact, transcriptionally repressive chromatin conformation. Peng et al., Histone deacetylase activity assay. Methods Mol Biol, 1288:95 - 108, 2015 Overall, histone acetylation and deacetylation play crucial roles in modifying chromatin structure and thereby regulating gene expression, cell proliferation, migration, apoptosis, immune function, and angiogenesis. Chen et al., Histone deacetylases and mechanisms of regulation of gene expression, Crit Rev Oncog, 20:35 - 47, 2015; Zhou et al., Role of histone deacetylases in vascular cell homeostasis and artioclerosis, Cardivasc Res, 90:413 - 420, 2011 Overall, the removal of acetyl groups has a profound impact on gene expression. Whole-genome expression profiling estimates suggest that 10% of gene transcription is regulated by histone deacetylases.

[0005] When discussing histone deacetylases (HDACs) and histone deacetylase inhibitors (HDACi), we need to keep in mind the following facts: (i) HDACs deacetylate not only histones but also non-histone proteins. BN Singh et al., Nonhistone protein acetylation as cancer therapy targets. Expert Rev. Anticancer Ther. 10, 935 - 954, 2010;MA Glozak et al., Acetylation and Nonhistone protein deacetylation. Gene. 363, 15 - 23, 2005 (ii) HDAC can also catalyze other deacylation reactions, such as demalonylation, desuccinylation, decrotonylation, or debutyrylation. W Li and Z Sun, Mechanism of Action for HDAC Inhibitors — Insights from Omics Approaches Int J Mol Sci. 20(7), 1616, 2019; https: / / doi.org / 10.3390 / ijms20071616 ; among which the references cited (iii) HDAC has non-enzymatic function. W Li and Z Sun, Mechanism of Action for HDAC Inhibitors — Insights from Omics Approaches Int J Mol Sci. 20(7), 1616, 2019; https: / / doi.org / 10.3390 / ijms20071616 ; among which the references cited Human histone deacetylases (HDACs) are classified into four classes based on sequence homology. E Seto and M Yoshida, Erasers of histone acetylation: The histone deacetylase enzymes. Cold Spring Harb Perspect Biol. 6, a018713, 2014Class I includes HDAC 1, 2, 3, and 8; Class IIa includes HDAC 4, 5, 7, and 9; Class IIb includes HDAC 6 and 10; Class IV includes HDAC 11; Class III includes SIRT 1-7. E Seto and M Yoshida, Erasers of histone acetylation: The histone deacetylase enzymes. Cold Spring Harb Perspect Biol. 6, a018713, 2014 Class I, II, and IV are classic zinc-dependent HDACs, often simply referred to as HDACs. Class III are NAD-dependent sirtuins, which are more distantly related to HDACs.

[0006] Transcriptional regulation is a crucial event in cell differentiation, proliferation, and apoptosis. The transcriptional activation of a set of genes determines cellular function and is tightly regulated by multiple factors. One of the regulatory mechanisms involved is alteration of DNA tertiary structure, which affects the action of transcription factors on their target DNA regimens. Nucleosome integrity is regulated by the acetylation state of core histones, which in turn allows transcription to occur. Regulation of transcription factors is thought to involve alterations in chromatin structure. Changes in histone affinity for the DNA coiled within the nucleosome alter chromatin structure. Low-acetylated histones are believed to have a stronger DNA affinity, forming tight-binding DNA-histone complexes that prevent DNA from receiving transcriptional regulation. The acetylation state of histones is controlled by a balance of activity between histone acetyltransferases (HATs) and histone deacetylases (HDACs).

[0007] Histone deacetylase inhibitors (HDACi) are known to block HDAC enzyme activity by binding to zinc ions at the catalytic site, thereby preventing substrate entry into that site. J Melesina et al., Strategies to Design Selective Histone Deacetylase Inhibitors, Chem Med Chem, 2021; https: / / doi.org / 10.1002 / cmdc.202000934; A Vannini et al., Substrate binding to histone deacetylases as shown by the crystal structure of the HDAC8 - substrate complex. EMBO Rep. 8, 879 - 884, 2007; BE Lauffer et al., Histone deacetylase (HDAC) inhibitor kinetic rate constants correlate with cellular histone acetylation but not 转录与细胞活力。《生物化学杂志》288卷,26926 - 26943页,2013年 HDACi typically consists of a zinc-binding group, a surface-binding group, and a linker that connects the two components and spans a hydrophobic catalytic site channel. A Vannini et al., Substrate binding to histone deacetylases as shown by the crystal structure of the HDAC8 - substrate complex. 《欧洲分子生物学组织报告》8卷,879 - 884页,2007年;BE Lauffer等人,组蛋白去乙酰化酶(HDAC)抑制剂动力学速率 常数与细胞组蛋白乙酰化相关,但与转录 和细胞活力无关。《生物化学杂志》288卷,26926 - 26943页,2013年 HDACi can be grouped according to their chemical properties. W Li和Z Sun,HDAC抑制剂的作用机制——来自组学方法的见解《国际分子科学杂志》20(7),1616,2019年; https: / / doi.org / 10.3390 / ijms20071616 ;其中引用的参考文献 W Li和Z Sun,Hydroxymates (such as SAHA (vorinostat), TSA (trichostatin A), LBH589 (panobinostat), and PXD101 (belinostat)) belong to the pan-HDACi group and inhibit all HDACs. Short-chain fatty acids (such as VPA (valproic acid) and butyrate) inhibit class I and IIa HDACs. Benzamides such as MS275 (entinostat) and depsipeptides such as FK228 (romidepsin) inhibit some class I HDACs. Cyclic tetrapeptides (such as TPX (trapoxin)) target some class I, IIa, and IV HDACs. ACY-1215 (ricolinostat) is a selective inhibitor of HDAC6. HDAC抑制剂的作用机制——来自组学方法的见解《国际分子科学杂志》 20(7),1616,2019年; https: / / doi.org / 10.3390 / ijms20071616 ;其中引用的 参考文献 Feser ].

[0008] With age, several histone acetylation markers decrease, including overall histone 4 acetylation levels and histone 3 acetylation at lysine residues 18, 27, and 56, which are thought to contribute to the aging process. J,Tyler J,染色质结构作为衰老的介质,《欧洲生物化学学会联合会快报》,2011年,585卷: Hsu AL,Murphy CT,Kenyon C,DAF - 16和热休克因子对衰老及 2041-2048 Therefore, HDAC inhibitors, by preventing further acetyl group removal from HDAC, have the potential to directly reverse or prevent these age-related changes. The role of epigenetic alterations in aging can be correlated with other biomarkers, thereby expanding the reach of HDAC inhibitors to exert positive benefits against aging at the molecular level.

[0009] Protein homeostasis involves (i) its ribosome-mediated biosynthesis, (ii) its folding mediated by molecular chaperones, and (iii) its degradation mediated by proteasomes and autophagy. HDAC inhibition may play a beneficial role against aging in all three stages of protein homeostasis. Following ribosome synthesis, multiple quality control mechanisms ensure the stability and functionality of proteins, including protein molecular chaperones such as heat shock proteins (HSPs). The heat shock response plays an active role in lifespan regulation. 与年龄相关疾病的调控。《科学》,2003年,300卷: Galmozzi A等人, 1142-1145The final step in protein homeostasis involves protein breakdown, achieved through proteasome degradation or autophagy, both of which play crucial roles in aging and are regulated by HDAC. This suggests that HDAC inhibitors may contribute to extended lifespan through protein quality assurance pathways. These findings indicate that HDAC inhibition can be beneficial in all steps required for protein homeostasis and directly improve this marker of aging. Intervention in mitochondrial biology may mitigate skin aging.

[0010] With age, several mitochondrial regulatory factors decrease, leading to a decline in mitochondrial energy production capacity, increased damage accumulation, and reduced mitochondrial turnover. Strong evidence suggests that HDAC inhibitors can prevent or reverse some of this degeneration. Multiple studies have confirmed that butyrate can promote mitochondrial biosynthesis, thereby increasing oxygen consumption (…). ​ I类组蛋白去乙酰化酶的抑制揭示了线粒体特征 并增强骨骼肌和脂肪组织中的氧化代谢, 《糖尿病》,2013年,第62卷:732 - 742页 (), 沃尔什ME,范雷门H(2016年)新兴作用 组蛋白去乙酰化酶在与年龄相关的肌肉萎缩中的作用,《营养与健康衰老》, 2016 4: 17-30 ).

[0011] Inducing senescence (a quiescent, non-dividing cell state) in cancer cells is a desired outcome of cancer treatment, and several studies have shown that HDAC inhibitors can induce senescence in various cancer cells. 巴尔加斯JE等人,HDAC的抑制 增加了天然多酚在胶质瘤细胞中诱导的衰老, 2014年,《生物化学与细胞生物学》,2014年,第92卷:297 - 304页 However, in the context of aging, the expectation is to reduce, rather than promote, senescent cells. Importantly, the ability of HDAC inhibitors to induce cellular senescence can be cancer-specific: studies have shown that sodium butyrate enhances senescence in human and rat glioma cell lines, but has no effect on normal astrocytes. 巴尔加斯JE等人 人,HDAC的抑制增加了天然 多酚在胶质瘤细胞中诱导的衰老,2014年,《生物化学与细胞生物学》,2014年,第92卷:297 - 304页 However, HDAC inhibitors may offer potential benefits in improving cellular senescence markers, but this remains an unexplored area.

[0012] HDACs have a wide range of functions. Epidermal keratinocytes participate in immune defense through their ability to recognize danger, trigger inflammation, and fight infection. However, normal skin immune function must tolerate contact with a large symbiotic microbiome without leading to undesirable inflammation that promotes disease. 阿尔费林克等人,新生儿 外周T细胞运输对组织抗原耐受性的控制。《科学》282卷, 1338 - 1341页,1998年;张等人,围产期免疫系统的独特方面, 《自然评论免疫学》,第17卷,495 - 507页,2017年 For example, failure of immune tolerance mechanisms can lead to classic allergic reactions to specific antigens, and common human inflammatory skin diseases such as psoriasis, atopic dermatitis, and acne reflect dysregulation of tolerance to innate immune stimuli. However, despite the fact that innate immune tolerance is crucial for overall immune homeostasis and may be associated with a variety of human diseases, the understanding and research of these mechanisms are still in their early stages.

[0013] A common mechanism by which the environment controls cellular function is through epigenetic control of gene expression. Microbial environmental conditions determine epigenetic events and lead to the molecular generation of keratinocytes that break down innate immune tolerance. *Propionibacterium acnes* (… 痤疮丙酸杆菌 ( 痤疮丙酸杆菌 This is one such symbiotic skin bacterium that produces short-chain fatty acids (SCFAs), which are important molecules involved in epigenetic control and can increase histone acetylation by inhibiting histone deacetylase (HDAC). SCFAs are produced by bacteria under anaerobic conditions. 阿尔帕亚等人,代谢产物 共生细菌产生的代谢产物促进外周调节性T细胞 [[ID= It can also accumulate in hair follicles through the fermentation of Propionibacterium acnes. Shu et al., Fermentation of Propionibacterium acnes, a commensal bacterium in the human skin microbiome, as skin probiotics against methicillin- resistant Staphylococcus aureus, PloS one 8, e55380, 2013 Although SCFAs such as butyrate are known to inhibit the inflammatory response of bone marrow-derived immune cells, […]. Arpaia et al., Metabolites produced by commensal bacteria promote peripheral regulatory T-cell generation, Nature, 504, 451-455, 2013; Furusawa Y et al., Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells, Nature, 504, 446-450, 201 [3] An important clue to understanding innate skin immune tolerance came from the discovery that SCFA enhances the inflammatory response of keratinocytes to TLR ligands. SCFA produced by Propionibacterium acnes inhibits HDAC8 and HDAC9 in keratinocytes, amplifying the inflammatory response of keratinocytes. Sanford et al., Inhibition of HDAC-8 and HDAC-9 by microbial short-chain fatty acids breaks immune tolerance of the eoidermis to TLR ligands, Science Immunology, 1, eaah4609, 2016 This response is the opposite of the effect of HDAC inhibition on the production of inflammatory cytokines.

