Synthesis and application of Otensin and derivative thereof

Abstract

The invention belongs to the technical field of medicinal chemistry, and particularly relates to synthesis and application of Otensin and derivatives thereof. According to the invention, Otensinin, derivatives thereof and pharmaceutically acceptable salts thereof are synthesized for the first time, and it is found that the compounds have good anti-tumor activity and can inhibit proliferation and migration of various tumor cells. Therefore, the Otensin and the derivative thereof synthesized by the invention have a good application prospect in the aspect of new anti-tumor drugs, so that a foundation is laid for the development of corresponding anti-tumor drugs.

Description

Technical Field

[0001] The present invention belongs to the technical field of medicinal chemistry, and particularly relates to the synthesis and application of Ottensinin and its derivatives. Background Art

[0002] The natural product ottensinin (as shown in Figure 1 ) was first extracted from the rhizomes of the sedative Zingiberaceae plant Zingiber ottensii Val grown in Malaysia in 2006 by Japanese scholar Nobuji Nakatani and his collaborators (see: Akiyama K. et al., 2006; Phumthum M. et al., 2018; Boonmee A. et al., 2011; Sivasothy Y. et al., 2013). In 2008, Canadian scholar John Boukouvalas and his collaborators (see: Boukouvalas J. et al., 2008) corrected the structure of this diterpenoid compound to ottensinin through total synthesis of the structure reported by Nobuji Nakatani and NMR data analysis. Subsequently, in 2013, Malaysian scholar Khalijah Awang and her collaborators isolated ottensinin from Malaysian Zingiberaceae plants (see: Sivasothy Y. et al., 2013). In addition, in 2014, 2018, 2021, and 2022, Chinese scholars Kong Lingyi (see: Luo J. G. et al., 2014), Yue Jianmin (see: Ji K.-L. et al., 2018), Gao Jinming (see: Yin H. et al., 2021), Chen Junjia (see: Lu C.-L. et al., 2022) and their collaborators respectively extracted ottensinin from Zingiberaceae plants Amomum maximum, Amomum villosum, and Amomum tsaoko in Yunnan region of China.

[0003] Experimental findings showed that ottensinin isolated from Amomum maximum has significant antibacterial activity, with a minimum inhibitory concentration against Bacillus cereus of 0.2500 ± 0.0000 μg / μL (see: Sivasothy Y. et al., 2013). In the tumor cell activity test, the IC50 ± SD values of this compound against MCF-7 (human breast cancer cells), SMMC-7721 (human liver cancer cells), and MG-63 (human osteosarcoma cells) were > 100 μg / ml, 30.3 ± 2.3 μg / ml, and > 100 μg / ml respectively, indicating that it has significant cell activity against human breast cancer cells, human liver cancer cells, and human osteosarcoma cells, that is, it has anti-tumor activity. In the test of nitric oxide (NO) inhibitory activity in lipopolysaccharide (LPS)-induced RAW264.7 macrophages, the IC50 value was 42.2 μM, indicating effective NO inhibitory activity (see: Yin H. et al., 2021). Nuclear factor κB is a potential target for regulating immune and inflammatory dysfunctions. In the test of the inhibitory activity of nuclear factor κB (NF-κB), ottensinin showed significant NF-κB inhibitory effects, with an IC50 value of 7.99 ± 1.77 μΜ (see: Ji K.-L. et al., 2018). In the hypoglycemic experiment, ottensinin showed significant inhibitory effects on α-glucosidase, with an IC50 value of 18.64 ± 0.94 μg / mL, showing no significant difference from the first-line hypoglycemic drug acarbose (p > 0.05), and the IC50 value of ottensinin for inhibiting α-amylase was 78.54 ± 7.44 μg / mL, significantly higher than that of acarbose (p < 0.05), indicating that it has a selective inhibitory effect on α-glucosidase and can significantly inhibit the side effects of diarrhea and abdominal distension caused by high levels of α-amylase (see: Lu C.-L. et al., 2022). In addition, in the test of the high blood glucose level after oral starch meal in streptozotocin (STZ)-induced mice, compared with the diabetes mellitus (DM) control group, in the ottensinin treatment group, the blood glucose level decreased by 26.3% at 30 minutes and 20.9% at 120 minutes, and there was no significant difference in the blood glucose level between 30 - 180 minutes and the acarbose treatment group (p > 0.05), indicating that ottensinin has a significant inhibitory effect on the postprandial blood glucose level in hyperglycemic mice and has potential application prospects as a hypoglycemic drug (see: Lu C.-L. et al., 2022).

