Organosilicon compound derived from ascorbic acid and retinoic acid, and preparation method therefor and use thereof

Abstract

The present invention belongs to the technical field of cosmetics, and relates to an organosilicon compound derived from ascorbic acid or retinoic acid, and a preparation method therefor and the use thereof. The ascorbic-acid-derived organosilicon compound prepared from ascorbic acid in the present invention shows higher cell proliferation-promoting activity on human immortalized keratinocyte cell line HaCaT and better skin anti-aging activity while maintaining anti-oxidant activity, and has good application potential in improving skin condition. Compared with retinoic acid, retinyl retinoate and pinacolone retinoate, the retinoic-acid-derived organosilicon compound prepared from retinoic acid has better proliferation-promoting activity on fibroblasts and human immortalized keratinocyte cell line HaCaT, has good light / thermal stability, potentially better transdermal absorption and causes less skin irritation, and has great development prospects.

Description

Ascorbic acid and retinoic acid derived organosilicon compounds, and preparation methods and applications thereof Technical Field

[0001] The present invention belongs to the technical field of cosmetics and relates to an organosilicon compound derived from ascorbic acid and retinoic acid, and a preparation method and application thereof. Background Art

[0002] Silicones are non-toxic, possess good lipophilicity, and possess membrane permeability, showing promising application prospects in the development of skin medications. Secondly, research has shown that skin aging is accompanied by the loss of silicon, primarily silanols. Consequently, silanols are used in cosmetics to demonstrate anti-aging effects. Finally, high-molecular-weight silicones, as matrix materials, have long been widely used in cosmetics, demonstrating excellent skin affinity.

[0003] Ascorbic acid (L-Ascorbic Acid), also known as vitamin C (VC), is one of nature's most powerful water-soluble antioxidants. It effectively scavenges free radicals and protects skin cells from damage caused by oxidative stress. VC also inhibits tyrosinase, reducing melanin production and is used as a whitening ingredient in cosmetics. However, VC is sensitive to external factors such as light, metals, and oxygen, easily deteriorating, and has poor transdermal absorption, often requiring high concentrations to be effective. These limitations have limited its further application in cosmetics.

[0004] Given the excellent skin affinity and anti-aging activity of silicones, this study selectively introduced a silyl group at the 3-hydroxyl group of VC to design and synthesize a class of single-site modified ascorbic acid silyl ether compounds. These compounds exhibit antioxidant activity similar to VC, potentially superior transdermal absorption and chemical stability, and significantly superior proliferation-promoting activity in fibroblasts and human immortalized keratinocyte cell line HaCaT cells. Furthermore, by combining silylation and acylation modifications at other sites, a series of novel ascorbic acid silyl ether derivatives were prepared. Compared to single-site silylation modifications, these derivatives exhibited enhanced proliferation-promoting activity in human immortalized keratinocyte cell line HaCaT cells, as well as superior anti-aging and skin protective activities.

[0005] Long-term exposure to ultraviolet rays can lead to dryness, loss of elasticity, and increased wrinkling of the skin, a condition known as photoaging, a major contributing factor to skin aging. All-trans retinoic acid (RA), also known as all-trans retinoic acid or simply retinoic acid, can bind to retinoic acid receptors (RAR / RXR), regulate related gene expression, and promote the production and repair of collagen and elastin, making it an effective ingredient for preventing and treating photoaging and anti-aging. However, its structure contains carboxyl groups, which are extremely irritating to the skin, making it a banned ingredient in cosmetics.

[0006] Retinol, lacking a carboxyl group, exhibits minimal skin irritation. It undergoes oxidative metabolism in vivo to produce retinoic acid, which exerts anti-aging effects on the skin, leading to its application in cosmetics. However, its poor photostability often requires use in the dark, and its skin anti-aging activity is weaker than that of retinoic acid. These drawbacks have become bottlenecks hindering its further application. Various retinol esters, such as retinyl palmitate (RP), have been developed, which have enhanced thermal stability, but have failed to effectively address the photostability issue and require secondary metabolism to produce retinoic acid, further weakening its skin anti-aging activity. In recent years, retinoic acid esters, such as retinyl retinoate (RR) and tocopheryl retinoate (TR), have been developed as cosmetic ingredients with low skin irritation and excellent photostability. These ingredients undergo further enzymatic hydrolysis in vivo to produce two active ingredients, which synergistically exert anti-aging effects on the skin. However, the high molecular weight of these ingredients inevitably impairs transdermal absorption. Hydroxypinacolone Retinoate (HPR) is a new retinoic acid ester active ingredient developed in recent years. It has a moderate molecular weight, relatively good transdermal absorption, and photostability. It can directly bind to retinoic acid receptors to exert its anti-aging effects on the skin, resulting in relatively low irritation. Despite this, its anti-aging activity has not been substantially improved, and it has been reported to promote the production of inflammatory factors in skin cells. Consequently, its content in cosmetics is strictly controlled.

[0007] Given the excellent skin affinity and anti-aging properties of silicones, the present invention uses retinoic acid as a starting point to prepare a class of retinoic acid-derived organosilicon compounds, specifically retinoic acid silane esters and silyl esters. Retinoic acid silane esters, compared to retinoic acid, retinol retinoate, and pinacolone retinoate, maintain antioxidant activity while exhibiting superior cell proliferation in fibroblasts and the human immortalized keratinocyte cell line HaCaT, good light and heat stability, low irritation, and potentially superior transdermal absorption. Summary of the Invention

[0008] This invention aims to design and synthesize a series of VC derivatives by introducing a silyl group at the 3-hydroxyl group of VC, combined with variations in substituents at positions 2, 5, and 6. The research also aims to investigate their antioxidant, anti-aging, and other skin-protective activities, with the goal of obtaining ascorbic acid derivatives with even superior antioxidant and anti-aging properties, thereby providing superior raw materials for skin-protective cosmetics. Furthermore, the research involves the preparation of a class of retinoic acid silane esters and silyl ester derivatives, with the goal of improving transdermal absorption and photostability through silicon modification, while simultaneously enhancing skin anti-aging activity and reducing irritation, thereby developing novel functional cosmetic raw materials.