[0014] In addition to suppressing inflammatory responses, certain SCFAs (i.e., butyrates) have also been shown to play a key role in influencing the dominance of specific skin microbiome profiles, which subsequently trigger skin immune defense mechanisms by protecting against infection and ultraviolet radiation and providing adequate nutrition to skin cells. Salem I. et al., The Gut Microbiome as a Major Regulator of the Gut-Skin Axis. Front, Micribiol, 2018, 10:1459 In fact, it has been shown that butyric acid alone, or in combination with topical glycerin preparations containing Staphylococcus epidermidis, can significantly improve UVB-induced skin inflammation in mice. Keshari S Balasubramaniam et al., Butyric Acid from Probiotic Staphylococcus epidermidis in the Skin Microbiome Down-Regulates the Ultraviolet-Induced Pro-Inflammatory IL-6 Cytokine via Short-Chain Fatty Acid Receptor, Int J Mol Sci, 2019; 11:4477 Butyrate significantly reduced UVB-induced skin ulceration and epidermal thickening, and significantly decreased IL-6 and IL-8 levels. These immunomodulatory effects of butyrate are mediated by binding to GPR43, which controls the production of pro-inflammatory cytokines triggered by skin injury. Keshari S Balasubramaniam et al 人,皮肤中来自益生菌表皮葡萄球菌的丁酸 微生物群通过短链脂肪酸受体下调紫外线诱导的促炎IL-6 细胞因子,《国际分子科学杂志》,2019年;11:4477Topical butyrate administration has the potential to be a useful therapeutic application for inflammatory skin diseases, showing promise of "cure." Therefore, butyrate is not only effective against overt skin conditions but can also be used as a cosmetic ingredient to prevent skin changes. Unfortunately, the main limiting factor for the dermatological use of butyrate is its unpleasant sensory properties (extremely unpleasant odor) and physicochemical properties. Butyrate esters are also extremely unstable, even releasing butyric acid at room temperature.

[0015] Furthermore, although sodium butyrate has been reported to have HDAC inhibitory activity (IC50 against HDAC 1, 2 and 7), 50 The values ​​were 0.3, 0.4, and 0.3 mM, respectively, but it had no inhibitory effect on HDAC6 and 10. https: / / www.abcam.com / 钠 丁酸盐-组蛋白脱乙酰酶抑制剂-ab120948.html Furthermore, its short systemic half-life limits its use as a systemic treatment. 米勒A等人,钠的临床药理学 急性白血病患者的丁酸盐,《欧洲癌症临床肿瘤学杂志》,1987年;23 (9) 1283- 1287 ].

[0016] Based on the preceding discussion of epigenetic control, multiple independent lines of evidence support the conclusion that MAP2K3 is directly influenced by HDAC8 and HDAC9, thereby achieving epigenetic control over the immune function of keratinocytes. Few reported studies focus on MAP2K3-related skin diseases. 李等人,p38-MAPK / SAPK途径是 人角质形成细胞在真皮胶原蛋白上迁移所必需的,《皮肤病学研究杂志》,117 1601-1611, 2001 Previously published transcriptional data on human skin diseases have shown elevated MAP2K3 expression levels in major inflammatory skin diseases such as atopic dermatitis, psoriasis, and acne vulgaris. This association is consistent with some of the findings that MAP2K3 functional regulation may be a key checkpoint for maintaining homeostasis. Furthermore, additional research has shown that inhibiting the downstream target of MAP2K3, p38MAPK, suppresses the IMQ-induced inflammatory response in psoriatic inflammation. 樱井等人,皮肤p38 丝裂原活化蛋白激酶激活引发银屑病性皮炎,《过敏与临床免疫学杂志》 144, 1036 - 1049, 2019 Skin inflammation induced by Propionibacterium acnes 韦伯 等人,纳武单抗与化疗治疗抗CTLA-4治疗后进展的晚期黑色素瘤患者(CheckMate 037):一项随机 对照、开放标签、3期试验。《柳叶刀肿瘤学》16, 375 - 384, 2015 希尔德斯海姆等人,p38丝裂原活化蛋白激酶 ] and skin inflammation induced by ultraviolet radiation [ ​ 抑制剂可保护表皮免受 紫外线照射的急性损伤作用,《皮肤病学研究杂志》,122卷,497 - 502页,2004年 DC Beshore et al., Redefining the Histone Deacetylase Inhibitor ].

[0017] Although a diverse class of small-molecule HDACi has been identified, as previously mentioned, many known HDACi possess strong zinc-binding warheads, which can lead to unintended off-target effects, particularly against other metalloenzymes. Recently, DC Beshore et al. developed a series of novel cyclic peptide HDAC inhibitors that do not contain a zinc-binding moiety. Pharmacophore: High Potency with No Zinc Cofactor Interaction, ACS Med. Chem. Lett. 2021, 12, 4, 540 - 547 T Bir This could alleviate concerns about such off-target interactions.

[0018] While the impact of HDAC should not be underestimated, it is not the only factor contributing to skin aging and health problems. Chronic stress accelerates the appearance of signs of skin aging, including the development of fine lines and deep wrinkles, uneven skin tone, and sagging, as well as early signs of impaired skin barrier function, including skin discomfort symptoms such as visible redness, sensitivity, dryness, and blemishes. One of the body's defense mechanisms is its natural ability to combat stress through the endocannabinoid system (ECS), which, when activated by stress, helps restore homeostasis and produces a calming effect. 等人, 皮肤在健康与疾病中的内源性大麻素系统:新视角与治疗 机会, 《药理学趋势》. 2009年8月; 30(8): 411 - 420, 2009; SK Baswan等人, 大麻二酚(CBD)对皮肤健康和 疾病的治疗潜力, 《临床、美容与研究皮肤病学》, 13:927 - 942, Z Zhang等人, 支链氨基酸作为 健康与疾病中的关键开关, Z Zhang, 《高血压》, 2018; 72: 2020 ).

[0019] The endocannabinoid system (ECS) plays multiple regulatory roles in both healthy and disease states. Interestingly, recent studies have revealed the existence of a functional ECS in the skin, indicating its involvement in various biological processes, such as the proliferation, growth, differentiation, apoptosis, and production of cytokines, mediators, or hormones in various cells of the skin and its appendages, including hair follicles and sebaceous glands. The primary physiological function of the skin ECS appears to be the sustained control of a well-balanced proliferation, differentiation, and survival of skin cells, as well as immune capacity and / or tolerance. Disruption of this delicate balance can lead to a variety of skin pathologies and diseases, such as acne, seborrheic dermatitis, atopic dermatitis, pruritus and pain, psoriasis, hair growth disorders, systemic sclerosis, and cancer.

[0020] Endocannabinoids are molecules synthesized by the human body on demand. Experts have identified arachidonic acid ethanolamine (AEA, also known as anandamide, the euphoric molecule) and 2-arachidonic acid glycerol ester (2-AG) as key endocannabinoids. After these endocannabinoids have completed their function, enzymes are responsible for their degradation. The degradation of AEA and 2-AG is primarily regulated by two enzymes—fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), respectively. Certain transport proteins have also been found to play crucial roles in the endocannabinoid system. Fatty acid-binding proteins such as FABP-3 and FABP-5 appear to enhance cellular uptake of AEA or 2-AG, promoting the hydrolysis of AEA or 2-AG into arachidonic acid, thereby exacerbating inflammation. It has also been shown that FABP-3 and FABP-5 can bind arachidonic acid and transport it to the cell nucleus, leading to the expression of pro-inflammatory genes.

[0021] Branched-chain amino acids (BCAAs)—leucine, isoleucine, and valine—have structurally similar side chains. BCAAs, along with lysine, belong to the essential amino acid (EAA) group, meaning that mammals, including humans, must obtain them through adequate dietary intake to meet their metabolic needs. The BCAAs leucine, isoleucine, and valine constitute approximately 17% of human skeletal muscle. BCAAs play three distinct roles. First, they provide building blocks for protein synthesis and promote protein synthesis. Second, they serve as an energy source when catabolized via the TCA (as previously described). Finally, they balance cell growth and autophagy by activating mTOR, which stimulates cell signaling, uncoupling insulin signaling and regulating protein translation. Terminalia chebula 1012-1022 ].

[0022] Surprisingly, we discovered a specific group of amino acids (i.e., lysine and the branched-chain amino acids leucine, isoleucine, and valine and their derivatives) with divalent salts (especially Zn). 2+ Salts have HDAC modification / regulation capabilities, especially HDAC suppression properties.

[0023] Subsequently, we discovered salts and compositions containing such salts with the following properties: they can maintain stem cell characteristics, elongate telomeres, and promote collagen regeneration; they can be used as therapeutic or modifiers to prevent and / or reverse signs of skin aging; improve wound healing; improve barrier function and repair and skin hydration; control pigmentation, inflammation and immune aging; and alleviate, reverse and / or prevent various skin diseases and the adverse effects of physiological and environmental factors on the skin. Summary of the Invention

[0024] Based on this teaching, compounds according to structure 1 are provided: , in: • X is Zn, Ca, Mg or Mn, with Zn being preferred; • Each R 1 Independent selection -(CH2)4NHR 3 The group consisting of -CH2CH(CH3)2, -CH(CH3)CH2CH3 and -CH(CH3)2; • Each R 2 Independently select the groups consisting of -H, -COCH3, -COCH2CH3, -COCH2CH2CH3, -COCH(CH3)2; -COCH2CH2COOCH3; -COCH(COOCH3)2 and -COCH(CH3)COOCH3; • Each R 3 The groups are independently selected from -H, -COCH3, -COCH2CH3, -COCH2CH2CH3, -COCH(CH3)2; -COCH2CH2COOCH3; -COCH(COOCH3)2 and -COCH(CH3)COOCH3.

[0025] Preferably, each R 1 Same, each R 2 Same, and each R 3 Same. Furthermore, R is preferred in each compound. 1 and R 2 The same applies; however, mixtures of the compounds are also permitted, as described below, wherein the R of one compound in the mixture is... 1 and R 2 With another compound R 1 and R 2 different.

[0026] According to a second aspect of this teaching, compositions are provided that consist substantially of one or more compounds of Formula I, wherein the compounds are present in the form of their salts (especially divalent salts), metabolites, analogs, polymorphs, tautomers, clathrates, stereoisomers, hydrates, solvates, or prodrugs, or in mixtures of any two or more of the foregoing forms.

[0027] According to a third aspect of this teaching, compositions comprising one or more compounds according to Formula I or one or more alternative forms thereof described in the preceding paragraph are provided, particularly compositions suitable for human administration, for treating signs of skin aging, improving wound healing, improving barrier function and repair and skin hydration, controlling pigmentation, inflammation and immunosenescence, and alleviating skin diseases.

[0028] According to the fourth aspect of this teaching, methods are provided for treating signs of skin aging, improving wound healing, improving barrier function and repairing and hydrating the skin, controlling pigmentation, inflammation and immune aging, and alleviating skin diseases.

[0029] Such compositions typically contain additional ingredients and / or carriers, particularly dermatologically and pharmaceutically acceptable carriers, which can be used alone or in combination with other suitable ingredients. Detailed Implementation

[0030] For convenience, several terms used in the specification and embodiments are summarized herein before further description of this disclosure. These definitions should be interpreted in conjunction with the remainder of this disclosure and in a manner as understood by those skilled in the art. Although these terms are well known to those skilled in the art, for convenience and completeness, specific terms and their meanings are summarized below.

[0031] The articles “a” and “the” are used to refer to one or more (i.e., at least one) grammatical object of the article.

[0032] The term "amide-forming functional group" refers to carbonyl groups that can form amides or amide functional groups when combined with nitrogen atoms.

[0033] The term "comprising" is used in an inclusive and open definition, meaning that it may include additional elements. In this specification, unless the context requires otherwise, the term "comprising" and its variations should be understood to mean including the referred element or step or group of elements or steps, but not excluding any other element or step or group of elements or steps.

[0034] The term "including" is used to mean "including but not limited to". "Including" and "including but not limited to" are used interchangeably.

[0035] Although the compounds and compositions disclosed herein are described as conforming to Structure I and presented in salt form, it should be understood that the scope of this teaching covers other forms of those structures / compounds. In the following, the compounds described herein contain one or more chiral centers and / or may therefore exist in stereoisomeric forms, such as enantiomers or diastereomers. Therefore, the chemical structures shown herein cover all possible enantiomers and stereoisomers of the elucidated or identified compounds, including pure stereoisomeric forms (e.g., geometrically pure, enantiomerically pure, or diastereomerically pure forms) and mixtures of enantiomers and stereoisomers. Mixtures of enantiomers and stereoisomers can be resolved to their component enantiomers or stereoisomers using separation techniques or chiral synthesis techniques well known to those skilled in the art. The compounds may also exist in various tautomeric forms, including enol forms, ketone forms, and mixtures thereof. Therefore, the chemical structures shown herein cover all possible tautomeric forms of the elucidated or identified compounds. It should also be understood that those skilled in the art can separate certain isomer forms, such as diastereomers, enantiomers, and geometric isomers, by physical and / or chemical methods. Pharmaceutically acceptable solvates may be hydrates or contain other crystalline solvents such as alcohols, ethers, etc. As used herein, the term "solvate" refers to a crystal lattice containing a solvent. The term "hydrate" refers to a more specific form of solvate in which the solvent is water.