[0004] In summary, it can be seen that ottensinin has significant insecticidal, antibacterial, anti-tumor, NO inhibitory, NF-κB inhibitory, α-amylase inhibitory, α-glucosidase inhibitory and other multiple biological activities.

[0005] However, at present, the amount of this natural product isolated from nature is very small, making it difficult to conduct more in-depth research on its biological activities. Previously, in 2008, Canadian scholar John Boukouvalas and his collaborators completed the first total synthesis route of this compound on the basis of modifying ottensinin (as Figure 2 shown). Two major advantages of this work are that it uses (+)-sclareolide as the starting material and constructs γ-pyrone in 9 steps, revealing a new method for constructing γ-pyrone.

[0006] In 2024, the research group led by Academician Yue Jianmin completed the convergent synthesis of ottensinin (as Figure 3 shown). The researchers used commercially available (+)-sclareolide (2.6) as the raw material, obtained the key intermediate iodide through reduction, radical reaction, and then reduction, and obtained a single exocyclic double bond 2.14 through elimination under low-temperature control. Compound 2.14 reacted with pyrone trifluoromethanesulfonate 2.15, and the efficient total synthesis of ottensinin (2.1) was achieved through Ni-catalyzed C(sp2)-C(sp3) cross-electrophilic coupling reaction. This route has a total of 5 steps with an overall yield of 30%.

[0007] Malignant tumors are one of the most serious diseases threatening human health. Its incidence rate is second only to cardiovascular and cerebrovascular diseases, making it the second "killer" of human health. Moreover, its mortality rate even exceeds that of cardiovascular and cerebrovascular diseases, ranking first among all diseases. Therefore, searching for and developing new drugs for treating tumors is a major issue currently faced.

[0008] Colorectal cancer (CRC) is the fourth leading cause of cancer death in the world and one of the most common tumors of the human gastrointestinal digestive system. Its incidence ranks second among malignant tumors in my country (see: Alrushaid N. et al., 2023; Siegel RL et al., 2023; Adebayo AS et al., 2023). In recent years, with the change of people's lifestyle and the improvement of living conditions, people generally reduce physical activity and consume too much high-fat and high-protein food, which leads to an increase in gastrointestinal burden. Therefore, the incidence of colorectal cancer is also increasing. Due to the complex pathogenesis of colorectal cancer, its formation and development is a multi-factor, multi-stage process. The occurrence and development of its course are affected by multiple factors such as genetics, epigenetics, intestinal microenvironment and lifestyle. Typical colorectal cancer is a solid tumor, which generally appears in the colonic mucosal epithelium through adenomatous polyps and gradually develops into a malignant tumor. It is more common in middle-aged and elderly people. In recent years, the incidence population has shown a trend of younger age (see: Di Y., Ding L. et al., 2023; Spaander MC et al., 2023; Garutti M. et al., 2023). At present, the treatment for colorectal cancer is mainly surgical resection, followed by the use of first-line chemotherapy drugs oxaliplatin and 5-fluorouracil for treatment (see: Hossain MS et al., 2022). However, current drug treatment can only improve the quality of life of patients and prolong their life cycle, but cannot completely cure colorectal cancer.

[0009] Based on the above studies, ottensinin showed good anti-tumor activity against human breast cancer cells, human liver cancer cells, and human osteosarcoma cells, and curcumin, an active ingredient of ginger plants, can promote apoptosis of CRC cell line SW620 (see: Li Youling et al., 2021), and andrographolide, a compound with a similar skeleton to ottensinin, also has the effect of promoting apoptosis of CRC cell line HCT116 (see: Liu Tianfu et al., 2022; Liu Yanfei et al., 2023). Therefore, the present invention proposes ottensinin and its derivatives and explores the apoptosis ability of CRC cell line HCT116, providing a material basis for the study of the anti-colon cancer activity of helianthus annuus-type diterpenoid compounds. Summary of the invention

[0010] The purpose of the present invention is to provide a synthesis and application of Ottensinin and its derivatives to achieve effective anti-tumor effects.