[0009] In order to achieve the above object, the present invention designs and provides the following technical solutions:

[0010] The first aspect of the present invention discloses an ascorbic acid-derived organosilicon compound, specifically a silyl ether derivative, and the general structural formula of the ascorbic acid-derived organosilicon compound is as follows:

[0011] In the general structural formula, R 1 is a silyl group, a hydrogen atom or an alkanoyl group, R 2 and R 3 is a hydrogen atom or an alkanoyl group, R 4 、R 5 and R 6 Independently selected from hydrogen atom or C1-C6 alkyl and branched alkyl; n represents any one of 1, 2, 3, 4, 5, 6.

[0012] The present invention also discloses an ascorbic acid-derived organosilicon compound, specifically a silyl ether derivative, the general structural formula of which is shown below:

[0013] In the general structural formula, R 7 and R 8 is a hydrogen atom or an alkanoyl group.

[0014] The specific compound structure is shown below:

[0015] The specific compound structural formula is shown below:

[0016] The second aspect of the present invention discloses a method for preparing the above-mentioned compound. The preparation methods S1-S2 are as follows:

[0017] 1) Using triphenylphosphine and diethyl azodicarboxylate as promoting reagents, ascorbic acid and trimethylsilyl alcohol undergo a Mitsunobu reaction at room temperature to produce intermediate I (also S7);

[0018] 2) I undergoes cross-protection reaction with acetone in the presence of a catalytic amount of acetyl chloride to generate the key intermediate II. Intermediate II undergoes acylation reaction with acetyl chloride or propionyl chloride under alkaline conditions to generate intermediates III and IV. Subsequently, III and IV undergo deprotection reaction in the presence of acetic acid to generate the final products S1 and S2.

[0019] The preparation method of S3 is as follows:

[0020] Under alkaline conditions, the 2-hydroxyl group of compound I selectively undergoes nucleophilic substitution reaction with trimethylsilyl bromide to generate S3;

[0021] The preparation method of S4-S6 is as follows:

[0022] Compound I (also S7) and S3 undergo acylation reaction with palmitoyl chloride or isopalmitoyl chloride in the presence of triethylamine to generate S4-S6;

[0023] The preparation method of S7-S8 is as follows:

[0024] Ascorbic acid and silanyl alcohol undergo Mitsunobu reaction with triphenylphosphine (PPh3) and diethyl azodicarboxylate (DEAD) as promoting reagents to produce S7-S8.

[0025] Among them, the preparation method of S9-S10 is as follows:

[0026] 1) Compound V reacts with sodium iodide in acetone to undergo nucleophilic substitution to produce VI;

[0027] 2) VI undergoes a dinucleophilic substitution reaction with L-ascorbic acid in the presence of sodium bicarbonate to generate S9;

[0028] 3) S9 undergoes acylation reaction with palmitoyl chloride or isopalmitoyl chloride in the presence of triethylamine to generate palmitate S10.

[0029] The third aspect of the present invention discloses a retinoic acid-derived organosilicon compound, the general structural formula of which is shown below:

[0030] In the general structural formula Ⅰ, R 1 , R 2 , R 3 The group represents a C1-C6 alkyl group and a branched alkyl group; n represents any number among 0, 1, 2, 3, 4, 5, and 6;

[0031] or

[0032] In the general structural formula II, R 1 , R 2 , R 3 , R 4 The group represents a C1-C6 alkyl group and a branched alkyl group.

[0033] The structures of the retinoic acid-derived organosilicon compounds are shown in S1-S8:

[0034] The fourth aspect of the present invention also discloses a method for preparing the above-mentioned compounds. The preparation methods of S1-S6 are as follows:

[0035] Retinoic acid and silanol undergo condensation reaction at room temperature with dicyclohexylcarbodiimide (DCC) and 4-N,N-dimethylaminopyridine (DMAP) as promoting reagents to produce S1-S6;

[0036] The preparation method of compounds S7-S8 is as follows:

[0037] Retinoic acid and chlorosilane undergo a nucleophilic substitution reaction at room temperature with triethylamine (TEA) and 4-N,N-dimethylaminopyridine (DMAP) as promoting reagents to generate S7-S8.

[0038] The fifth aspect of the present invention discloses the use of the above-mentioned ascorbic acid silyl ether derivatives or retinoic acid derivatives in the preparation of skin protection products, including eye creams, face creams, essences, lotions and facial mask essences, etc.; the skin protection products have antioxidant, whitening, soothing and anti-aging skin protection activities.

[0039] Compared with the prior art, the present invention has the following advantages:

[0040] The ascorbic acid-derived organosilicon compound prepared from ascorbic acid in the present invention, compared with VC, ETVC (3-O-ethyl L-ascorbic acid), and VCIP (ascorbyl tetraisopalmitate), exhibits superior proliferation-promoting activity in the human immortalized keratinocyte line HaCaT cells while maintaining antioxidant activity, possesses superior skin anti-aging activity, has significant effects and application potential in improving skin conditions, and has great development prospects.

[0041] The retinoic acid-derived organosilicon compound prepared by the present invention, specifically retinoic acid silane ester, has superior proliferation activity in fibroblasts and human immortalized keratinocyte cell line HaCaT cells, good light / heat stability and irritation resistance, and potentially better transdermal absorption compared to retinoic acid, retinol retinoate, and pinacolone retinoate, and thus has great development prospects. BRIEF DESCRIPTION OF THE DRAWINGS

[0042] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the existing methods and experiments, the following is a brief introduction to the drawings required for use in the embodiments. It should be understood that the following drawings only illustrate certain embodiments of the present invention and therefore should not be regarded as limiting the scope. For ordinary technicians in this field, other relevant drawings can be obtained based on these drawings without paying any creative work.