[0036] The term "polymorph" refers to the crystalline form of the same molecule. Due to the specific arrangement or conformation of molecules in the crystal lattice, different polymorphs may have different physical properties, such as melting point, heat of fusion, solubility, dissolution rate and / or vibrational spectrum.

[0037] The term "prodrug" refers to a precursor of the compound of structure I, which undergoes chemical transformation through metabolism after administration, subsequently becoming an active pharmacological substance. Typically, such prodrugs are functional derivatives of the compounds of this invention, readily convertable in vivo into the compounds of this invention (as described below), forming, for example, lysine derivatives (Scheme 1) and corresponding free acids (e.g., acetic acid, propionic acid, butyric acid, and / or succinate monomethyl ether) and their corresponding Zn. 2+ Salt.

[0038]

[0039] Option 1: In vivo or in vitro conversion of the product of the composition of the present invention The terms "histone deacetylase" and "HDAC" are intended to refer to any member of a family of enzymes capable of removing an acetyl group from the ε-amino group of an N-terminal lysine residue of a histone or tubulin. Unless the context otherwise requires, the term "histone" means any histone from any species, including H1, H2A, H2B, H3, H4, and H5. Human HDAC proteins or gene products include, but are not limited to, HDAC-1, HDAC-2, HDAC-3, HDAC-4, HDAC-5, HDAC-6, HDAC-7, HDAC-8, HDAC-9, HDAC-10, and HDAC-11.

[0040] The term "histone deacetylase inhibitor" or "inhibitor of histone deacetylase" refers to compounds that interact with histone deacetylases and inhibit their activity, particularly their enzymatic activity. Inhibition of histone deacetylase activity means reducing the ability of histone deacetylases to remove acetyl groups from histones or tubulin. Preferably, such inhibition is specific, meaning that the histone deacetylase inhibitor reduces the ability of histone deacetylases to remove acetyl groups from histones or tubulin at concentrations below those required to produce other irrelevant biological effects.

[0041] The term "dermatologically acceptable carrier" refers to a substance that serves as a diluent, dispersant, solvent, or carrier for the active agent, which is considered acceptable or suitable for skin contact in the industry, preferably for long-term use, and most preferably free from excessive toxicity, incompatibility, irritation, allergic reactions, etc. Typically, and to the appropriate or applicable extent, dermatologically acceptable carriers include carriers approved or available by a government or regulatory body, or carriers listed in the United States Pharmacopeia or other recognized pharmacopoeias as suitable for human use. For topical compositions, each composition will include any known topical excipients and agents necessary to achieve the specific form of the final composition, and the choice of carrier depends in part on the form of the topical composition, such as lotion, cream, gel, foam, emulsion, dispersion, spray, liposome, coacervate, etc. The term "carrier" as used herein also refers to the base composition used to formulate cosmetic, skin care, dermatological treatment, and topical pharmaceutical products, as well as such products themselves. Typically, the carrier will account for about 30% to more than 99% by weight of the composition, preferably 40% to 99% by weight.

[0042] Suitable dermatologically acceptable carriers are well known, including, for example, mineral oil, silicone oil, emulsifiers, water, alcohol, combinations of water and alcohol, solvents, solvent systems and combinations thereof. Other suitable carriers and carrier compositions are described in detail in the following literature: for example, Gonzalez et al. - US 7,186,404; Aust et al. - US 7,175,834; Roseaver et al. - US 7,172,754; Simoulidis et al. - US 7,175,835; Mongiat et al. - US 7,101,536; Maniscalco - US 7,078,022; Forestier et al. US 5,175,340, US 5,567,418, US 5,538,716 and US 5,951,968; Deflandre et al. - US 5,670,140; Chaudhuri - US 7,150,876, US 6,831,191, US 6,602,515, US 7,166,273, US US 6,936,735, US 6,831,191 and US 6,699,463; Chaudhuri et al. - US 6,165,450 and US 7,150,876; Bonda et al. US 6,962,692; Rodan et al. - US 9,144,434; Wang et al. US 5,830,441 and Auspitz et al. - US 2007 / 0110685 A.

[0043] The term “pharmaceutically acceptable” means that the object referred to in this descriptor has been approved or is eligible for approval by a government or government regulatory authority, or is listed in the United States Pharmacopeia or other recognized pharmacopoeia for human use.

[0044] "Pharmaceutically acceptable carrier" means a pharmaceutically acceptable diluent, pharmaceutically acceptable adjuvant, pharmaceutically acceptable excipient, pharmaceutically acceptable solvent or carrier, or a combination of any of the foregoing, which can be used to administer a pharmacologically active agent, including the compounds provided in this disclosure, to a patient without destroying or significantly adversely affecting the pharmacological activity of the contained pharmacologically active agent or its metabolites, and preferably is non-toxic or has acceptable toxicity when the administered dose is sufficient to provide a therapeutically effective amount of the pharmacologically active agent or its metabolites. Those skilled in the art will understand that many (if not most) of the foregoing dermatologically acceptable carriers are also suitable as pharmaceutically acceptable carriers. Typically, the carrier will constitute from about 30% by weight to more than 99% by weight of the composition, preferably from 40% by weight to 99% by weight.

[0045] "Pharmaceutical composition" means a composition comprising a pharmaceutically acceptable carrier and a pharmacologically active agent or metabolite, and in particular the pharmaceutical composition described and claimed in this application.

[0046] "Treatment" or "management" for any disease or ailment means reversing, alleviating, preventing, suppressing, interfering with, and / or improving the onset and / or amplification of a disease or at least one clinical symptom of a disease, inhibiting the progression of a disease or at least one clinical symptom of a disease, and delaying the onset of a disease or at least one or more symptoms of a disease in a susceptible patient (especially those confirmed by genetic testing), even if the patient has not yet experienced or exhibited symptoms of the disease. In the following text, treatment also means the physical (e.g., stabilizing perceptible symptoms), physiological (e.g., stabilizing physical parameters), or both, suppression of a disease, and suppression of at least one physical parameter that the patient may or may not perceive.

[0047] "Improvement" is used to indicate that a pharmacologically active agent has induced or produced changes in the properties and / or physical characteristics of the tissue (including, for example, the epidermal-dermal junction, necrosis of skin cancer cells, etc.) that has been provided, applied, administered, or targeted, especially beneficial changes. These terms are also used to indicate that symptoms or physical characteristics associated with a disease state have been alleviated, reduced, or eliminated.

[0048] "Suppression" usually refers to delaying the onset of symptoms, slowing or stopping the progression of a disease and its symptoms, relieving symptoms, or eliminating a disease, condition, or disorder.

[0049] "Optional" or "optionally" indicates that the object, event, or situation described below is not a necessary or inevitable result, and the description covers situations where the event occurs or does not occur, and situations where the object exists or does not exist.

[0050] "Therapeutic effective amount" refers to the amount of a compound or composition sufficient to affect the treatment of a patient's disease or at least one clinical symptom of the disease, including improving affected organs or physiological processes adversely affected by the disease or symptom. Therapeutic effective amounts vary depending on a variety of factors, such as the compound or composition, the disease and / or disease symptoms, the severity of the disease and / or disease symptoms, the age, weight, and / or health status of the patient to be treated, the route of administration, the presence of synergistic agents, and the prescribing physician's judgment. The appropriate amount of any given compound or composition can be determined by a person skilled in the art and / or by routine laboratory testing.

[0051] "Therapeutic effective dose" refers to the dose of a given drug that provides an effective treatment for a patient's disease. Therapeutic effective doses vary depending on the compound / composition and / or on individual patient differences, depending on factors such as patient condition, route of administration, and those described in the foregoing definition of therapeutic effective dose. Therapeutic effective doses can be determined based on conventional pharmacological procedures known to those skilled in the art. Therapeutic effective doses also encompass the use of an initial dose or dosing dose, followed by subsequent doses daily, weekly, or at any other frequency, wherein the amount of active agent in the initial dose is greater than the amount of active agent in subsequent doses.

[0052] Based on the teachings of this application, compounds according to structure I are provided:

[0053] in: • X is Zn, Ca, Mg or Mn, with Zn being preferred; • Each R 1 Independent selection -(CH2)4NHR 3 The group consisting of -CH2CH(CH3)2, -CH(CH3)CH2CH3 and -CH(CH3)2; • Each R 2 Independently selected from the group consisting of -H, -COCH3, -COCH2CH3, -COCH2CH2CH3, -COCH(CH3)2; -COCH2CH2COOCH3; -COCH(COOCH3)2 and -COCH(CH3)COOCH3; preferably -H, -COCH3, -COCH2CH3, -COCH2CH2CH3, -COCH(CH3)2; • Each R 3 The group consisting of -H, -COCH3, -COCH2CH3, -COCH2CH2CH3, -COCH(CH3)2; -COCH2CH2COOCH3; -COCH(COOCH3)2 and -COCH(CH3)COOCH3 is selected independently; -COCH3, -COCH2CH3, -COCH2CH2CH3, and -COCH(CH3)2 are preferred; and -COCH2CH2CH3 and -COCH(CH3)2 are most preferred.

[0054] Preferably, each R 1 Same, each R 2 Same, and each R 3 Same. More preferably, in each compound, R 2 and R 3 The same; more preferably, R in each compound 2 or R 3At least one of them is not -H, that is, both R 2 At least one or two R 3 At least one of them is not -H; most preferably, R 2 and R 3 None of them are -H. This teaching also covers mixtures of these compounds, where one of the compounds in the mixture has an R... 1 R 2 and / or R 3 With another compound R 1 R 2 and / or R 3 different.

[0055] According to this teaching, a preferred group of compounds is those according to structure II:

[0056] Where R 2 and R 3 As described above. Preferably, but not necessarily, R 2 and R 3 At least one of the parts is not -H; more preferably, R 2 and R 3 None of them are -H. Furthermore, R 2 and R 3 They can be the same or different: the latter represents R. 2 and R 3 At least one of the portions is -H, and the other (or some others) is an amide-forming functional group or two different amide-forming functional groups. Exemplary compounds according to structure II include: Compound 1: Zinc bis(diacetyllysine): R 2 = R 3 = -COCH3.

[0057] Compound 2: Zinc di(acetyllysine): R 2 and R 3 One of them (preferred R) 3 One is -COCH3, and the other is -H; Compound 3: Zinc di(dipropionyllysine): R 2 = R 3 = -COCH2CH3.

[0058] Compound 4: Zinc di(propionyl lysine): R 2 and R 3 One of them (preferred R) 3 One is -COCH2CH, and the other is -H; Compound 5: Zinc di(di-n-butyryl lysine): R 2 = R3 = -COCH2CH2CH3.

[0059] Compound 6: Zinc di(n-butyryl lysine): R 2 and R 3 One of them (preferred R) 3 One is -COCH2CH2CH3, and the other is -H; Compound 7: Zinc bis(diisobutyryl lysine): R 2 = R 3 = COCH(CH3)2.

[0060] Compound 8: Zinc di(isobutyryl lysine): R 2 and R 3 One of them (preferred R) 3 One is -COCH(CH3)2, and the other is -H; Compound 9: Zinc di(dimethylsuccinyl lysine): R 2 = R 3 = COCH2CH2COOCH3.

[0061] Compound 10: Zinc di(dimethylsuccinyl lysine): R 2 With R 3 One of them (preferred R) 3 One is -COCH2CH2COOCH3, and the other is -H; Compound 11: Zinc dilysine: R 2 =R 3 =H.

[0062] The preferred and particularly advantageous group of compounds according to structures I and II is the following compound: wherein R 2 and R 3 (When R exists) 3 At least one of the (when) portions is a butyrate moieties, i.e., n-butyryl or isobutyryl, with n-butyryl being the most preferred: when R is present 3 When, the optimal choice R 2 and R 3 All are butyric acid moieties, with the n-butyryl group being the most preferred. As described in the background section above, butyrates can be effective active ingredients in topical health and beauty products and medications for certain skin conditions, but their use is limited (or even hindered) by their odor. Surprisingly, the butyrated compounds of structure I do not exhibit odor problems. Specifically, these compounds are odorless and potent HDAC inhibitors. Even with the slow release of butyric acid from the breakdown / metabolism / dissociation of these compounds, no unpleasant odor is produced. Furthermore, these compounds are more effective HDAC inhibitors than sodium butyrate.