[0011] To this end, the present invention provides the following technical solutions.

[0012] One aspect of the present invention provides a compound as shown in Formula I or II or a pharmaceutically acceptable salt thereof: Among them, R represents α-OH, β-OH or OCSSMe, and n is 0 or 1.

[0013] In some embodiments of the present invention, the compound represented by Formula I is any one of the following compounds: Another aspect of the present invention provides a pharmaceutical composition, which comprises: (1) The compound represented by Formula I as described above or a pharmaceutically acceptable salt thereof, and (2) Pharmaceutically acceptable excipients.

[0014] Another aspect of the present invention provides the use of the compound represented by Formula I as described above or a pharmaceutically acceptable salt thereof or a pharmaceutical composition in the preparation of a drug for treating and / or preventing diseases related to abnormal cell activities.

[0015] In some embodiments of the present invention, the diseases related to abnormal cell activities are selected from tumors.

[0016] In some embodiments of the present invention, the tumor is colon cancer.

[0017] By the above technical solutions, the present invention has at least the following advantages: The present invention synthesizes Ottensinin and its derivatives and their pharmaceutically acceptable salts for the first time, and finds that such compounds have good anti-tumor activities and can inhibit the proliferation and migration of various tumor cells. Therefore, the synthesized Ottensinin and its derivatives of the present invention have good application prospects in the aspect of new anti-tumor drugs, thus laying a foundation for the development of corresponding anti-cancer drugs. In addition, by preparing Ottensinin and its derivatives, the present invention can provide a material basis for the study of the structure-activity relationship of this family of compounds.

[0018] The above description is only an overview of the technical solutions of the present invention. In order to be able to understand the technical means of the present invention more clearly and implement them in accordance with the content of the specification, the following describes the preferred embodiments of the present invention in detail. Brief Description of the Drawings

[0019] Figure 1 is the structural formula of ottensinin; Figure 2 is one of the total synthesis routes of ottensinin in the prior art; Figure 3 is one of the total synthesis routes of ottensinin in the prior art; Figure 4The synthetic route of ottensinin of the present invention; Figure 5 The synthetic route of the ottensinin derivative of the present invention; Figure 6 The changing trend of the cell inhibition rate of ottensinin and its derivatives; Figure 7 It is the influence of ottensinin and its derivatives on cell viability. Among them, "Negative control" indicates comparison with other groups. * P < 0.05, ** P < 0.01, *** P < 0.001, **** P < 0.0001. Detailed implementation manners

[0020] In order to make the technical means, creative features, achieved purposes and effects of the present invention easy to understand, the technical solutions in the embodiments of the present invention will be clearly and completely described below in conjunction with the embodiments of the present invention. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without making creative efforts belong to the protection scope of the present invention.

[0021] Term explanation: In the present invention, unless otherwise specified, the scientific and technical terms used in the present invention have the meanings commonly understood by those skilled in the art. And the cell culture, molecular genetics, nucleic acid chemistry, immunology laboratory operation steps used in the present invention are all conventional steps widely used in the corresponding fields. At the same time, in order to better understand the present invention, the definitions and explanations of relevant terms are provided below.

[0022] The term "pharmaceutically acceptable" means relatively non-toxic, safe and suitable for use by patients.

[0023] The term "pharmaceutically acceptable salt" refers to a salt obtained by reacting a compound with a pharmaceutically acceptable acid or base. When a compound contains a relatively acidic functional group, the base addition salt can be obtained by contacting the compound with a sufficient amount of a pharmaceutically acceptable base in a suitable inert solvent. When a compound contains a relatively basic functional group, the acid addition salt can be obtained by contacting the compound with a sufficient amount of a pharmaceutically acceptable acid in a suitable inert solvent. For details, see Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P. Heinrich Stahl, Camille G. Wermuth, 2011, 2nd Revised Edition).

[0024] The term "pharmaceutically acceptable excipient" refers to all substances contained in a pharmaceutical preparation other than the active pharmaceutical ingredient, generally divided into two categories: excipients and additives. For details, see Pharmacopoeia of the People's Republic of China (2020 Edition), Handbook of Pharmaceutical Excipients (Paul J Sheskey, Bruno C Hancock, Gary P Moss, David J Goldfarb, 2020, 9th Edition).