[0043] FIG1 shows the proliferation-promoting ability of different ascorbic acid-derived organosilicon compounds on immortalized keratinocyte cell line HaCaT cells in Example 11;

[0044] FIG2 is a graph showing the free radical scavenging ability of different ascorbic acid-derived organosilicon compounds in Example 12;

[0045] FIG3 is a graph showing the viability of human immortalized keratinocyte cell line HaCaT cells after treatment with different retinoic acid-derived silicones in Example 15;

[0046] FIG4 shows the ability of different retinoic acid-derived silicones in Example 15 to promote proliferation of human immortalized keratinocyte cell line HaCaT cells;

[0047] FIG5 shows the proliferation-promoting ability of different retinoic acid-derived silicones on mouse fibroblast cell line 3T3-L1 cells in Example 15;

[0048] FIG6 shows the free radical scavenging ability of different retinoic acid-derived organosilicones in Example 16;

[0049] FIG7 is a graph showing the oxidative stress detection of human immortalized keratinocyte cell line HaCaT cells after treatment with different retinoic acid-derived organosilicon in Example 16. DETAILED DESCRIPTION

[0050] The technical solutions of the present invention are described in detail below with reference to the accompanying drawings and examples, but the present invention is not limited to the scope of the examples. Experimental methods and techniques in the following examples where specific conditions are not specified are generally performed in accordance with conventional conditions in the art or the conditions recommended by the manufacturer.

[0051] Example 1: Synthesis of ascorbic acid-derived organosilicon S1

[0052] VC (352.0 mg, 2.0 mmol, 1.0 equiv.) was dissolved in 5.0 mL of dry THF. Ph3P (682.0 mg, 2.6 mmol, 1.3 equiv.), DEAD (377.0 μL, 2.6 mmol, 1.3 equiv.), and trimethylsilylmethanol (328.0 μL, 2.6 mmol, 1.3 equiv.) were added and stirred at room temperature for 8 h. After completion of the reaction, the crude product was concentrated and purified by silica gel column chromatography (PE:EA = 1:1) to afford 398.2 mg of Compound I as a yellow oil in a 76% yield. 1H NMR(400MHz, CDCl3)δ4.63(d,J=2.0Hz,1H),4.39–4.27(m,2H),3.97-3.89(m,1H),3.86-3.72(m,2H),0.09(s,9H).HRMS(ESI)Calcd.for C 10 H 19 O6Si[(M+H) + ]263.0951, measured value 263.0953.

[0053] Compound I (52.4 mg, 0.2 mmol, 1.0 equiv.) was weighed and dissolved in 5.0 mL of acetone. A catalytic amount of acetyl chloride (2.0 μL, 0.02 mmol, 0.1 equiv.) was added and stirred at room temperature for 4 h. After completion of the reaction, the crude product was concentrated and purified by silica gel column chromatography (PE:EA = 2:1) to obtain 57.5 mg of compound II as a white solid in a 95% yield. Compound II (60.5 mg, 0.2 mmol, 1.0 equiv.) was dissolved in 5.0 mL of anhydrous dichloromethane. Triethylamine (27.8 μL, 0.2 mmol, 1.0 equiv.) was added, and acetyl chloride (21.4 μL, 0.3 mmol, 1.5 equiv.) was slowly added dropwise at 0°C. After the addition was complete, the reaction was allowed to proceed at room temperature for 4 h. After the reaction, the crude product was concentrated and purified by silica gel column chromatography (PE:EA = 10:1) to afford 62.7 mg of white solid III (91% yield). Compound III (68.9 mg, 0.2 mmol, 1.0 equiv.) was dissolved in 5.0 mL of MeOH, and 5.0 mL of AcOH was added. The mixture was reacted at 65°C for 8 h. After the reaction, the crude product was concentrated and purified by silica gel column chromatography (PE:EA = 2:1) to afford 54.2 mg of compound S1 as a yellow oil (95% yield). 1 H NMR (400MHz, CDCl3) δ4.79 (d, J = 2.7Hz, 1H), 4.07 (s, 2H), 3.99-3.94 (m, 1H), 3.88 -3.82(m,1H),3.81-3.76(m,1H),2.28(s,3H),0.12(s,9H).HRMS(ESI)Calcd.for C 12 H 21 O7Si[(M+H) + ]305.1057, measured value 305.1055.

[0054] Example 2: Synthesis of Ascorbic Acid-Derived Organosilicon S2

[0055] Compound IⅠ (60.5 mg, 0.2 mmol, 1.0 equiv.) was dissolved in 5.0 mL of anhydrous dichloromethane, and triethylamine (27.8 μL, 0.2 mmol, 1.0 equiv.) was added slowly dropwise at 0°C. The reaction was allowed to react at room temperature for 4 h. After completion of the reaction, the crude product was concentrated and purified by silica gel column chromatography (PE:EA = 10:1) to afford 64.5 mg of compound IV as a white solid with a 90% yield. Compound IV (71.7 mg, 0.2 mmol, 1.0 equiv.) was dissolved in 5.0 mL of MeOH, and 5.0 mL of AcOH was added. The reaction was allowed to react at 65°C for 8 h. After completion of the reaction, the crude product was concentrated and purified by silica gel column chromatography (PE:EA = 2:1) to afford 59.2 mg of compound S2 as a yellow oil with a 93% yield. 1 H NMR (400MHz, CDCl3) δ4.79 (d, J = 2.7Hz, 1H), 4.05 (s, 2H), 3.99-3.94 (m, 1H), 3.88-3.81 (m, 1H), 3 .81-3.74(m,1H),2.57(q,J=7.5Hz,2H),1.23(t,J=7.5Hz,3H),0.11(s,9H).HRMS(ESI)Calcd.for C 13 H 23 O7Si[(M+H) + ]319.1213, measured value 319.1211.

[0056] Example 3: Synthesis of Ascorbic Acid-Derived Organosilicon S3

[0057] Compound I (52.4 mg, 0.2 mmol, 1.0 equiv.) was weighed and dissolved in 2.0 mL of DMF. Trimethylsilyl bromide (28.6 μL, 0.2 mmol, 1.0 equiv.) and K₂CO₃ (27.6 mg, 0.2 mmol, 1.0 equiv.) were added and stirred at room temperature for 4 h. After completion, the reaction was diluted with water and extracted three times with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (PE:EA = 2:1) to afford 31.2 mg of compound S3 as a yellow oil in a 45% yield. 1 H NMR(400MHz, CDCl3)δ4.61(d,J=2.9Hz,1H),4.32-4.21(m,2H),3.90-3.78(m,5H),0.12(s,9H),0.10(s,9H).HRMS(ESI)Calcd.for C 14 H29 O6Si2[(M+H) + ]349.1503, measured value 349.1500.