[0063] While the compounds of this teaching are preferably divalent salts of structures I and II, these compounds and compositions substantially composed of these compounds can be generated in various forms and mixtures thereof, depending on their preparation methods, reactant molar ratios, etc., including: monovalent salts; divalent salts; as metabolites, analogs, polymorphs, tautomers, inclusion compounds, stereoisomers, hydrates, solvates, and prodrugs, or combinations of any two or more of the above forms. Additionally, and / or alternatively, for a given application and / or performance, it may be desirable to convert the compounds or salts or their products into one of these alternative forms. For ease of discussion of compositions comprising these compounds, compositions substantially composed of these compounds, and methods of their application and use, references to these compounds or compounds of this teaching below should be understood to encompass both these compounds and their various forms, as well as compositions substantially composed of them. Furthermore, the scope of this teaching also covers monovalent salts of structures I and II, and those structures in which amino acid functional groups may not be completely neutralized by Zn, Ca, Mg, or Mn ions.

[0064] The compounds described in this teaching, namely those according to structure I above, and most particularly those according to structure II above, can be incorporated into a variety of compositions and products as major components, particularly major active components, or as auxiliary / additional active agents and / or synergistic active agents, to achieve the intended use of said compositions and products. Given the effects of these compounds on HDAC and other physiological processes and the associated benefits, these compounds are particularly desirable as active pharmaceutical ingredients, therapeutic agents, cosmetic and skincare active agents, etc.

[0065] In the following, the present invention also relates to pharmaceutical and non-pharmaceutical topical compositions comprising: at least one compound of the present teachings and a dermatologically acceptable carrier and / or a pharmaceutically acceptable carrier, wherein the compound of the present teachings is preferably wherein R 2 and R 3 (If present) compounds that are neither -H in structures I nor II, with R being the most preferred. 2 and R 3Compounds of structure II, preferably n-butyryl or isobutyryl, and most particularly n-butyryl, are present in an effective amount (therapeutic effective amount for pharmaceutical compositions) to achieve the desired / anticipated effect. Exemplary non-pharmaceutical compositions include, for example, specialized compositions (for addressing skin conditions, improving skin, or achieving other purposes for which they are intended), and formulated cosmetics, health and beauty aids, personal care products, and / or OTC health products. Similarly, these compounds can be used in the manufacture and formulation of topical medicines, particularly as APIs, for the treatment of various skin conditions and / or symptoms. In such cases, these compounds are typically formulated in an effective amount into a pharmaceutically acceptable carrier. The effective amount in both cases is typically from about 0.01% by weight to about 10% by weight, preferably from about 0.1% by weight to about 10% by weight, and more typically from about 0.1% by weight to about 5% by weight, based on the total weight of the final composition.

[0066] Depending on their intended use, method of application, etc., topical formulations or products made from these compounds can take many forms. For example, topical formulations containing these substances can be in the following forms: creams, ointments, gels, pastes, powders, sprays, suspensions, dispersions, solutions, salads, lotions, patches, liposomes, microcapsules, nanocapsules, liquids, serums, foams, liquid foundations, balms, antiperspirants, emulsions, dispersions, aggregates, pads, swabs, wipes, patches, sponges, and (where applicable) combinations thereof. Depending on the mechanism of application and delivery or form, the formulation or product may further contain penetration enhancers.

[0067] Furthermore, compositions and products containing compounds of this teaching, particularly consumer products and (where applicable) pharmaceutical products formulated therein, may include one or more additional ingredients such as antioxidants, sunscreens, skinlightening agents, exfoliants, anti-acne agents, vitamins, anti-inflammatory agents, self-tanning agents, moisturizers, emollients, humectants, amphoteric surfactants, alcohols (more specifically, ethanol), compatible solutes, darkening agents, oil-controlling agents, antimicrobial agents, anti-inflammatory agents, antifungal agents, antiparasitic agents, topical analgesics, photoprotectants, keratolytic agents, detergents, surfactants, moisturizers, nutrients, energy enhancers, antiperspirants, astringents, deodorants, hair removal agents, firming agents, anti-callus agents, hair conditioners, nail conditioners, and skin care agents. Other active agents that may be present, especially cosmetic active agents, include: hydroxy acids, alkyl resorcinols, ascorbic acid and its derivatives, hyaluronic acid, retinoids, isosorbide dilinoleate, isosorbide disunflowerseedate, isosorbide dicaprylate, bakuchiol, D-panthenol, octyl methoxycinnamate, titanium dioxide, zinc oxide, octyl salicylate, homosalate, avobenzone, polyphenols, carotenoids, free radical scavengers, ceramides, polyunsaturated fatty acids, essential fatty acids, enzymes, enzyme inhibitors, zingerone, acetyl zingerone, minerals, estrogens, steroids (such as hydrocortisone), 2-dimethylaminoethanol, zinc salts, calcium salts, magnesium salts, coenzyme Q10, lipoic acid, amino acids, vitamins, acetyl coenzyme A, niacin, riboflavin, thiamine, ribose, NADH, FADH2, and Terminalia chebula. 余甘子 印度醋栗 Fruit extract, Phyllanthus emblica ( 睡茄 Fruit extract, Ashwagandha ( Withania somniferaExtracts, aloe vera, chamomile, soybean, and combinations thereof. In each case, such other components are present in their typical amounts; however, if a synergistic effect is found between the compounds of this teaching and such other active agents, a smaller amount may be used. Particularly preferred supplementary active ingredients include, but are not limited to: acetyl gingerone, psoralen, isosorbide dicaprylate, Terminalia chebula fruit extract, ethyl linoleate, isosorbide dilinoleate, isosorbide disel oleate, and any combination of two or more thereof. Each of these active agents will be present in its conventional amount, but given the shared characteristics of some of these active agents with the compounds of this teaching, a synergistic effect is believed to exist, thereby allowing a reduction in the amount of conventional active agents or the compounds of this teaching, or both, to achieve the same effect as that achieved with conventional active agents without the compounds of this invention, and vice versa. However, typically, the amount of these active agents present is from about 0.01% by weight to about 20% by weight, preferably from about 0.1% by weight to about 10% by weight, and more typically from about 0.1% by weight to about 5% by weight, based on the total weight of the final composition.

[0068] Alternatively or additionally, these compositions may also include other ingredients that have little or no effect on the intended end use or application of these compositions for therapeutic purposes, but contribute to the preparation and / or longevity / stability and aesthetic aspects of these compositions. Exemplary inactive ingredients include: solubilizers, surfactants, stabilizers, thickeners, preservatives, wetting agents, emulsifiers, suspending agents, dispersants, flavoring agents, fillers or compatibilizers, disintegrants, absorption enhancers, adsorbents, lubricants, buffers, dyes, perfumes, scents, opacifiers, colorants, etc. When present, each of these ingredients is typically present in the usual amounts of those ingredients. It is unnecessary to identify all possible specific active and inactive ingredients and additives that may be incorporated into the compositions of this teaching, as they are well known and widely available, and any attempt to do so in any case would result in excessive detail.

[0069] Another type of usable ingredient is a penetration enhancer, which is not a true skin-active agent or inactive ingredient. Specifically, these are additives that directly affect the permeability of the skin barrier when applied to the skin: increasing the rate and / or amount of penetration of certain other compounds into the skin layers. Exemplary organic penetration enhancers include: dimethyl sulfoxide; isopropyl myristate; decanol, undecyl alcohol, or dodecanol; propylene glycol; polyethylene glycol; C 9-11 C 12-13 Or C 12-15Fatty alcohols; azone; alkylpyrrolidones; transcutol; lecithin, etc. Surfactants, especially amphoteric surfactants, can also be used as penetration enhancers. Similarly, each ingredient is used in its usual amounts.

[0070] Alternatively, as previously described, the compounds of this teaching may be incorporated into existing or newly formulated topical products similar to those described above, particularly cosmetics, hair and skin care products, sunscreens, moisturizers, acne treatment products, deodorants, etc. In each case, the content and amount of the compound according to this teaching in such a product will be the effective amount to achieve the intended objective (i.e., the purpose for which the compound is added).

[0071] This teaching also relates to the use of topical compositions in the treatment of individuals and animals. Specifically, this teaching relates to methods of treating individuals and animals with the compounds of this teaching, wherein the compounds are applied topically in the form of a composition (with or without other active agents) in an effective amount to the skin (whole or part) to revitalize and / or repair the skin and its functions, including but not limited to: reducing the appearance of fine lines and / or wrinkles; reducing dermatological signs of aging due to time, photoaging, hormonal aging, and / or photochemical aging; reducing the visibility of facial fine lines, wrinkles, and age spots, facial wrinkles on the cheeks, forehead wrinkles, interocular wrinkles, supraorbital wrinkles, and perioral wrinkles, and especially deep wrinkles or folds; reducing and / or diminishing the appearance and / or depth of fine lines and / or wrinkles; improving the appearance of infraorbital fine lines and / or periorbital fine lines; reducing the appearance of crow's feet; revitalizing and / or rejuvenating the skin, especially aging skin; reducing skin fragility; reducing and / or treating hyperpigmentation or hypopigmentation, minimizing skin discoloration; and improving skin tone, radiance, and translucency. And / or tautness; reduce and / or improve skin laxity; improve skin firmness, plumpness, suppleness and / or softness; improve skin texture; improve skin barrier repair and / or function; improve skin contour appearance; restore skin radiance and / or brightness; minimize dermatological signs of fatigue and / or stress; resist environmental stressors such as climate, sun exposure, radiation damage, oxygen free radicals, hydrogen peroxide and reactive oxygen species intermediates; reduce skin cracking; replenish skin components lost due to aging and / or menopause; promote cell proliferation and / or multiplication; enhance skin cell metabolism reduced due to aging and / or menopause; improve skin hydration; enhance skin elasticity and / or resilience; enhance exfoliation; improve microcirculation; reduce rosacea-related redness; reduce skin erythema; reduce drug-induced skin atrophy; limit skin deformation; reduce progressive degeneration at the dermal-epidermal junction and / or decreased intercellular adhesion; and any combination of the above effects. Furthermore, the teaching compositions can be used as adjunctive therapy after laser surgery or laser resurfacing to promote the revitalization of aging and damaged skin. Although the discussion herein is specifically directed at skin-related conditions and symptoms, it should be noted that these topical compositions can serve as a convenient method for administering compounds to internal working areas and components of the body, and subsequently to target cells, tissues, or organs: utilizing the skin alone as a channel or corridor for the compounds.

[0072] Similarly, as previously described, these compounds and topical compositions comprising them can be used, but are not limited to, to treat aging skin and skin texture, minimize fine lines and wrinkles, age spots, skin pigmentation and skin tone, dry skin, acne, psoriasis, and atopic dermatitis. The topical compositions of the present invention visibly improve the skin condition of subjects shortly after application to the skin. Such immediate improvement involves coverage or concealing of skin imperfections, such as discontinuous texture (including those associated with skin aging, such as enlarged pores), or providing a more even skin tone or color. With prolonged topical application, the compositions of the present invention also provide visible improvement in skin condition. “Prolonged topical application” refers to continuous topical application of the composition for a relatively long period, preferably at least about one week, one month, three months, six months, or one year. Long-term conditioning of skin condition involves improvement in skin condition after multiple topical applications.

[0073] Finally, as previously stated, the compounds of this teaching and compositions comprising such compounds (alone or in combination with other dermoactive agents), particularly when present in a dermatologically or cosmetically acceptable carrier, can be used to address and counteract human skin aging, dry skin, pigmentation defects, barrier defects, UV damage to the skin, skin unevenness (such as wrinkles, fine lines, rough skin, or enlarged skin pores), and skin aging-related conditions (such as defective keratosis, acne, eczema, inflammation, and skin atrophy).

[0074] Although the foregoing focuses on the dermatology field, the practical applications of these compounds are not limited thereto and can be applied to any number of diseases and physiological conditions where activation / inhibition of various enzymes (including histone deacetylase (HDAC), COX-2, NF-κB, PGE-2, and IL-6, etc.), maintenance / repair of stem cell properties, telomere elongation, and promotion (boosting) and regeneration of collagen are desirable and beneficial.

[0075] In the following, the invention also relates to non-topical pharmaceutical compositions and oral supplements, particularly nutritional supplements, comprising: at least one compound according to structures I and II, wherein R 2 and R 3 (If present) those compounds that are not -H, with R being the most preferred. 2 and R 3One or preferably both of these are n-butyryl or isobutyryl, most particularly n-butyryl, combined with a pharmaceutically acceptable carrier; or, if used as a supplement, the compound is used as an active agent in combination with a carrier suitable for human consumption, or more commonly as an additional active ingredient in conventional supplements, particularly nutritional supplements such as tablets, capsules, gummies and powders, as well as beverages (especially hydrating beverages) and energy bars. The compounds of this teaching are present in an effective amount to achieve the desired / expected results of using the compound, such as anti-inflammatory effects, metal chelation therapy, gastrointestinal regulation, reduction of oxidative stress in visceral organs and physiological functions and processes, and other typical applications of butyrates and zinc supplements. In all cases, the composition must contain an effective amount of the compound: a therapeutically effective amount in the case of pharmaceutical compositions. Typically, the effective amount in both cases is from about 0.01% to 20% by weight, preferably from about 0.1% to 10% by weight, and more typically from about 0.1% to 5% by weight, based on the total weight of the final composition.