[0025] The term "treatment" refers to eliminating the cause or alleviating the symptoms.

[0026] The term "prevention" refers to reducing the risk of developing a disease.

[0027] The term "pharmaceutical composition" refers to a mixture containing one or more of the compounds described herein or their physiologically / pharmaceutically acceptable salts or prodrugs, together with other chemical components, as well as other components such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate the administration to an organism, promote the absorption of the active ingredient, and thereby exert its biological activity.

[0028] The method of the present invention will be described below through specific examples. It should be understood that these examples are used to illustrate the basic principles, main features, and advantages of the present invention, and the present invention is not limited by the scope of the following examples; the implementation conditions used in the examples can be further adjusted according to specific requirements, and the implementation conditions not specified are usually the conditions in conventional experiments or selected according to the product instructions. The reagents and raw materials used in the present invention are all commercially available.

[0029] Those involved and mentioned in the following examples: Micro melting point determinator: Model: RS-232, purchased from Stanford Research Systems (SRS), USA.

[0030] Full-automatic digital polarimeter: Model: P-2000, purchased from Rudolph, USA.

[0031] Fourier transform infrared spectrometer: Model: Nicolet iS50 + iN10, purchased from Thermo Nicolet, USA High-resolution mass spectrometer: Model: KE375, purchased from Micromass UK Limited.

[0032] X-ray single crystal diffractometer: Model: Supernova, purchased from Rigaku Corporation, Japan.

[0033] Nuclear magnetic resonance spectrometer: Model: Z115310, purchased from Bruker, Germany.

[0034] Example 1: Synthesis of compound 2.65 The synthesis route of compound 2.65 is as follows: The specific synthesis process is as follows: Dissolve the substrate sclareolide 2.6 (10.0 g, 40.0 mmol, 1.0 equiv) in ether (80 mL), and dropwise add MeLi (1.6 M in Et2O, 40.0 mL, 64.0 mmol, 1.6 equiv) at -78 °C. After the addition is complete, stir at this temperature for 1 hour. Then quench with saturated ammonium chloride solution (20 mL), extract with ethyl acetate (200 mL × 3), wash the combined organic phase once with saturated brine (50 mL), and then dry over anhydrous Na2SO4, filter, and concentrate to obtain the crude product. The crude product is purified by silica gel column chromatography (hexanes: EtOAc 10:1 → 5:1) to obtain the white solid product 2.65 (10.0 g, yield 99%).

[0035] The detection data of the obtained compound 2.65 are as follows: Rf = 0.2 (silica gel, hexanes: EtOAc = 4: 1); m.p. (hexane / DCM): 63 - 65 °C; [α]22 D = -5.7 (c = 1.0, CHCl3); IR (film) 3446, 2925, 1703, 1470, 1387, 1168, 1069, 750, 665 cm –1 ; 1 H NMR (300 MHz, CDCl3) δ 2.56 – 2.31 (m, 2H), 2.13 (s, 3H), 1.94 – 1.80 (m, 3H), 1.70 – 1.58 (m, 1H), 1.56 – 1.43 (m, 1H), 1.42 – 1.32 (m, 3H), 1.31 – 1.27 (m, 1H), 1.26 – 1.18 (m, 1H), 1.17 – 1.09 (m, 1H), 1.06 (s, 3H), 0.97 (dd, J = 12.1, 2.3 Hz, 1H), 0.83 (s, 3H), 0.74 (s, 6H); 13 C NMR (75 MHz, CDCl3) δ 210.2, 72.9, 55.8, 55.7, 44.3, 41.7, 39.5, 39.3, 38.2, 33.3, 33.1, 30.2, 23.1, 21.3, 20.5, 18.3, 15.6; HRMS (ESI) Calculated for C 17 H 30 NaO2 [M+Na] + : 289.2138, Found: 289.2134. Example 2: Synthesis of Compound 2.57 The synthetic route of Compound 2.57 is as follows: The specific synthesis process is as follows: Dissolve Ac2O (42.3 mL, 451 mmol, 12.0 equiv) in dichloromethane (200 mL). Add 30% H2O2 (49.0 mL, 488 mmol, 13.0 equiv) at 5 ºC. After addition, stir for 1 hour at this temperature. Then, add maleic anhydride (29.5 g, 301 mmol, 8.0 equiv) at 8 ºC. After addition, stir for 2 hours at this temperature. Next, dissolve substrate 2.65 (10.0 g, 37.6 mmol, 1.0 equiv) in dichloromethane (40 mL) at 5 ºC and add it dropwise to the reaction system. After completion, stir for 16 hours at this temperature. Then, add saturated sodium thiosulfate (50 mL) and saturated sodium bicarbonate solution (50 mL) to quench the reaction. Extract with dichloromethane (200 mL × 3). Wash the combined organic phases once with saturated brine (100 mL), then dry over anhydrous Na2SO4, filter, and obtain the crude product. Purify the crude product by silica gel column chromatography (hexanes: EtOAc = 10:1 → 6:1) to obtain the colorless oily product 2.57 (9.10 g, yield 81%).