[0058] Example 4: Synthesis of Ascorbic Acid-Derived Organosilicon S4

[0059] Compound I (52.4 mg, 0.2 mmol, 1.0 equiv.) was weighed and dissolved in 5.0 mL of anhydrous dichloromethane. Triethylamine (27.8 μL, 0.2 mmol, 1.0 equiv.) was added, and palmitoyl chloride (245 μL, 0.8 mmol, 4.0 equiv.) was slowly added at 0°C. After the addition was complete, the reaction was allowed to proceed at room temperature for 8 h. After completion of the reaction, the crude product was concentrated and purified by silica gel column chromatography (PE:EA = 50:1) to afford 84.1 mg of S4 as a white solid in a 43% yield. 1 H NMR (400MHz, CDCl3) δ5.45–5.36(m,1H),4.85(d,J=1.9Hz,1H),4.44-4.33(m,1H),4.30-4.21(m,1H),4.05-3.98(m,1H),3.91-3.84(m,1H),2.51( t,J=7.5Hz,2H),2.39-2.25(m,4H),1.75-1.64(m,2H),1.65-1.52(m,4H),1.25(s,72H),0.88(t,J=6.7Hz,9H),0.11(s,9H).HRMS(ESI)Calcd.for C 58 H 109 O9Si[(M+H) + ]977.7841, measured value 977.7839.

[0060] Example 5: Synthesis of Ascorbic Acid-Derived Organosilicon S5

[0061] Compound I (52.4 mg, 0.2 mmol, 1.0 equiv.) was weighed and dissolved in 5.0 mL of anhydrous dichloromethane. Triethylamine (27.8 μL, 0.2 mmol, 1.0 equiv.) was added, and isopalmitoyl chloride (242 μL, 0.8 mmol, 4.0 equiv.) was slowly added at 0°C. After the addition was complete, the mixture was allowed to react at room temperature for 8 h. After completion of the reaction, the crude product was concentrated and purified by silica gel column chromatography (PE:EA = 50:1) to afford 76.3 mg of compound S5 as a yellow oil in a 39% yield. 1H NMR (400MHz, CDCl3) δ5.50-5.44(m,1H),5.40-5.29(m,1H),4.87-4.81(m,2H),4.04(s,2H),2.60-2.52(m,1H),2.39-2.30 (m,2H),2.09-1.96(m,2H),1.80-1.66(m,10H),1.30-1.22(m,60H),0.90-0.84(m,18H),0.12(s,9H).HRMS(ESI)Calcd.for C 58 H 109 O9Si[(M+H) + ]977.7841, measured value 977.7843.

[0062] Example 6: Synthesis of Ascorbic Acid-Derived Silicone S6

[0063] Compound S3 (69.7 mg, 0.2 mmol, 1.0 equiv.) was dissolved in 5.0 mL of anhydrous dichloromethane. Triethylamine (27.8 μL, 0.2 mmol, 1.0 equiv.) was added, followed by the slow dropwise addition of palmitoyl chloride (245.0 μL, 0.8 mmol, 4.0 equiv.) at 0°C. After the addition was complete, the mixture was allowed to react at room temperature for 8 h. The reaction was purified by silica gel column chromatography (PE:EA = 50:1) to afford 80.8 mg of S6 as a white solid in a 49% yield. 1 H NMR (400MHz, CDCl3) δ5.37–5.31(m,1H),4.71(d,J=2.4Hz,1H),4.39–4.32(m,1H),4.26–4.17(m,2H),4.11–4.05(m,1H),3.84–3.7 4(m,2H),2.33–2.25m,4H),1.64–1.56(m,4H),1.29–1.24(m,48H),0.90–0.85(m,6H),0.10(d,J=2.4Hz,18H).HRMS(ESI)Calcd.for C 46 H 89 O8Si2[[(M+H) + ]825.6096, measured value 825.6098.

[0064] Example 7: Synthesis of ascorbic acid-derived organosilicon S7:

[0065] Triphenylphosphine (682 mg, 2.6 mmol) was dissolved in 10 mL of anhydrous tetrahydrofuran. Diethyl azodicarboxylate (0.4 mL, 2.6 mmol) was added dropwise at -78°C and stirred for 30 minutes. Ascorbic acid (352 mg, 2.0 mmol) was dissolved in 10 mL of anhydrous DMF and added to the reaction mixture at -78°C. After stirring for 5 minutes, the mixture was removed from the cooler and allowed to warm to room temperature for 10 minutes. Finally, trimethylsilyl alcohol (328 μL, 2.6 mmol) was added and allowed to react at room temperature for 8 hours. After completion of the reaction, the mixture was concentrated and diluted with 20 mL of water, followed by extraction with ethyl acetate. The organic phases were combined and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated, and the crude product was separated by silica gel column chromatography (eluent: dichloromethane:methanol = 20:1) to obtain S1 (240 mg, 45% yield) as a pale yellow oil. 1 H NMR (400MHz, CDCl3) δ4.63 (d, J=2.0Hz, 1H), 4.41-4.25 (m, 2H), 3.98-3.91 (m, 1H), 3.87-3.75 (m, 2H), 0.10 (s, 9H); MS (ESI) Calcd.for C 10 H 19 O6Si[(M+H) + ]263.1Actual value: 263.1.

[0066] Example 8: Synthesis of ascorbic acid-derived organosilicon S8:

[0067] The same synthetic route as S7 was used to obtain S8 (232 mg, 40% yield) as a pale yellow oil. 1 H NMR (400MHz, CDCl3) δ4.67 (d, J=2.1Hz, 1H), 4.51-4.38 (m, 2H), 4.01-3.96 (m, 1H), 1.74 -1.69(m, 2H), 0.54-0.49(m, 2H), 0.10(s, 9H); HRMS(ESI)Calcd.for C 12 H 23 O6Si[(M+H) + ]291.1Actual measured value 291.1.