[0076] The form and route of administration of the non-topical therapeutic composition depend on the specific nature of the ailment and / or disease and / or condition to be addressed. In fact, the specific method of application or administration depends in part on the form of the non-topical composition and its primary purpose or objective; for example, if the aim is to address the disease holistically or to provide the compound as a nutritional supplement, the application may be oral. Non-topical formulations containing the compounds of this teaching can be in the following forms: solid, gel, paste, liquid, suspension, dispersion, subcutaneous patch, suppository, liposome form, mouthwash, enema, injection, eye drops, ear drops, infusion, microcapsules, etc. Suitable routes of administration include, for example, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, oral, sublingual, intracerebral, intravaginal, transdermal, rectal, or inhalation. Preferred routes are oral and those involving absorption through the epithelium or mucosa (e.g., oral, rectal, and intestinal mucosa), with oral administration being preferred. Furthermore, depending in part on the form of administration and the primary purpose or objective, the non-pharmaceutical compositions of this disclosure can be administered systemically or locally. Finally, the form of the non-pharmaceutical compositions and their delivery systems can also vary according to the foregoing parameters. For example, the oral pharmaceutical compositions of this teaching can be in an encapsulated form, such as encapsulated in liposomes, or as microparticles, microcapsules, capsules, etc. Another consideration for non-topical application is the concept of dosage. These compositions will be administered at a therapeutically effective dose: said dose is calculated based on factors such as the concentration of the active compound, the weight and age of the individual to be administered, the route of administration, and other factors that may affect the metabolism of the active ingredient; all of which are within the knowledge of those skilled in the art.

[0077] Finally, this teaching also relates to the treatment of individuals suffering from various ailments and diseases, focusing on eliminating or alleviating their symptoms and / or improving normal bodily functions. In this regard, the compounds and compositions of this teaching possess numerous properties in activating / inhibiting the expression of various enzymes and genes associated with a variety of medical conditions, including inflammation, and disorders related to oxidative stress in visceral organs and physiological functions and processes. Furthermore, the compounds and compositions of this teaching may be applicable in metal chelation therapy, cancer treatment, treatment and regulation of gastrointestinal disorders, etc. Therefore, the invention also relates to the use of non-topical compositions for the treatment of individuals and animals, and for the improvement of overall health through supplementation. Specifically, this teaching relates to methods of treating individuals and animals using the compounds of this teaching, and methods of enhancing overall health and well-being by use as nutritional supplements.

[0078] Having characterized and described the invention, we now focus on the following examples relating to the preparation of the compounds of the invention and their efficacy demonstrations, particularly regarding their effects on HDAC, skin hydration, COX-2, and other skin-related processes and gene expression.

[0079] Example Example 1: Preparation of di-n-butyryl lysine L-lysine hydrochloride (1 mol) and butyric anhydride (2.2 mol) or butyryl chloride (2.2 mol) were added to tetrahydrofuran and distilled water, and the mixture was stirred at 30 ± 5 °C for 12 to 16 hours. Sodium carbonate was then added to the reaction mixture, and stirring continued at 30 ± 5 °C for another 12 to 16 hours. Sodium chloride and hydrochloric acid were then added, and the mixture was stirred for 30 minutes. The aqueous layer was then separated. The remaining organic layer was vacuum distilled at <40 °C. The crude product was further purified by column chromatography. The purified product was identified as di-n-butyryl lysine (also known as di-n-butyryl lysine) by spectroscopic analysis.

[0080] Example 2: Preparation of diisobutyryl lysine Diisobutyryl lysine (also known as diisobutyryl lysine) was prepared according to the same procedure as described in Example 1, except that butyric anhydride or butyryl chloride was replaced with isobutyric anhydride (2.2 mol) or isobutyryl chloride (2.2 mol), respectively.

[0081] Example 3: Preparation of n-Butyryl Lysine n-Butyryl lysine (also known as n-butyryl lysine) is prepared according to the same procedure as described in Example 1, except that the amount of n-butyric anhydride or n-butyryl chloride is halved (1.1 mol).

[0082] Example 4: Preparation of isobutyryl lysine Isobutyryl lysine (also known as isobutyryl lysine) was prepared according to the same procedure as described in Example 2, except that the amount of isobutyryl chloride was halved (1.1 mol).

[0083] Example 5: Preparation of n-butyryl leucinate Leucine hydrochloride (1 mol) and butyryl chloride (1.1 mol) were added to a solution of tetrahydrofuran and distilled water, and the mixture was stirred at 30 ± 5 °C for 12 to 16 hours. Sodium carbonate was then added to the reaction mixture, and the mixture was stirred at 30 ± 5 °C for another 12 to 16 hours. Sodium chloride and hydrochloric acid were then added, and the mixture was stirred for 30 minutes to allow the aqueous layer to separate. The remaining organic layer was vacuum distilled at <40 °C, and the crude product was further purified by column chromatography. The purified product was vacuum dried at <40 °C and identified by spectroscopic analysis as n-butyrylleucine salt (also known as n-butyryl leucine salt).

[0084] Example 6: Preparation of Zinc Di(n-Butyryl Lysine) The di-n-butyryl lysine (2 mol) obtained in Example 1 was mixed with methanol and zinc hydroxide (1.1 mol) and heated to 65°C. The mixture was maintained at this temperature for 12 hours. The reaction mixture was then filtered to remove undissolved salts. The filtrate was vacuum distilled at <40°C to remove the solvent. The crude product was washed with acetone and n-heptane. The purified product was vacuum dried at <40°C and identified by spectroscopic analysis as zinc di(n-butyryl lysine) (also known as zinc di(n-butyryl lysine)).

[0085] Example 7: Preparation of bis(diisobutyryl lysine)zinc Zinc di(diisobutyryl lysine) was prepared according to the same procedure as described in Example 6, except that di-n-butyryl lysine was replaced with diisobutyryl lysine from Example 2.

[0086] Example 8: Preparation of bis(n-butyryl lysine) zinc and bis(isobutyryl lysine) zinc Zinc di(n-butyryl lysine) and zinc di(isobutyryl lysine) were prepared according to the method described in Example 6, except that di-n-butyryl lysine and di-n-butyryl lysine were replaced with n-butyryl lysine and isobutyryl lysine from Examples 3 and 4, respectively.

[0087] Example 9: Preparation of bis(di-n-butyryl lysine)calcium The di-n-butyryl lysine (2 mol) obtained in Example 1 was mixed with methanol and calcium hydroxide (1.1 mol) and heated to 65°C. The mixture was maintained at this temperature for 12 hours. The reaction mixture was then filtered to remove any undissolved salts. The filtrate was vacuum distilled at <40°C to remove the solvent. The crude product was washed with acetone and n-heptane. The purified product was vacuum dried at <40°C and identified by spectroscopic analysis as calcium di(di-n-butyryl lysine).

[0088] Example 10: Preparation of bis(diisobutyryl lysine)calcium Di(diisobutyryl lysine) calcium was prepared according to the same procedure as described in Example 9, except that di-n-butyryl lysine was replaced with diisobutyryl lysine from Example 2.

[0089] Example 11: Method for preparing zinc dilysine Zinc dilysine was prepared according to the method in Example 6, except that di-n-butyryl lysine was replaced with lysine hydrochloride.

[0090] Example 12: Method for preparing bis(n-butyrylleucine)zinc Zinc di(n-butyrylleucine) was prepared according to the method of Example 6, except that di-n-butyryl lysine was replaced with n-butyrylleucine.

[0091] Example 13: Method for preparing bis(n-butyryl isoleucine)zinc Zinc di(n-butyryl isoleucine) was prepared according to the method of Example 6, except that di-n-butyryl lysine was replaced with n-butyryl isoleucine.

[0092] Example 14: Method for preparing bis(butyrylvaline)zinc Zinc di(n-butyrylvaline) was prepared according to the method of Example 6, except that di-n-butyryl lysine was replaced with n-butyrylvaline.

[0093] Example 15: Method for preparing magnesium salts The method for preparing magnesium salts includes the following steps: (1) adding 75-200 g of modified amino acids and 100-400 g of deionized water into a four-necked reaction flask and stirring to dissolve the amino acids; (2) adding 20-53 g of magnesium oxide into the flask, heating the mixture to about 70-80°C, and stirring the reaction mixture for 2-3 hours; (3) turning on the vacuum and stirring and concentrating at 70-80°C for 2-3 hours; (4) cooling the concentrated mixture to 45-50°C, adding 90-250 g of alcohol, stirring the mixture and cooling it to room temperature; and (5) filtering with a Buchner funnel and drying under vacuum at 40°C for 2 hours to obtain magnesium salts.

[0094] Example 16: Method for preparing manganese salts The method for preparing manganese salts includes the same steps as in Example 15, except that magnesium oxide is replaced with manganese oxide.

[0095] Example 17: HDAC Inhibition Activity General procedures Test materials were stored at room temperature, and stock solutions were prepared in DMSO at a concentration of 20 mg / ml. Further dilution was performed in sterile distilled water, and the solutions were immediately added to the reaction mixture containing the substrate. The reaction was initiated by adding purified HDAC enzyme. Double-distilled water was used as a negative control, and trogostatin (1.5 μg / ml) was used as a positive control for validation in each study. Assay procedures were performed according to the kit instructions. Reaction products were determined by fluorescence assay at excitation / emission wavelengths (ex / em) of 350 / 450 nm using a Cytofluor 4000 multi-well fluorometer (Applied Biosystem, Foster City, CA) or a SpectraMax i3x multimode detection platform from Molecular Devices (Sunnyvale, CA).

[0096] Statistical significance was assessed using the two-tailed Student's test. A deviation of ≥20% compared to the water control group and a p-value less than 0.05 were considered statistically significant.

[0097] HDAC enzyme used to demonstrate the effect / effectiveness of the teaching compound on HDAC expression.

[0098] • HDAC 1 Fluorescence Assay Kit # 50061, BPS Biosciences, San Diego, CA • HDAC 2 Fluorescence Assay Kit # 50062, BPS Biosciences, San Diego, CA • HDAC 3 Fluorescence Assay Kit # 50073, BPS Biosciences, San Diego, CA • HDAC 4 Fluorescence Assay Kit # 50064, BPS Biosciences, San Diego, CA •HD AC 5 Fluorescence Assay Kit #50065, BPS Biosciences, San Diego, CA • HDAC 6 Fluorescence Assay Kit # 50076, BPS Biosciences, San Diego, CA • HDAC 7 Fluorescence Assay Kit # 50067, BPS Biosciences, San Diego, CA • HDAC 8 Fluorescence Assay Kit # 50068, BPS Biosciences, San Diego, CA • HDAC 9 Fluorescence Assay Kit # 50069, BPS Biosciences, San Diego, CA • HDAC 10 Fluorescence Assay Kit # 50060, BPS Biosciences, San Diego, CA • HDAC 11 Fluorescence Assay Kit # 50687, BPS Biosciences, San Diego, CA Tables 1A to 1C show the results of the inhibitory / excitatory activity of the teaching compounds against specific HDACs compared to various controls. In each table, the numerical values ​​represent the residual activity level: therefore, a 23% activity level indicates the presence of 77% inhibition.

[0099] Table 1A: HDAC enzyme activity, expressed as a percentage (%) of the water-treated control.

[0100]

[0101] Table 1B: HDAC enzyme activity, expressed as a percentage (%) of the water-treated control.

[0102]

[0103] Table 1C: HDAC enzyme activity, expressed as a percentage (%) of the water-treated control.