[0036] The detection data of the obtained compound 2.57 are as follows: Rf = 0.30 (silica gel, hexanes: EtOAc = 4: 1); m.p. (hexane / DCM): 74 - 76 ºC; [α]22 D = –7.25 (c = 0.91, CHCl3); IR (film) 3446, 2923, 1723, 1464, 1387, 1239 1071, 752 cm –1 ; 11H NMR (600 MHz, CDCl3) δ 4.39 – 4.17 (m, 2H), 2.26 (d, J = 6.3 Hz, 1H), 2.03 (s, 3H), 1.93 – 1.83 (m, 1H), 1.71 – 1.59 (m, 2H), 1.55 – 1.42 (m, 3H), 1.41 – 1.33 (m, 1H), 1.32 – 1.21 (m, 2H), 1.16 (s, 3H), 1.09 – 1.00 (m, 1H), 0.94 (dd, J = 2.2, 12.1 Hz, 1H), 0.86 (d, J = 6.1 Hz, 6H), 0.79 (s, 3H); 13 13C NMR (150 MHz, CDCl3) δ 171.5, 72.7, 62.7, 60.1, 55.8, 44.1, 41.8, 39.8, 38.2, 33.6, 33.3, 24.7, 21.7, 21.4, 20.4, 18.5, 15.9; HRMS (ESI) Calculated for C 17 H 30 NaO3 [M+Na] + : 305.2087, Found: 305.2082. Example 3: Synthesis of Compound 2.58 The synthetic route of Compound 2.58 is as follows: The specific synthesis process is as follows: Compound 2.57 (9.10 g, 32.3 mmol, 1.0 equiv) was dissolved in dichloromethane (100 mL). At -78 ºC, pyridine (2.59 mL, 323 mmol, 10.0 equiv) and thionyl chloride (1.17 mL, 162 mmol, 5.0 equiv) were added successively, and the mixture was stirred at this temperature for 2 hours. After the reaction was completed, saturated sodium bicarbonate solution (20 mL) was added to quench the reaction. The mixture was extracted with dichloromethane (200 mL × 3), and the combined organic phases were washed once with saturated brine (100 mL), then dried over anhydrous Na2SO4, filtered, and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (hexanes: EtOAc = 200:1 → 150:1), dissolved in dichloromethane (100 mL), and at -78 ºC, sodium bicarbonate (13.5 g, 162 mmol, 5.0 equiv) and m-chloroperbenzoic acid (1.95 g, 11.3 mmol, 0.35 equiv) were added successively. The temperature was raised to -20 ºC and the mixture was stirred for 2 hours until the reaction was completed. Then, saturated sodium bicarbonate solution (20 mL) was added to quench the reaction. The mixture was extracted with dichloromethane (200 mL × 3), and the combined organic phases were washed once with saturated brine (100 mL), then dried over anhydrous Na2SO4, filtered, and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (hexanes: EtOAc = 200:1 → 150:1) to obtain colorless oily product 2.58 (5.20 g, yield 61%).