[0068] Example 9: Synthesis of Ascorbic Acid-Derived Organosilicon S9

[0069] V (29.0 μL, 0.2 mmol, 1.0 equiv.) was dissolved in 10 mL of acetone, and NaI (90 mg, 0.6 mmol, 3.0 equiv.) was added. The mixture was refluxed at 80°C for 12 h, and the acetone was removed by rotary evaporation to obtain crude product VI. This product was dissolved in 5 mL of DMF, and ascorbic acid (35.2 mg, 0.2 mmol, 1.0 equiv.) and NaHCO₃ (50.4 mg, 0.6 mmol, 3.0 equiv.) were added. The mixture was reacted at 60°C for 12 h. After completion of the reaction, the mixture was diluted with ethyl acetate, washed three times with saturated brine, and dried over anhydrous sodium sulfate. The resulting product was filtered and concentrated, and purified by silica gel column chromatography (PE:EA = 1:1) to obtain 15.0 mg of compound S7 as a yellow oil in a 29% yield. 1 H NMR (400MHz, CDCl3) δ4.66 (d, J = 2.7Hz, 1H), 4.44–4.25 (m, 2H), 4.08 (s, 2H), 3.94 –3.89(m,1H),3.88–3.76(m,2H),0.28(s,3H),0.25(s,3H).HRMS(ESI)Calcd.for C 10 H 17 O6Si[[(M+H) + ]261.0794, measured value 261.0796.

[0070] Example 10: Synthesis of Ascorbic Acid-Derived Silicone S10

[0071] Compound S9 (52.0 mg, 0.2 mmol, 1.0 equiv.) was dissolved in 5.0 mL of anhydrous dichloromethane. Triethylamine (27.8 μL, 0.2 mmol, 1.0 equiv.) was added, and palmitoyl chloride (245.0 μL, 0.8 mmol, 4.0 equiv.) was slowly added dropwise at 0°C. After the addition was complete, the reaction was allowed to react at room temperature for 8 h. After completion, the reaction was diluted with ethyl acetate, washed three times with saturated brine, and dried over anhydrous sodium sulfate. The resulting product was filtered and concentrated, and purified by silica gel column chromatography (PE:EA = 50:1) to afford 53.1 mg of S8 as a white solid in a 36% yield. 1H NMR(400MHz, CDCl3) δ4.62(d,J=2.2Hz,1H),4.43–4.37(m,1H),4.33–4.26(m,1 H),4.25–4.21(m,1H),4.08(d,J=1.2Hz,2H),3.96–3.80(m,1H),3.76–3.57(m, 1H),3.02–2.88(m,1H),2.41–2.30(m,4H),1.66–1.61(m,4H),1.29–1.24(m,48 H),0.90–0.85(t,J=6.7Hz,6H),0.28(s,3H),0.24(s,3H).HRMS(ESI)Calcd.For C 42 H 78 O8Si[[(M+H) + ]737.5388, measured value 737.5385.

[0072] Example 11: Cytotoxicity assay of ascorbic acid-derived organosilicones S1–S10 and their effects on cell proliferation

[0073] HaCaT cells, an immortalized human skin keratinocyte cell line (purchased from the Chinese Academy of Sciences Cell Bank), were cultured in DMEM complete medium (DMEM medium + 10% fetal bovine serum). 6 / mL HaCaT cells were seeded in a 96-well culture plate and cultured at 37°C, 5% CO2 for 12 hours. Test compounds at various concentrations were then added and cultured for another 24 hours. Then, 10 μL of CCK-8 solution was added to each well. After incubation at 37°C for 2 hours, the absorbance at 450 nm was measured using a microplate reader.

[0074] Cell viability is calculated as follows:

[0075] Cell viability*(%)=[A(drug added)-A(blank)] / [A(0 drug added)-A(blank)]×100

[0076] A (drug added): absorbance of the wells containing cells, CCK-8 solution, and drug solution

[0077] A (blank): absorbance of the well with culture medium and CCK-8 solution but no cells

[0078] A (0 drug addition): absorbance of a well containing cells and CCK-8 solution but no drug solution.

[0079] Plotting the absorbance at 450 nm measured by the CCK-8 assay can more directly reflect a compound's ability to promote HaCaT cell proliferation. Higher absorbance indicates a stronger compound's ability to promote cell proliferation. Directly plotting absorbance values ​​can demonstrate a compound's effect on the proliferation of human immortalized keratinocytes, HaCaT cells. As shown in Figure 1, compared with the VC and ETVC groups, compounds S1-S10 and 3-trimethylsilyl-L-ascorbic acid (Compound I, CN118388519A) significantly improved the proliferation ability of HaCaT cells at concentrations of 100 and 200 μM (*all significantly increased compared with the VC group (p<0.05)); S3, S6 and S9 had significant proliferation-promoting ability compared with VC, ETVC and VCIP at a concentration of 50 μM; compared with 3-trimethylsilyl-L-ascorbic acid (Compound I, CN118388519A), S3, S5, S6, S9 and S10 showed better HaCaT cell proliferation-promoting ability; the above results indicate that hydroxyl disilylation at positions 2 and 3, as well as hydroxyl silyl substitution at position 3 and palmitoylation / isopalmitoylation of the remaining hydroxyl groups, can effectively enhance the ability to promote skin cell proliferation, and may have stronger anti-aging activity than VC, ETVC and VCIP when used on the skin.

[0080] Example 12: Free Radical Scavenging and Antioxidant Capacity Testing of Ascorbic Acid-Derived Silicones S1–S10

[0081] 1,1-Diphenyl-2-trinitrophenylhydrazine (DPPH) is a stable free radical that can be used to measure the free radical scavenging activity of antioxidants. The odd-numbered electrons of the nitrogen atom in DPPH are reduced to the corresponding hydrazine by absorbing a hydrogen atom from the antioxidant. DPPH appears purple in aqueous solution, but after the free radical is scavenged and a covalent bond is formed, the color changes to pale yellow. After the compound reacts with the DPPH solution, the absorbance at 517 nm can be measured spectrophotometrically to determine the free radical scavenging activity of the test compound. Compounds S1-S0, I, VC, ETVC, and VCIP (50, 100, and 200 μM concentrations) were mixed with a 200 μM DPPH solution in a 96-well microtiter plate. After reacting in the dark for 10 minutes, the absorbance at 517 nm was measured using a microplate reader. As shown in Figure 2 , at concentrations of 50, 100, and 200 μM, except for S2, S3, and S10, the other compounds showed no significant changes compared with VC, indicating that at concentrations of 50, 100, and 200 μM, compounds S1, S4, S5, S6, and S9 had free radical scavenging abilities similar to those of VC or ETVC, thereby indicating that they had antioxidant abilities similar to those of VC and ETVC.