[0104]

[0105] Example 18: Reprogramming of aging mesenchymal stem cells (MSCs) MSCs are pluripotent stem cells that directly or indirectly influence many physiological processes, including epidermal cell proliferation and differentiation, and epidermal regeneration; however, as they age, they exhibit lower stem cell characteristics and regenerative potential. Studies have shown that MSCs can promote wound healing, restore skin barrier function, and address skin aging, especially aging caused by sun exposure and natural aging, including reducing the appearance and / or severity of wrinkles. To determine the effects of zinc di(di-n-butyryl)-lysine (ZDBL) on MSCs (if any), an investigation was conducted. Specifically, normal human adipose-derived mesenchymal stem cells (MSCs) (ATCC, Manassas, VA - PCS-500-011) were seeded in basal mesenchymal stem cell medium (ATCC, Manassas, VA - PCS500-030) supplemented with MSC growth kit starvation medium (ATCC, Manassas, VA - PCS500-040-811S) and cultured in a VWR tissue culture incubator at 37°C in a humidified 5% CO2 atmosphere. Approximately 24 hours after some cells were placed in starvation medium to induce stress, they were exposed to ZDBL (10 μg / ml) and incubated for 72 hours; the remaining cells were not exposed to ZDBL. RNA was then extracted for gene expression quantification analysis by qPCR. Table 2 shows the PCR analysis results (fold change of ZDBL relative to control), which showed that two of the three Yamanaka factors, as well as other genes associated with reversing or mitigating the effects of skin bioaging, were upregulated.

[0106] Table 2: Gene Expression Profile

[0107] Example 19: Telomerase activation Telomeres are protective caps at the ends of chromosomes that shorten with each cell division. The gradual shortening of telomeres can lead to somatic cell aging, apoptosis, or carcinogenic transformation, thus affecting an individual's health and lifespan: shorter telomeres have been shown to be associated with increased disease incidence and poor survival. Telomerase is an enzyme that adds nucleotide sequences back into telomeres. Studies were conducted to determine the effect, if any, of the compounds described herein on telomerase activity.

[0108] Normal neonatal human skin fibroblasts (HDF, cat. # 2310; ScienCell, Oceanside, CA) were grown to confluence in 6-well plates and incubated for three days with the test materials shown in Table 3. After incubation, cells were lysed, and telomerase activity was measured using the ScienCell Telomerase Activity Quantification qPCR Assay Kit (cat. # 8928). Real-time quantitative PCR was performed using Forget-Me-Not™ EvaGreen® qPCR Master Mix (low ROX) (Biotium, Fremont, CA) on a C1000 Touch system equipped with a CFX384™ optical module detector. Activity levels were quantified using the comparative Cq method, calculated as follows: ΔCq (TPS) = Cq (TPS,H2O) Cq (TPS,样品) TPS is a set of telomere primers that recognizes and amplifies newly synthesized telomere sequences, Cq. (TPS) The value represents the quantification cycle value obtained from qPCR software. The relative difference in telomerase activity between experimental conditions and the control is expressed as 2. -ΔCq Telomerase activity was considered to be different when the expression level was sufficiently high (Cq≤33 cycles for detection), the difference compared to the control was >2-fold, and the p-value assessed by the two-tailed Stokes test was <0.05. The results are summarized in Table 3.

[0109] Example 20: Collagen Promotion Collagen constitutes 70-80% of the dry weight of skin, with type I collagen being the main collagen, accounting for 80%-90% of skin collagen and primarily responsible for the mechanical and structural integrity of the skin. Type IV collagen, another key skin collagen, is the main collagen in the extracellular basement membrane (especially the stratum compacta), separating various epithelial and endothelial cells. Six human genes are associated with type IV collagen: COL4A1, COL4A2, COL4A3, COL4A4, COL4A5, and COL4A6. AM Abreu - Velez和MS Howard, Ⅳ型胶原蛋白在 正常皮肤和病理过程中的作用, 《北美医学科学杂志》, 4(1): 1 - 8, 2012 In recent years, the basement membrane has been recognized as an important regulator of cell behavior, rather than just a structural feature of tissues.

[0110] Table 3: Quantification of telomerase activity, relative telomerase activity compared to water, and fold change (FC) compared to water.

[0111] From early adulthood, fibroblast activity gradually declines, and collagen production decreases by approximately 1.0%–1.5% per year. This reduction in collagen is one of the characteristic hallmarks of aging, accompanying the appearance of fine lines and deep wrinkles. Studies were conducted to determine the effect, if any, of the teaching compounds on collagen activation.

[0112] In this study, human neonatal fibroblasts were seeded in each well of a 48-well plate with 0.25 mL of fibroblast growth medium (FGM) and incubated overnight at 37 ± 2 °C in a 5 ± 1% CO2 atmosphere. The following day, the medium was removed by aspiration to remove non-adherent cells, and 0.5 mL of fresh FGM was added. Cells were allowed to grow to confluence, with the medium changed every 48 to 72 hours. After confluence, cells were treated for 24 hours in Dulbecco modified Eagle medium (DMED) supplemented with 1.5% fetal bovine serum (FBS) to wash out any effects from growth factors included in the normal medium. After this 24-hour washout period, cells were treated with test material dissolved in FGM containing 1.5% FBS at a specified concentration. Sodium ascorbate (10 μg / mL) was used as a positive control. Untreated cells (negative control) received only DMEM containing 1% FBS. Cells were incubated for 48 hours. At the end of the incubation period, the cell culture medium was collected and stored frozen (at -75°C) or immediately analyzed. Triple replicates were performed on the materials.

[0113] Type I collagen assay A series of type I collagen peptide standards ranging from 0 ng / ml to 640 ng / ml were prepared. ELISA microplates were prepared by removing any unwanted bands from the plate frame and then adding 100 μl of peroxidase-labeled anti-procollagen type IC peptide antibody to each well used in the assay. Subsequently, 20 μl of each collected tissue culture medium sample or standard was added to the appropriate well, the microplate was capped, and incubated at 37°C for 3 ± 0.25 h. After incubation, the wells were aspirated and washed three times with 400 μl of wash buffer. After removing the final wash buffer, 100 μl of peroxidase substrate solution (hydrogen peroxide + tetramethylbenzidine as the chromogenic agent) was added to each well, and the plate was incubated at room temperature for 15 ± 4 min. After this incubation, 100 μl of stop solution (1N sulfuric acid) was added to each well, and the plate was read using a microplate reader at 450 nm. The results are shown in Table 4.

[0114] Type IV collagen assay A series of type IV collagen peptide standards ranging from 0 ng / ml to 640 ng / ml were prepared. 100 μl of each standard or each collected tissue culture medium was added to the wells of a type IV collagen ELISA plate. The plate was then incubated at 37°C for 1 hour. After incubation, the ELISA plate was washed twice with wash buffer, followed by the addition of 100 μl of detection antibody solution. The ELISA plate was then incubated at 37°C for 1 hour. After incubation, the ELISA plate was washed with wash buffer, followed by the addition of 100 μl of HEP conjugate solution, and incubated at 37°C for 30 minutes. After the last incubation, the ELISA plate was washed again, and 100 μl of substrate solution was added to each well. The plate was incubated at room temperature for 10–30 minutes to allow for colorimetric reaction. At the end of the colorimetric reaction, 100 μl of stop solution (1N sulfuric acid) was added to each well, and the plate was read at 460 nm using a microplate reader. The results are shown in Table 5.

[0115] Calculation / Statistical Analysis To quantify the amount of each substance present, a standard curve was generated using the known concentration of each substance. Regression analysis was performed to establish a line that best fits these data points. The amount of each substance present in each sample was determined using the absorbance values ​​of the test material and the untreated sample. ANOVA was used to compare the treatments, with n+3 treatment groups per group. Statistical significance was set at p≤0.05.

[0116] Table 4: Type I Collagen Measurement

[0117] As shown in Table 4, zinc bis(di-n-butyryl)excretion at concentrations of 20 μg / ml and 30 μg / ml exhibited statistically significant (p<0.05) type I collagen-promoting effects: at 30 μg / ml, it promoted collagen production by approximately 50% compared to the control. Similarly, as shown in Table 5, zinc bis(n-butyryl)excretion exhibited dose-dependent and statistically significant (p<0.05) type IV collagen-promoting effects: at 30 μg / ml and 20 μg / ml, it promoted collagen production by approximately 320% and approximately 250% compared to the control, respectively. Surprisingly, sodium butyrate, even at concentrations up to 100 μg / ml, did not show any type I or type IV collagen-promoting activity.

[0118] Table 5: Type IV Collagen Assay

[0119] Example 21: Activation of aminoacylproline dipeptidase (Prolidase) Amino-proline dipeptidase (PEPD) is a cytosolicimidodipeptidase that cleaves dipeptides and tripeptides containing carboxyl-terminal proline or hydroxyproline, and is essential for protein metabolism, collagen turnover and regeneration, and matrix remodeling. Its activity is regulated by multiple mechanisms, including activation of the β1 integrin receptor, insulin-like growth factor 1 (IGF-1) receptor, and transforming growth factor (TGF)-β1 receptor. In addition to its catalytic activity, amino-proline dipeptidase also regulates numerous biological processes. At the cellular level, PEPD acts as a regulator of epidermal growth factor receptor (EGFR) and epidermal growth factor receptor 2 (HER2)-dependent signaling pathways, p53 activity, and interferon α / β receptor expression. It is also crucial for wound healing: amino-proline dipeptidase deficiency has been found to be associated with poor wound healing. Given the desirableness of aminoacylproline dipeptidase activation, studies were conducted to assess the effect (if any) of the teaching compounds on aminoacylproline dipeptidase activity.

[0120] A series of standards were prepared. 50 μl of the standards and equal aliquots of the test samples shown in Table 6 were added to the wells of an aminoacylproline dipeptidase ELISA plate, followed by 100 μl of HDR-conjugated anti-aminoacylproline dipeptidase antibody. The plate was incubated at 37°C for 1 hour. After incubation, the ELISA plate was washed, and 100 μl of substrate solution was added to each well. The plate was incubated at room temperature for 10–15 minutes to allow for colorimetric reaction. At the end of the colorimetric reaction, 50 μl of stop solution (1N sulfuric acid) was added to each well, and the plate was read at 460 nm using a microplate reader. The results are shown in Table 6.

[0121] Quantitative / Statistical Analysis To quantify the amount of each substance present, a standard curve was generated using the known concentration of each substance. Regression analysis was performed to establish a line that best fits these data points. The amount of each substance present in each sample was determined using the absorbance values ​​of the test material and the untreated sample. ANOVA was used to compare the treatments, with n+3 treatment groups per group. Statistical significance was set at p≤0.05.

[0122] Table 6: Results of Aminoacylproline dipeptidase assay

[0123] As shown in Table 6, bis(di-n-butyryl)zinc exhibited a statistically significant (p<0.05) dose-dependent promotion of aminoacylproline dipeptidase: a 50% increase compared to the control at a concentration of 60 μg / ml. Unexpectedly, conversely, sodium butyrate exhibited a statistically significant (p<0.05) dose-dependent inhibition of aminoacylproline dipeptidase: a 50% decrease compared to the control at a concentration of 60 μg / ml.

[0124] Example 22: Modulation of the endocannabinoid system Multiple enzyme activity assessments were conducted, focusing on enzymes related to the endocannabinoid system (ECS), and the inhibitory / activating effects of the teachable compounds on enzyme activity and their consequent effects on the ECS itself (if any). Specifically, the expression of FAAH, FABP-3, FABP-5, and MAGL enzyme inhibitory activities was evaluated using test materials (including the teachable compounds). Each study was performed in duplicate, and the results were averaged.

[0125] FAAH — Prepare a stock solution by dissolving 0.1 g of each test material sample in 1 mL of DMSO. Each stock solution is serially diluted with DMSO from 1 to 5 times for IC50 determination. 50 Values. FAAH activity was detected using a fluorescence-based assay with AMC arachidonicamide as the substrate. The FAAH enzyme hydrolyzes the substrate, leading to the release of highly fluorescent 7-amino-4-methylcoumarin (AMC), which was monitored at an excitation wavelength of 355 nm and an emission wavelength of 460 nm. Results are shown in Table 7.

[0126] FABP-3 and FABP-5 — Dissolve 0.1 g of each test material sample in 1 mL of DMSO to prepare a stock solution. Each stock solution is serially diluted 1 to 2 times with buffer for IC50 determination. 50 Value. Add 50 μL of each test sample and 50 μL of 200 ng / mL FABP-5 (Raybiotech #268-10276-1) or FABP-3 (Neovateinbio #PT-40525) to each well for analysis.

[0127] Analysis was performed using either the FABP-5 ELISA kit (Raybiotech #ELH-FABP-5) or the FABP-3 ELISA kit (Raybiotech #ELH-FABP-3), following the supplier's operating procedures. Results are shown in Table 7.

[0128] MAGL — Dissolve 0.1 g of each test material sample in 1 mL of DMSO to prepare a stock solution. Each stock solution is serially diluted 1 to 2 times with buffer for IC50 determination. 50 Values. The final concentrations per well were: 10 μl of sample, 5.6 μM MMAGL (Cayman catalog # 10007812), and 23.6 μM 2-arachidonic acid glyceride (Cayman catalog # 62160). The results are shown in Table 7.