[0037] The detection data of the obtained compound 2.58 were as follows: Rf = 0.80 (silica gel, hexanes: EtOAc = 5:1); [α]22 D = +22 (c = 0.50, CHCl3); IR (film) 2925, 2866, 1737, 1459, 1365, 1231, 1027, 888 cm –1 ; 11H NMR (300 MHz, CDCl3) δ 4.84 (d, J = 1.6 Hz, 1H), 4.50 (d, J = 1.6Hz, 1H), 4.36 – 4.12 (m, 2H), 2.45 – 2.34 (m, 1H), 2.04 – 2.02 (m, 2H), 2.01(s, 3H), 1.74 – 1.68 (m, 2H), 1.66 – 1.63 (m, 1H), 1.55 – 1.48 (m, 2H), 1.45– 1.40 (m, 1H), 1.39 – 1.37 (m, 1H), 1.34 – 1.29 (m, 1H), 0.95 (s, 1H), 0.87(s, 3H), 0.80 (s, 3H), 0.74 (s, 3H); 13 13C NMR (75 MHz, CDCl3) δ 171.5, 146.9, 107.3, 61.6, 55.2, 54.8, 42.0,39.1, 39.1, 37.7, 33.8, 33.6, 24.0, 21.9, 21.3, 19.3, 15.2; HRMS (ESI) Calculated for C 17 H 28 NaO2 [M+Na] + : 287.1982, Found: 287.1980. Example 4: Synthesis of compound (+)-albicanol (2.16) The synthetic route of compound (+)-albicanol (2.16) is as follows: The specific synthesis process is as follows: Dissolve the known compound 2.58 (5.20 g, 19.7 mmol, 1.0 equiv) in methanol (100 mL). At 25 ºC, add potassium carbonate (13.6 g, 98.5 mmol, 5.0 equiv), and stir at this temperature for 4 hours. After the reaction is completed, add saturated ammonium chloride solution (20 mL) to quench the reaction. Extract with ethyl acetate (100 mL × 3). Wash the combined organic phases once with saturated brine (100 mL), then dry over anhydrous Na2SO4, filter, and concentrate to obtain the crude product. Purify the crude product by silica gel column chromatography (hexanes: EtOAc = 30:1 → 15:1) to obtain the colorless solid product (+)-albicanol (2.16) (3.90 g, yield 90%).

[0038] The detection data of the obtained compound (+)-albicanol (2.16) are as follows: Rf = 0.83 (silica gel, hexanes: EtOAc = 10:1); m.p. (hexane / DCM): 62 - 65 ºC; [α]22 D = +13.8 (c = 0.5, CHCl3); IR (film) 3358, 2923, 2866, 2844, 1458, 1440, 1020, 754 cm –1 ; 1 1H NMR (300 MHz, CDCl3) δ 4.94 (d, J = 1.6 Hz, 1H), 4.63 (d, J = 1.6 Hz, 1H), 3.88 – 3.69 (m, 2H), 2.49 – 2.36 (m, 1H), 2.01 (d, J = 15.6 Hz, 2H), 1.81 – 1.07 (m, 9H), 0.87 (s, 3H), 0.80 (s, 3H), 0.71 (s, 3H); 13 13C NMR (75 MHz, CDCl3) δ 148.0, 106.4, 59.3, 58.9, 55.3, 42.1, 39.1, 39.1, 38.0, 33.76, 33.6, 24.3, 21.9, 19.3, 15.4; HRMS (ESI) Calculated molecular weight: C15 H 26 NaO[M+Na] + : Theoretical value of molecular weight: 245.1876, measured value of molecular weight: 245.1875. Example 5: Synthesis of compound (-)-albicanal (2.38) The synthetic route of compound (-)-albicanal (2.38) is as follows: The specific synthesis process is as follows: Oxalyl chloride (7.47 mL, 88.0 mmol, 5.0 equiv) was dissolved in dichloromethane (200 mL), and DMSO (16.2 mL, 176 mmol, 10.0 equiv) was added at -78 ºC. After addition, the mixture was stirred at this temperature for 15 minutes. Then, substrate 2.16 (3.90 g, 17.6 mmol, 1.0 equiv) was dissolved in dichloromethane (40 mL) and added dropwise to the reaction system at -78 ºC. The mixture was stirred at this temperature for 15 minutes. Subsequently, triethylamine (24.5 mL, 176 mmol, 10.0 equiv) was added. After addition, the mixture was stirred at this temperature for 15 minutes and then allowed to warm to room temperature and stirred for 1 hour. Then, saturated ammonium chloride (50 mL) was added to quench the reaction. The mixture was extracted with dichloromethane (200 mL × 3). The combined organic phases were washed once with saturated brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (hexanes: EtOAc = 200:1 → 150:1) to obtain a colorless oily product (–)-albicanal (2.38) (3.60 g, yield 93%).