[0082] Example 13: Synthesis of Retinoic Acid-Derived Silicones S1-S6

[0083] Under dark conditions, retinoic acid (300 mg, 1 mmol) was dissolved in 5 mL of dichloromethane. DCC (206 mg, 1 mmol) and DMAP (24.5 mg, 0.2 mmol) were then added, followed by trimethylsilyl alcohol (208 mg, 2 mmol). The mixture was stirred at room temperature for 8 hours. The mixture was diluted with 20 mL of water and extracted with dichloromethane (3 × 10 mL). The organic phases were combined and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated, and the crude product was separated by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 20:1) to obtain S1 (120 mg, 34% yield) as a yellow oil. 1 H NMR(400MHz, CDCl3)δ6.98(dd,J=15.0,11.4Hz,1H),6.31–6.25(m,2H),6.15–6.11(m,2H),5.79(s,1H),3.80(s,2H),2.35(s,3H) ,2.02(t,J=5.1Hz,2H),2.00(s,3H),1.71(s,3H),1.64–1.60(m,2H),1.52–1.43(m,2H),1.03(s,6H),0.08(s,9H);MS(ESI)[(M+H) + ]=387.3.

[0084] The synthesis of compound S2 was carried out according to the above-mentioned synthesis method of S1, resulting in a yellow oil (110 mg, yield 27%). 1 H NMR(400MHz, CDCl3)δ7.04–6.92(m,1H),6.32–6.23(m,2H),6.15-6.12(m,2H),5.77(s,1H),4.27–4.15(m,2H),2.35(s,3H),2.06–2.0 1(m,2H),2.00(s,3H),1.71(s,3H),1.64–1.59(m,2H),1.48–1.44(m,2H),1.36–1.23(m,2H),1.02(s,6H),0.04(s,9H);MS(ESI)[(M+H) + ]=401.3.

[0085] The synthesis of compound S3 was carried out according to the above-mentioned synthesis method of S1, resulting in a yellow oil (140 mg, yield 34%). 1H NMR(400MHz, CDCl3)δ7.00(dd,J=16.0,12.0Hz,1H),6.31–6.25(m,2H),6.15–6.11(m,2H),5.78(s,1H),4.15–4.05(m,2H),2.35(s,3H) ),2.04-2.00(m,5H),1.70(s,3H),1.64–1.59(m,4H),1.48–1.45(m,2H),1.03(s,6H),0.54–0.50(m,2H),0.00(s,9H); MS(ESI)[(M+H) + ]=415.8.

[0086] The synthesis of compound S4 was carried out according to the above-mentioned synthesis method of S1, resulting in a yellow oil (150 mg, yield 35%). 1 H NMR (400MHz, CDCl3) δ7.00 (dd, J=16.0, 12.0Hz, 1H), 6.38–6.22 (m, 2H), 6.16 (s, 1H),6.15–6.10(m,1H),5.79(s,1H),4.13(t,J=6.6Hz,2H),2.37(s,3H),2.05-2. 00(m,5H),1.73(s,3H),1.72–1.66(m,2H),1.66–1.57(m,2H),1.53–1.45(m,2H) ,1.45–1.37(m,2H),1.05(s,6H),0.62–0.41(m,2H),0.01(s,9H);MS(ESI)[(M+H) + ]=429.8.

[0087] The synthesis of compound S5 was carried out according to the above-mentioned synthesis method of S1, resulting in a yellow oil (130 mg, yield 32%). 1 H NMR (400MHz, CDCl3) δ6.97(dd,J=16.0,12.0Hz,1H),6.31–6.24(m,2H),6.15–6.11(m,2H),5.77(s,1H),4.79(q,J=5.2Hz,1H),2.35(s,3H ),2.06–2.00(m,5H),1.71(s,3H),1.63–1.56(m,2H),1.48–1.45(m,2H),1.23(d,J=5.2Hz,3H),0.98(s,6H),0.01(s,9H); MS(ESI)[(M+H) + ]=401.7.

[0088] The synthesis of compound S6 was carried out according to the above-mentioned synthesis method of S1, resulting in a yellow oil (180 mg, yield 42%). 1 H NMR (400MHz, CDCl3) δ6.98 (dd, J=14.8, 11.2Hz, 1H 1H),6.43–6.22(m,2H),6.15–6.11(m,2H),5.75(s,1H),3.89(s,2H),2.35(s,3H),2.04-2.00(m,5H),1.71(s,3H) ,1.65–1.57(m,2H),1.51–1.43(m,2H),1.03(s,6H),0.991(t,J=8.0Hz,9H),0.61(q,J=8.0Hz,6H);MS(ESI)[(M+H) + ]=429.8.

[0089] Example 14: Synthesis of Retinoic Acid-Derived Silicones S7-S8

[0090] Retinoic acid 1 (300 mg, 1 mmol) was dissolved in 5 mL of dichloromethane under light-shielding conditions. 4-N,N-dimethylaminopyridine (24.5 mg, 0.2 mmol), tert-butyldimethylsilyl chloride (300 mg, 2 mmol), and triethylamine (0.4 mL, 2 mmol) were then added and stirred at room temperature for 8 hours. The mixture was diluted with 20 mL of water and extracted with dichloromethane (3 × 10 mL). The combined organic phases were dried over anhydrous sodium sulfate. The mixture was filtered and concentrated, and the crude product was separated by silica gel column chromatography (eluent: PE:EA = 20:1) to afford S7 (80 mg, 19% yield) as a yellow oil. 1 H NMR(400MHz, CDCl3)δ7.00(dd,J=16.0,12.0Hz,1H),6.31–6.25(m,2H),6.15–6.09(m,2H),5.77(s,1H),2.33(s,3H),2.0 4-2.00(m,5H),1.71(s,3H),1.62–1.60(m,2H),1.56(s,9H),1.48–1.43(m,2H),0.95(s,6H),0.07(s,6H);MS(ESI)[(M+H) + ]=415.3.