[0129] Surprisingly, this teachable compound was found to have multi-target regulatory effects on the endocannabinoid system, activating barrier function-related genes and proteins and reducing pro-inflammatory transcription factors, enzymes, and cytokines. As the results show, this teachable compound stimulates the healing effects of anandamide and 2-AG by inhibiting the enzymatic activity of transport enzymes (such as FABP-3 and FABP-5) and degradative enzymes FAAH and MAGL, thereby maintaining AEA and 2-AG levels. These results point to the establishment of a strong barrier function, which is the most important factor in maintaining skin health and longevity.

[0130] Table 7: Inhibitory activities of FAAH, FABP-3, FABP-5 and MAGL

[0131]

[0132] Example 23: Skin barrier repair and hydration Multiple gene expression assays were performed on genes related to skin barrier function and hydration.

[0133] Experiments were conducted using EpiDermFT (Mattek full-thickness) skin substitutes. Sequencing data were generated by Azenta LifeSciences (HiSeq 2x150bp) and analyzed based on the raw FastQ files provided by Azenta. Differential expression assays were performed to compare the test materials di(di-n-butyryl)zinc (ZDBL) and di(di-n-butyryl)calcium (CDBL) with controls.

[0134] Although additional work for further validation is ongoing, the results show that ZDBL significantly enhances the activity of late keratinized capsule 3D (LCE3D), late keratinized capsule 3E (LCE3E), small protein reach repeat (SPRR2B) and S100 calcium-binding protein P (S100P), while CDBL greatly enhances the activity of late keratinized capsule (LCE2D) and late keratinized capsule (LCE3A). Both ZDBL and CDBL increased the expression of almost all late differentiation marker genes such as FLG, IVL, LOR, SPINK5, and TGM1, with ZDBL also increasing the expression of several early differentiation marker genes (including DSC1, KRT1, and KRT10). On the other hand, FABP3 expression was suppressed by both ZDBL and CDBL.

[0135] Example 24: Inflammation—NF-κB and COX-2 Acute and chronic inflammation can damage cells, tissues, and organs. While acute inflammatory responses are generally beneficial and desirable, excessive inflammatory responses can lead to adverse consequences. Similarly, in some cases, acute inflammatory responses are unnecessary, or at least should not reach their current extent, such as in sunburn. Therefore, the mitigation of acute inflammation is often a desirable outcome. On the other hand, chronic inflammation is generally undesirable, leading to a variety of diseases involving multiple organs, including the skin and skin function. A delicate balance of NF-κB activity in both epithelial and immune cells is crucial for maintaining immune homeostasis and preventing chronic inflammation in epithelial tissues. Similarly, inhibition of pro-inflammatory biomarkers, including COX-2, PGE-2, and IL-6, is considered key in overall inflammation control. Furthermore, given that COX-2 has been found to be associated with increased tumor incidence and promotion of tumor growth and metastasis, inhibition of COX-2 has several other benefits, particularly related to cancer. In the following sections, several inhibition assays were performed to evaluate the effects of the teaching compounds on NF-κB and COX-2 activity (if any).

[0136] NF-κB inhibition The determination was carried out following the method proposed by Yang et al. 体外总抗氧化能力和 anti-inflammatory activity of three common oat-derived avenanthramides, Food Chemistry, 160:338-345, 2014 Mouse C2C12 myoblasts transfected with NFκB and a luminescent reporter gene were used, with 1% DMSO as a control and TNFα as an activator. NFκB expression was quantified by the luminescent signals released from cells treated with the test product and the control (untreated).

[0137] IC50 of bis(di-n-butyryl lysine)zinc 50The value was 70.4 μg / ml, and its inhibitory efficacy against NFκB was that of sodium butyrate (IC50). 50 It was about 110 times stronger than the value of 7695 μg / ml, demonstrating a strong inhibitory effect.

[0138] COX-2 inhibitory effect Dissolve 0.1 g of each test material sample in 1 mL of propylene glycol to prepare a stock solution. Each stock solution is serially diluted 1 to 2 times with buffer solution for IC50 determination. 50 Testing and analysis were performed according to the protocols for COX-2 Kt (Cayman Catalog # 701080) (Cayman Catalog # 62160). Cannabidiol (CBD) and sodium butyrate were used as controls due to their known anti-inflammatory effects. CBD is recognized as a potent inhibitor of COX-1 and COX-2 enzymes and is widely used in the treatment of chronic inflammation. Sodium butyrate is also known, but its popularity is far less than that of CBD, mainly due to its aforementioned odor problem. The results are shown in Table 8.

[0139] Table 8: COX-2 Inhibition

[0140] As shown in Table 8, the two compounds described in this teaching, namely zinc di(di-n-butyryl) and calcium di(di-n-butyryl), both exhibited unexpected and significant inhibitory effects on COX-2 enzyme.

[0141] preparation The following are exemplary topical product formulations using the preferred compounds of this teaching. In each formulation, the "novel active agent" is selected from: bis(di-n-butyryl lysine) zinc, bis(diisobutyryl lysine) zinc, bis(n-butyryl lysine) zinc, bis(isobutyryl lysine) zinc, bis(di-n-butyryl lysine) calcium, bis(diisobutyryl lysine) calcium, bis(n-butyryl lysine) calcium, bis(isobutyryl lysine) calcium, zinc dilysine, calcium dilysine, bis(di-n-butyryl lysine) manganese, bis(diisobutyryl lysine) manganese, bis(n-butyryl lysine) manganese, bis(di- ... Manganese (isobutyryl lysine), di(di-n-butyryl lysine) magnesium, di(diisobutyryl lysine) magnesium, di(n-butyryl lysine) magnesium, di(isobutyryl lysine) magnesium, di(n-butyryl leucine) zinc and di(isobutyryl leucine) zinc, and mixtures thereof; most preferably di(n-butyryl lysine) zinc, di(diisobutyryl lysine) zinc, di(n-butyryl lysine) calcium and di(diisobutyryl lysine) calcium, and mixtures thereof.

[0142] Formulation 1: Skin lotion

[0143] The preparation of this formulation involves first adding phase A to a main reactor equipped with a homogenizer. Then, phase B is slowly added to phase A. After the former is completely dispersed in the latter, the mixture is heated to 65-70°C. Simultaneously, phase C is mixed in a secondary reactor and heated to 70-75°C. Once both mixtures reach suitable temperatures, phase C is added to the phase A-B mixture, and the mixture is stirred for 15-20 minutes. Simultaneously, phase D is mixed in the secondary reactor and heated to 75°C. Once the new activator has dissolved, phase D is added to the ABC mixture and mixed for 5-10 minutes. Once the mixture is homogeneous, mixing is switched to side-sweep mixing, and the mixture is cooled to room temperature. Note: pH - 4.5-5.0; Viscosity: Rotor - TE, S95; Speed ​​- 0.3 rpm; Range - 200,000-500,000 mPas.

[0144] Formulation 2: Moisturizing Essence

[0145] Formulation 2 was prepared as follows: Phase A components were mixed in a reactor equipped with a homogenizer. While mixing Phase A, Phase B components were added and mixed until homogeneous. Simultaneously, Phase C components were mixed until homogeneous in a secondary reactor and then added to the Phase A / B mixture, which was mixed for 10-15 minutes. Phase D components were mixed in the secondary reactor and heated to 75°C to dissolve the new activator. Once dissolved, heating was stopped, and the mixture was allowed to cool to room temperature before being added to the Phase A / B mixture, which was then mixed for 5-10 minutes. Note: pH value - 5.5-6.0; Viscosity: Rotor - TD, S94; Speed ​​- 2.0 rpm; Range - 8000-11000 mPas.

[0146] Formulation 3: Skin-even toning lotion Formulation 3 was prepared by first adding phase A to the main reactor equipped with a homogenizer. Then, phase B was slowly added to phase A. Once the former was completely dispersed in the latter, the mixture was heated to 65-70°C. Simultaneously, phase C was mixed in a secondary reactor and heated to 70-75°C. Once both mixtures reached the appropriate temperature, phase C was added to the phase A-B mixture, and the mixture was mixed for 15-20 minutes. Simultaneously, the first two phases of phase D were placed in the secondary reactor and heated to 75°C. Once the new activator dissolved, the mixture was cooled to 45°C, hexylresorcinol was added, and the mixture was mixed until homogeneous. The mixing of the ABC phases was then switched to a side-sweep mixing method, and the mixture was cooled to 45°C. Phase D was then added to the ABC phase mixture, and the mixture was mixed for 5-10 minutes, allowing the entire mixture to cool to room temperature. Note: pH - 4.5-5.0; Viscosity: Rotor - TE, S95; Speed ​​- 0.3 rpm; Range - 200,000-500,000 mPas.

[0147]

[0148] Formulation 4: Skin Brightening Lotion

[0149] Formulation 4 was prepared by first adding phase A to the main reactor equipped with a homogenizer. Then, phase B was slowly added to phase A. Once the former was fully dispersed in the latter, the mixture was heated to 65-70°C. Simultaneously, phase C was mixed in a secondary reactor and heated to 70-75°C. Once both mixtures reached the appropriate temperature, phase C was added to the phase A-B mixture, and the mixture was mixed for 15-20 minutes. Simultaneously, phase D was mixed in a secondary reactor and heated to 75°C. Once the new activator dissolved, phase D was added to the ABC mixture and mixed for 5-10 minutes. Once the mixture was homogeneous, mixing was switched to side-sweep mixing, and the mixture was cooled to room temperature. Note: pH - 4.5-5.0; Viscosity: Rotor - TE, S95; Speed ​​- 0.3 rpm; Range - 200,000-500,000 mPas.

[0150] Formulation 5: Anti-aging skin lotion

[0151] Formulation 5 was prepared using the same method as formulation 4.

[0152] Formulation 6: Protective skin lotion Formulation 6 was prepared by first adding phase A to a main reactor equipped with a homogenizer. Phase B was then slowly added to phase A. Once the former was fully dispersed in the latter, the mixture was heated to 65-70°C. Simultaneously, phase C was mixed in a secondary reactor and heated to 70-75°C. Once both mixtures reached the appropriate temperature, phase C was added to the phase AB mixture, and the mixture was mixed for 15-20 minutes. Simultaneously, the new activator of phase D was dissolved, and phase D was added to the ABC mixture and mixed for 5-10 minutes. The mixing of the ABC mixture was then switched to side-sweep mixing, and the mixture was cooled to 45°C. Simultaneously, the aqueous component of phase E was added to a separate reactor and heated to 45°C, and Terminalia chebula extract was added and mixed until dissolved. Phase E was then added to the ABCD mixture and mixed until homogeneous, and the batch was cooled to room temperature. Note: pH value - 4.5-5.0; viscosity: rotor - TE, S95; speed - 0.3 rpm; range - 200000-500000 mPas.

[0153]

[0154] Formulation 7: Anti-aging Cream Formulation 7 is prepared as follows: Phase A is mixed in a reactor equipped with a homogenizer. While mixing Phase A, Phase B is added, and the mixture is stirred until homogeneous. Simultaneously, Phase C is mixed until homogeneous in a secondary reactor, then added to the Phase AB mixture, and the mixture is stirred for 10-15 minutes. Phase D is then mixed in the secondary reactor until homogeneous. Once the new activator has dissolved (slight heating may be necessary to promote dissolution), Phase D is added to the Phase ABC mixture, and the mixture is stirred for 5-10 minutes. Then, Component E is added and mixed until homogeneous. Note: pH - 5.5-6.0; Viscosity: Rotor - TE, S95; Rotation speed - 0.3 rpm; Range - 400,000-700,000 mPas.

[0155]

[0156] Formulation 8: Skin Whitening Lotion

[0157] Formulation 8 is prepared as follows: Phase A components are mixed in a reactor equipped with a homogenizer. While mixing phase A, phase B components are added, and the mixture is stirred. Once phase B is dispersed, the mixture is heated to 65-70°C. Simultaneously, phase C components are mixed in a secondary reactor and heated to 70-75°C until homogeneous. Once phases AB and C have reached the specified temperatures, phase C is added to phase AB and mixed for 15-20 minutes. Phase D components are mixed in the secondary reactor until homogeneous (slight heating may be necessary to promote the dissolution of the new activator). The mixing of phases ABC is switched to a side-sweep mixing method and cooled to 45°C, while phase D is added during mixing. Phase E is prepared in the secondary reactor and mixed until homogeneous. Phase E is then added to phases ABCD and mixed for 5-10 minutes, then cooled to room temperature. Note: pH - 4.5-5.0; Viscosity: Rotor - TE, S95; Speed ​​- 0.3 rpm; Range - 200,000-500,000 mPas.