[0039] The detection data of the obtained compound (-)-albicanal (2.38) are as follows: Rf = 0.80 (silica gel, hexanes: EtOAc = 10: 1); [α]22 D = -70.6 (c = 0.435, CHCl3); IR (film) 2926, 2845, 1714, 1458, 1388, 1109, 893, 753 cm –1 ; 11H NMR (300 MHz, CDCl3) δ 9.85 (d, J = 4.9 Hz, 1H), 4.90 (s, 1H), 4.48(s, 1H), 2.48 – 2.35 (m, 2H), 2.15 – 1.91 (m, 1H), 1.76 – 1.63 (m, 1H), 1.62– 1.51 (m, 2H), 1.51 – 1.34 (m, 4H), 1.26 – 1.21 (m, 1H), 1.20 – 1.17 (m,1H), 1.13 (s, 3H), 0.86 (s, 3H), 0.84 (s, 3H); 13 13C NMR (75 MHz, CDCl3) δ205.8, 145.1, 109.3, 68.0, 54.1, 42.0, 40.0,39.1, 36.8, 33.6, 33.5, 23.2, 22.0, 18.8, 16.1; HRMS (ESI) Calculated for C 15 H 25 O [M+H] + : 221.1900, Found: 221.1897. Example 6: Synthesis of Compounds 2.64a and 2.64b The synthetic routes of Compounds 2.64a and 2.64b are as follows: The specific synthesis process is as follows: Dissolve 3-iodo-4H-pyran-4-one 2.24 (767 mg, 3.46 mmol, 1.5 equiv) in diethyl ether (3 mL). At -95 °C, add dropwise 1.6 M n-BuLi (2.37 mL, 3.80 mmol, 1.7 equiv). After addition, stir at this temperature for 1 hour. Then dissolve substrate 5 (500 mg, 2.30 mmol, 1.0 equiv) in diethyl ether (3 mL), add dropwise to the reaction system, and stir at -95 °C for 1 hour. After the reaction is complete, quench the reaction by adding saturated ammonium chloride solution (2 mL). Extract with ethyl acetate (5 mL × 3). Wash the combined organic phases once with saturated brine (2 mL), then dry over anhydrous Na2SO4, filter, and concentrate to obtain the crude product. Purify the crude product by silica gel column chromatography (hexanes: EtOAc 4:1) to obtain the colorless solid product 2.64a (342 mg, yield 47%) and the colorless oily product 2.64b (147 mg, yield 20%).