[0091] The synthesis of compound S8 was carried out according to the above-mentioned synthesis method of S7, resulting in a yellow oil (120 mg, yield 26%). 1H NMR(400MHz, CDCl3)δ7.00(dd,J=16.0,12.0Hz,1H),6.36–6.21(m,2H),6.16–6.12(m,2H),5.82(s,1H),2.34(s,3H),2.04-2.00( m,5H),1.72(s,3H),1.66–1.57(m,2H),1.51–1.42(m,2H),1.38–1.25(m,3H),1.09(d,J=7.6Hz,18H),1.03(s,6H);MS(ESI)[(M+H) + ]=457.3.

[0092] Retinoic acid silyl esters S1-S6, synthesized in this invention, demonstrated significantly greater proliferation activity in fibroblasts and the human immortalized keratinocyte cell line HaCaT than RA, RR, and HPR at the same dose, while retinoic acid silyl esters S7-S8 exhibited comparable activity to the control. At the same dose, S1-S8 exhibited antioxidant and free radical scavenging abilities comparable to those of RA, RR, and HPR. Furthermore, S1-S8 exhibited no significant toxicity.

[0093] Example 15: Cytotoxicity Test of Retinoic Acid-Derived Silicones S1-S8 and Their Effects on Cell Proliferation

[0094] Immortalized human keratinocytes (HaCaT) and mouse fibroblasts (3T3-L1) (both purchased from the Chinese Academy of Sciences Cell Bank) were cultured in complete DMEM (DMEM supplemented with 10% fetal bovine serum). 1×10⁶ / mL of HaCaT cells were seeded in 96-well plates and incubated at 37°C, 5% CO₂ for 12 hours. Test compounds were then added at varying concentrations and incubated for an additional 24 hours. 10 μL of CCK-8 solution was then added to each well. After incubation at 37°C for 2 hours, the absorbance at 450 nm was measured using a microplate reader.

[0095] Cell viability is calculated as follows:

[0096] Cell viability*(%)=[A(drug added)-A(blank)] / [A(0 drug added)-A(blank)]×100

[0097] A (drug added): absorbance of the wells containing cells, CCK-8 solution, and drug solution

[0098] A (blank): absorbance of the well with culture medium and CCK-8 solution but no cells

[0099] A(0 drug addition): absorbance of the well with cells and CCK-8 solution but no drug solution;

[0100] As shown in Figure 3, compared to the 0 μM group, with the exception of retinoic acid RA as a control, the remaining compounds, including RR and HPR, did not reduce cell viability at concentrations of 50, 100, and 200 μM, and showed no significant cytotoxicity (*significantly increased compared to the 0 μM group, #significantly decreased compared to the 0 μM group (p<0.05)). This demonstrates that silyl / silyl esterification can significantly reduce the cytotoxicity of retinoic acid.

[0101] Cell proliferation can be directly reflected by absorbance at 450 nm. As shown in Figure 4, trimethylsilyl retinoate S1-S5 significantly enhanced HaCaT cell proliferation compared to RA, RR, and HPR at concentrations of 50, 100, and 200 μM, suggesting that S1-S5 possess potentially stronger skin anti-aging properties (*significantly increased compared to the RA group, #significantly decreased compared to the RA group (p < 0.05)). Considering that S1-S5 require enzymatic hydrolysis to generate RA and trimethylsilyl alcohol to exert their effects, we speculate that the in situ generated trimethylsilyl alcohol may have additional keratinocyte proliferation-promoting and skin anti-aging properties. Furthermore, triethylsilyl retinoate S6 and silyl retinoate S7-S8 failed to effectively promote keratinocyte proliferation, suggesting that these molecules are sterically hindered and difficult to hydrolyze, and the resulting silyl alcohols and silyl alcohols lack keratinocyte proliferation-promoting properties.

[0102] As shown in Figure 5, S1-S5 exhibited a superior pro-proliferative effect in 3T3-L1 fibroblasts at a high concentration of 200 μM compared to RA, RR, and HPR, whereas the effect was not significant at lower concentrations (50 and 100 μM). Considering that these compounds require enzymatic hydrolysis to RA to exert their effects, this result can be inferred to be related to the low esterase activity in fibroblasts (* significantly increased compared to the RA group, # significantly decreased compared to the RA group (p < 0.05)). S6–S8 also lacked this activity, consistent with the experiments shown in Figure 3 and demonstrating that trimethylsilyl alcohol generated by in situ hydrolysis has additional fibroblast proliferation-promoting properties.

[0103] Example 16: Free Radical Scavenging and Antioxidant Capacity Testing of Retinoic Acid-Derived Silicones S1-S8

[0104] 1,1-Diphenyl-2-trinitrophenylhydrazine (DPPH) is a stable free radical that can be used to measure the free radical scavenging activity of antioxidants. The odd-numbered electrons of the nitrogen atom in DPPH are reduced to the corresponding hydrazine by absorbing a hydrogen atom from the antioxidant. DPPH appears purple in aqueous solution, but the color changes to pale yellow after the free radical is scavenged and a covalent bond is formed. After the compound reacts with the DPPH solution, the absorbance at 517 nm can be measured spectrophotometrically to determine the free radical scavenging activity of the test compound. Compounds S1-S8 and controls RA, RR, and HPR (100 μM concentration) were mixed with a 200 μM DPPH solution in a 96-well microtiter plate. After incubation in the dark for 10 minutes, the absorbance at 517 nm was measured using a microplate reader.

[0105] As shown in Figure 6 , the absorbance values ​​of each group were similar with no significant statistical difference, indicating that silyl retinoate / silyl ester has a free radical scavenging ability similar to that of RA, RR, and HPR.