[0158] Formulation 9: Anti-aging emulsion

[0159] Formulation 9 is prepared as follows: Phase A is placed in a reactor equipped with a homogenizer and mixed. While mixing Phase A, Phase B is added, and the mixture is further mixed. Once Phase B is dispersed, the mixture is heated to 65-70°C. Simultaneously, Phase C is mixed in a secondary reactor and heated to 70-75°C until homogeneous. Once both Phases AB and C have reached the specified temperatures, Phase C is added to Phase AB and mixed for 15-20 minutes. Phase D is mixed in the secondary reactor until homogeneous (slight heating may be necessary to promote the dissolution of the new activator). The mixing of Phases ABC is switched to a side-sweep mixing method and cooled to room temperature. Once at room temperature, Phase D is added and mixed for 5-10 minutes. Note: pH - 4.5-5.0; Viscosity: Rotor - TE, S95; Speed ​​- 0.3 rpm; Range - 200,000-500,000 mPas.

[0160] It is understood that those skilled in the art will be able to fully utilize the present invention based on the foregoing description without further elaboration. Furthermore, although the present invention has been described through the specific embodiments and examples described above, it should be understood that other embodiments, changes, and modifications based on the inventive concept are possible and are within the knowledge of those skilled in the art without departing from the spirit and scope of the invention. Therefore, the foregoing preferred embodiments should be interpreted as merely illustrative and do not limit the remainder of this disclosure in any way.

Claims

1. A topical composition comprising i) at least one compound according to structure I: in: • X is Zn, Ca, Mg, or Mn; • each R is independently selected from the group consisting of -(CH2)4NHR 1 3 , -CH2CH(CH3)2, -CH(CH3)CH2CH3, and -CH(CH3)2;​ • Each R 2 Independently select the group consisting of -COCH3, -COCH2CH3, -COCH2CH2CH3, -COCH(CH3)2; -COCH2CH2COOCH3; -COCH(COOCH3)2 and -COCH(CH3)COOCH3; • Each R 3 Independently select the groups consisting of -H, -COCH3, -COCH2CH3, -COCH2CH2CH3, -COCH(CH3)2; -COCH2CH2COOCH3; -COCH(COOCH3)2 and -COCH(CH3)COOCH3; provided that when at least one of R 1 is -(CH2)4NHR 3 , R 2 may also be -H, provided that at least one of R 2 and R 3 is not -H; and ii) a dermatologically acceptable carrier or a pharmaceutically acceptable carrier suitable for dermatological use, wherein compound (i) is present in an amount of 0.01% to 20% by weight based on the weight of the composition.

2. The composition of claim 1, wherein X is Zn.

3. The composition of claim 1, wherein each R 1 is the same and each R 2 is the same.

4. The composition of claim 1, wherein each R 1 is -(CH2)4NHR 3 .

5. The composition of claim 1, wherein each R 1 is -(CH2)4NHR 3 , and each R 3 is the same and is selected from the group consisting of -COCH3, -COCH2CH3, -COCH2CH2CH3, and -COCH(CH3)2.

6. The composition of claim 5, wherein all R 2 and R 3 are the same.

7. The composition of claim 6, wherein R 2 and R 3 is -COCH2CH2CH3.

8. A composition comprising: i) at least one compound according to structure I: in: • X is Zn, Ca, Mg, or Mn; • each R is independently selected from the group consisting of -H, -OH, -CH3, -CH2CH3, -CH2CH2CH3, -CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)CH2CH3, and -CH(CH3)2; 1 is independently selected from the group consisting of -(CH2)4NHR 3 , -CH2CH(CH3)2, -CH(CH3)CH2CH • Each R 2 Independently select the group consisting of -COCH3, -COCH2CH3, -COCH2CH2CH3, -COCH(CH3)2; -COCH2CH2COOCH3; -COCH(COOCH3)2 and -COCH(CH3)COOCH3; • Each R 3 Independently select the groups consisting of -H, -COCH3, -COCH2CH3, -COCH2CH2CH3, -COCH(CH3)2; -COCH2CH2COOCH3; -COCH(COOCH3)2 and -COCH(CH3)COOCH3; The premise is that when R 1 At least one of them is -(CH2)4NHR 3 At that time, R 2 It can also be -H, but only if R is present. 2 and R 3 (i) at least one of which is not -H; and (ii) a pharmaceutically acceptable carrier or a carrier suitable for oral administration to humans, wherein the compound (i) is present in an amount of 0.01% by weight to 20% by weight based on the weight of the composition.

9. The composition of claim 8, wherein X is Zn.

10. The composition of claim 8, wherein each R 1 is the same and each R 2 is the same.

11. The composition of claim 8, wherein each R 1 is -(CH2)4NHR 3 .

12. The composition of claim 8, wherein each R 1 is -(CH2)4NHR 3 , and each R 3 is the same and is selected from the group consisting of -COCH3, -COCH2CH3, -COCH2CH2CH3, and -COCH(CH3)2.

13. The composition of claim 12, wherein all R 2 and R 3 are the same.

14. The composition of claim 13, wherein R 2 and R 3 is -COCH2CH2CH3.

15. A topical composition comprising: i) at least one compound according to structure I in: • X is Zn, Ca, Mg, or Mn; • each R is independently selected from the group consisting of -H, -OH, -CH3, -CH2CH3, -CH2CH2CH3, -CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)CH2CH3, and -CH(CH3)2; 1 is independently selected from the group consisting of -(CH2)4NHR 3 , -CH2CH(CH3)2, -CH(CH3)CH2CH • Each R 2 Independently select the groups consisting of -H, -COCH3, -COCH2CH3, -COCH2CH2CH3, -COCH(CH3)2; -COCH2CH2COOCH3; -COCH(COOCH3)2 and -COCH(CH3)COOCH3; • Each R 3 Independently select the groups consisting of -H, -COCH3, -COCH2CH3, -COCH2CH2CH3, -COCH(CH3)2; -COCH2CH2COOCH3; -COCH(COOCH3)2 and -COCH(CH3)COOCH3; ii) At least one active ingredient in skin care products; (iii) A dermatologically acceptable carrier wherein compound (i) is present in an amount of 0.01% by weight to 20% by weight based on the weight of the composition.

16. The composition of claim 15, wherein X is Zn.

17. The composition of claim 15, wherein each R 1 is the same and each R 2 is the same.

18. The composition of claim 15, wherein each R 1 is -(CH2)4NHR 3 .

19. The composition of claim 15, wherein each R 1 is -(CH2)4NHR 3 , and each R 3 is the same and is selected from the group consisting of -COCH3, -COCH2CH3, -COCH2CH2CH3, and -COCH(CH3)2.

20. The composition of claim 19, wherein all R 2 and R 3 are the same. It is -COCH2CH2CH3 or -COCH(CH3)2.

21. The composition of claim 20, wherein R 2 and R 3 is -COCH2CH2CH3.

22. The composition of claim 15, wherein the skin care product active ingredient is described.

23. The composition of claim 15, wherein the skin care product active agent is selected from acetyl gingerone, psoralen, isosorbide dicaprylate, Terminalia chebula fruit extract, ethyl linoleate, isosorbide dilinoleate, isosorbide disel oleate, and any combination of two or more thereof.

24. Based on the compound with structure I: in: • X is Zn, Ca, Mg, or Mn; • each R is independently selected from the group consisting of -H, -OH, -CH3, -CH2CH3, -CH2CH2CH3, -CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)CH2CH3, and -CH(CH3)2; 1 is independently selected from the group consisting of -(CH2)4NHR 3 , -CH2CH(CH3)2, -CH(CH3)CH2CH • Each R 2 Independently select the group consisting of -COCH3, -COCH2CH3, -COCH2CH2CH3, -COCH(CH3)2; -COCH2CH2COOCH3; -COCH(COOCH3)2 and -COCH(CH3)COOCH3; • Each R 3 Independently select the groups consisting of -H, -COCH3, -COCH2CH3, -COCH2CH2CH3, -COCH(CH3)2; -COCH2CH2COOCH3; -COCH(COOCH3)2 and -COCH(CH3)COOCH3; The premise is that when R 1 At least one of them is -(CH2)4NHR 3 At that time, R 2 It can also be -H, but only if R is present. 2 and R 3 At least one of them is not -H.

25. The compound of claim 24, wherein X is Zn.

26. The compound of claim 24, wherein each R 1 is the same and each R 2 is the same.

27. The compound of claim 24, wherein each R 1 is -(CH2)4NHR 3 .

28. The compound of claim 24, wherein each R 1 is -(CH2)4NHR 3 , and each R 3 is the same and is selected from the group consisting of -COCH3, -COCH2CH3, -COCH2CH2CH3, and -COCH(CH3)2.

29. The compound of claim 28, wherein all R 2 and R 3 are the same. It is -COCH2CH2CH3 or -COCH(CH3)2.

30. The compound of claim 29, wherein R 2 and R 3 is -COCH2CH2CH3.

31. A method for mitigating or reversing the effects of aging and / or environmental influences on skin and / or its physiological processes, alleviating the effects of skin disorders, and revitalizing, enhancing, and / or improving the appearance, feel, integrity, and / or physiological processes of skin, said method comprising applying a composition topically to the skin, said composition comprising an effective amount of at least one compound according to structure I: in: • X is Zn, Ca, Mg, or Mn; • each R is independently selected from the group consisting of -H, -OH, -CH3, -CH2CH3, -CH2CH2CH3, -CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)CH2CH3, and -CH(CH3)2; 1 is independently selected from the group consisting of -(CH2)4NHR 3 , -CH2CH(CH3)2, -CH(CH3)CH2CH • Each R 2 Independently select the groups consisting of -H, -COCH3, -COCH2CH3, -COCH2CH2CH3, -COCH(CH3)2; -COCH2CH2COOCH3; -COCH(COOCH3)2 and -COCH(CH3)COOCH3; • Each R 3 The groups are independently selected from -H, -COCH3, -COCH2CH3, -COCH2CH2CH3, -COCH(CH3)2; -COCH2CH2COOCH3; -COCH(COOCH3)2 and -COCH(CH3)COOCH3.

32. The composition of claim 31, wherein X is Zn.

33. The composition of claim 31, wherein each R 1 is the same and each R 2 is the same.

34. The composition of claim 33, wherein each R 2 is -H.

35. The composition of claim 31, wherein each R 1 is -(CH2)4NHR 3 .

36. The composition of claim 31, wherein each R 1 is -(CH2)4NHR 3 , and each R 3 is the same and is selected from the group consisting of -COCH3, -COCH2CH3, -COCH2CH2CH3, and -COCH(CH3)2.

37. The composition of claim 36, wherein all R 2 and R 3 are the same. It is -COCH2CH2CH3 or -COCH(CH3)2.

38. The composition of claim 37, wherein R 2 and R 3 is -COCH2CH2CH3.

39. A method for alleviating or reversing chronic inflammation and / or its adverse effects, and / or improving overall health and well-being, said method comprising administering an orally bioavailable composition comprising an effective amount of at least one compound according to structure I: in: • X is Zn, Ca, Mg, or Mn; • each R is independently selected from the group consisting of -H, -OH, -CH3, -CH2CH3, -CH2CH2CH3, -CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)CH2CH3, and -CH(CH3)2; 1 is independently selected from the group consisting of -(CH2)4NHR 3 , -CH2CH(CH3)2, -CH(CH3)CH2CH • Each R 2 Independently select the groups consisting of -H, -COCH3, -COCH2CH3, -COCH2CH2CH3, -COCH(CH3)2; -COCH2CH2COOCH3; -COCH(COOCH3)2 and -COCH(CH3)COOCH3; • Each R 3 Independently select the groups consisting of -H, -COCH3, -COCH2CH3, -COCH2CH2CH3, -COCH(CH3)2; -COCH2CH2COOCH3; -COCH(COOCH3)2 and -COCH(CH3)COOCH3; The premise is that when R 1 At least one of them is -(CH2)4NHR 3 At that time, R 2 It can also be -H, but only if R is present. 2 and R 3 At least one of them is not -H.

40. The compound of claim 39, wherein X is Zn.

41. The compound of claim 39, wherein each R 1 is the same and each R 2 is the same.

42. The compound of claim 39, wherein each R 1 is -(CH2)4NHR 3 .

43. The compound of claim 39, wherein each R 1 is -(CH2)4NHR 3 , and each R 3 is the same and is selected from the group consisting of -COCH3, -COCH2CH3, -COCH2CH2CH3, and -COCH(CH3)2.

44. The compound of claim 43, wherein all R 2 and R 3 are the same. It is -COCH2CH2CH3 or -COCH(CH3)2.

45. The compound of claim 44, wherein R 2 and R 3 is -COCH2CH2CH3.

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