[0106] Dihydroethidium (DHE) is the most commonly used superoxide anion fluorescence detection probe. It can effectively measure the reactive oxygen species in cells and is used to study the antioxidant capacity of compounds. DHE itself has blue fluorescence with a maximum excitation wavelength of 370nm and a maximum emission wavelength of 420nm. After dehydrogenation, it combines with RNA or DNA to produce red fluorescence with a maximum excitation wavelength of 300nm and a maximum emission wavelength of 610nm. In actual observation, 518nm can also be used as the excitation wavelength. 6 / mL HaCaT cells were seeded in 96-well, black-framed, clear-bottom culture plates. After 12 hours of incubation at 37°C and 5% CO2, 10μM H2O2 was added to induce oxidative stress. Test compounds (100μM concentration) were then added and incubated for 24 hours. After adding 10μM DHE probe and incubating at 37°C for 30 minutes, the supernatant was aspirated and fresh culture medium was added. Fluorescence was then measured using a multi-functional microplate reader with fluorescence detection (Ex / Em 518 / 610nm). The mean fluorescence intensity (MFI) reflects the oxidative stress status within the cells; a lower MFI indicates a compound with higher antioxidant capacity.

[0107] As shown in Figure 7, compounds S1-S5 and S7 showed no significant statistical differences compared to the RA control group, indicating that these retinoic acid-derived organosilicon compounds possess similar antioxidant activity (*significantly increased compared to the RA group (p<0.05)). The antioxidant activity of S6 and S8 was slightly lower, likely due to the steric hindrance of these two compounds, making them difficult to hydrolyze into RA, and their own antioxidant activity being slightly lower.

[0108] The above embodiments are preferred implementation modes of the present invention, but the implementation modes of the present invention are not limited to the above embodiments. Any other changes, modifications, substitutions, combinations, and simplifications that do not deviate from the spirit and principles of the present invention should be considered as equivalent replacement methods and are included in the scope of protection of the present invention.

Claims

1. An ascorbic acid-derived organosilicon compound, specifically a silyl ether derivative, characterized in that: The general structural formula of the derivative is shown below: In the general structural formula, R 1 is a silyl group, a hydrogen atom or an alkanoyl group, R 2 and R 3 is a hydrogen atom or an alkanoyl group, R 4 、R 5 and R 6 Independently selected from hydrogen atom or C1-C6 alkyl and branched alkyl; n represents any one of 1, 2, 3, 4, 5, 6.

2. An ascorbic acid-derived organosilicon compound, specifically a silyl ether derivative, characterized in that: The general structural formula of the derivative is shown below: In the general structural formula, R 7 and R 8 is a hydrogen atom or an alkanoyl group.

3. [Corrected 27.03.2025 according to Rule 26] The ascorbic acid-derived organosilicon compound according to claim 1, specifically a silyl ether derivative, characterized in that The specific compound structural formula is as follows:

4. [Corrected 27.03.2025 according to Rule 26] The ascorbic acid-derived organosilicon compound according to claim 2, specifically a silyl ether derivative, characterized in that The specific compound structural formula is as follows:

5. The method for preparing an ascorbic acid-derived organosilicon compound according to claim 3, wherein: The preparation method of S1-S2 is as follows: 1) Using triphenylphosphine and diethyl azodicarboxylate as promoting reagents, ascorbic acid and trimethylsilyl alcohol undergo a Mitsunobu reaction at room temperature to produce intermediate I (also S7); 2) I undergoes cross-protection reaction with acetone in the presence of a catalytic amount of acetyl chloride to generate the key intermediate II. Intermediate II undergoes acylation reaction with acetyl chloride or propionyl chloride under alkaline conditions to generate intermediates III and IV. Subsequently, III and IV undergo deprotection reaction in the presence of acetic acid to generate the final products S1 and S2. The preparation method of S3 is as follows: Compound I, under alkaline conditions, selectively undergoes nucleophilic substitution reaction between the 2-hydroxyl group and trimethylsilyl bromide to generate S3; The preparation method of S4-S6 is as follows: Compounds I and S3 undergo acylation reaction with palmitoyl chloride or isopalmitoyl chloride in the presence of triethylamine to generate S4-S6; The preparation method of S7-S8 is as follows: Ascorbic acid and silanyl alcohol undergo Mitsunobu reaction with triphenylphosphine (PPh3) and diethyl azodicarboxylate (DEAD) as promoting reagents to produce S7-S8.

6. The method for preparing an ascorbic acid-derived organosilicon compound according to claim 4, wherein: The preparation method of S9-S10 is as follows: 1) Compound V reacts with sodium iodide in acetone to undergo nucleophilic substitution to produce VI; 2) VI undergoes a dinucleophilic substitution reaction with ascorbic acid in the presence of sodium bicarbonate to produce S9; 3) S9 undergoes acylation reaction with palmitoyl chloride in the presence of triethylamine to generate palmitate S10.

7. A retinoic acid-derived organosilicon compound, characterized in that: The compound structural formula is as follows: In the general structural formula Ⅰ, R 1 , R 2 , R 3 The group represents a C1-C6 alkyl group and a branched alkyl group; n represents any number among 0, 1, 2, 3, 4, 5, 6; or In the general structural formula II, R 1 , R 2 , R 3 , R 4 The group represents a C1-C6 alkyl group and a branched alkyl group.

8. [Corrected 27.03.2025 in accordance with Rule 26] A retinoic acid-derived organosilicon compound according to claim 7, having structures as shown in S1-S8:

9. The method for preparing a retinoic acid-derived organosilicon compound according to claim 8, wherein: The preparation methods of compounds S1-S6 are as follows: Retinoic acid and silanol undergo condensation reaction at room temperature with dicyclohexylcarbodiimide (DCC) and 4-N,N-dimethylaminopyridine (DMAP) as promoting reagents to produce S1-S6; The preparation method of compounds S7-S8 is as follows: Retinoic acid and chlorosilane undergo a nucleophilic substitution reaction at room temperature with triethylamine (TEA) and 4-N,N-dimethylaminopyridine (DMAP) as promoting reagents to generate S7-S8.

10. Use of the ascorbic acid-derived organosilicon compound according to any one of claims 1 to 4, or the retinoic acid-derived organosilicon compound according to any one of claims 7 to 8, in the preparation of skin protection products, wherein the skin protection products include eye creams, face creams, essences, lotions, and mask essences; the skin protection products have antioxidant, whitening, soothing, and anti-aging skin protection activities.

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