[0040] The detection data of the obtained compound 2.64a are as follows: Rf = 0.50 (silica gel, hexanes: EtOAc = 2: 1); [α]22 D = -5.4 (c = 0.343, CHCl3); IR (film) 2925, 2852, 1651, 1461, 1264, 1081, 896, 704 cm –1 ; 11H NMR (500 MHz, CDCl3) δ 7.77 (s, 1H), 7.73 (d, J = 5.4 Hz, 1H), 5.41– 5.34 (m, 1H), 5.09 (d, J = 2.0 Hz, 1H), 4.94 (d, J = 2.1 Hz, 1H), 2.36 –2.29 (m, 2H), 2.16 (s, 1H), 2.05 – 1.97 (m, 1H), 1.93 (d, J = 12.5 Hz, 2H),1.75 – 1.69 (m, 1H), 1.43 – 1.38 (m, 2H), 1.35 – 1.32 (m, 1H), 1.30 – 1.27(m, 1H), 1.22 – 1.19 (m, 1H), 1.13 (s, 3H), 0.86(d, J = 4.7 Hz, 6H); 13 13C NMR (126 MHz, CDCl3) δ 179.2, 155.2, 154.1, 145.6, 131.7, 117.2,111.4, 66.3, 56.9, 55.9, 42.1, 40.5, 39.3, 39.0, 33.9, 29.8, 24.5, 21.9,19.4, 17.0; HRMS (ESI) Calculated for C 20 H 28 O3 [M+Na] + : 339.1931, Found: 339.1928. The detection data of the obtained compound 2.64b are as follows: Rf = 0.40 (silica gel, hexanes: EtOAc = 2: 1); [α]22 D = -68.6 (c = 1.0, CHCl3); IR (film) 3387, 2925, 1644, 1596, 1436, 1322, 837, 734 cm –1 ; 11H NMR (500 MHz, CDCl3) δ 7.70 (dd, J = 1.0, 5.7 Hz, 1H), 7.67 (s,1H), 6.33 (d, J = 5.8 Hz, 1H), 4.89 (d, J = 8.4 Hz, 1H), 4.78 (s, 1H), 4.32(d, J = 1.5 Hz, 1H), 2.53 (d, J = 8.4 Hz, 1H), 2.29 – 2.16 (m, 2H), 2.07 –1.95 (m, 1H), 1.77 – 1.68 (m, 1H), 1.62 – 1.48 (m, 1H), 1.44–1.23 (m, 5H),1.21 – 1.12 (m, 2H), 1.03 (s, 3H), 0.84 (d, J = 4.3 Hz, 6H); 13 13C NMR (126 MHz, CDCl3) δ178.9, 155.1, 153.4, 149.1, 132.19, 117.5,109.8, 69.6, 58.3, 54.2, 42.2, 41.8, 37.06, 34.0, 33.8, 24.5, 22.1, 19.5,15.9; HRMS (ESI) Calculated for C 20 H 28 O3[M+Na] + : 339.1931, Found: 339.1928. Example 7: Synthesis of Compound 2.66 The synthetic route of Compound 2.66 is as follows: The specific synthesis process is as follows: Substrate 2.64a (100 mg, 0.316 mmol, 1.0 equiv) was dissolved in tetrahydrofuran (2 mL). At -78 °C, 1.0 M NaHMDS (0.475 mL, 0.475 mmol, 1.5 equiv) and CS2 (380 μL, 6.33 mmol, 20.0 equiv) were added successively, and the mixture was stirred at this temperature for 1 hour. Then, methyl iodide (390 μL, 6.33 mmol, 20.0 equiv) was added, and the mixture was stirred at this temperature for 1 hour. After the reaction was completed, the reaction was quenched with saturated ammonium chloride solution (2 mL). The mixture was extracted with ethyl acetate (5 mL × 3), and the combined organic phases were washed once with saturated brine (5 mL), then dried over anhydrous Na2SO4, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (hexanes: EtOAc = 8:1) to obtain the yellow solid product 2.66 (79.0 mg, yield 60%).

[0041] The detection data of the obtained compound 2.66 are as follows: Rf = 0.80 (silica gel, hexanes: EtOAc = 2: 1); m.p. (hexane / DCM): 100 - 105 °C; [α]22 D = -175.6 (c = 0.475, CHCl3); IR (film) 3243, 2921, 2848, 1652, 1610, 1420, 1323, 1138, 838, 809 cm –1 ; 11H NMR (300 MHz, CDCl3) δ 7.68 (d, J = 1.0, 5.8 Hz, 1H), 7.55 (s, 1H),7.05 (s, 1H), 6.31 (d, J = 5.7 Hz, 1H), 4.95 (s, 2H), 2.59 (s, 3H), 2.32 –2.23 (m, 1H), 1.99 – 1.91 (m, 1H), 1.85 – 1.77 (m, 1H), 1.72 – 1.67 (m, 1H),1.66 – 1.63 (m, 1H), 1.60 – 1.54 (m, 3H), 1.43 – 1.35 (m, 3H), 1.22 – 1.15(m, 1H), 0.93 (s, 3H), 0.84 (s, 3H), 0.82 (s, 3H); 13 13C NMR (75 MHz, CDCl3) δ 214.0, 176.7, 155.0, 153.5, 145.7, 128.3,117.3, 110.2, 56.9, 55.6, 41.9, 40.5, 39.2, 39.0, 33. 8, 33.7, 24.7, 21.9,19.5, 19.4, 16.5, 1.2; HRMS (ESI) Calculated for C 22 H 30 NaO3S2 [M+Na] + : 429.1529, Found: 429.1525. Example 8: Synthesis of Compound ottensinin (2.1) The synthetic route of Compound ottensinin (2.1) is as follows: The specific synthesis process is as follows: Dissolve substrate 2.66 (80.0 mg, 0.192 mmol, 1.0 equiv) in toluene (2 mL), and add AIBN (6.30 mg, 0.0383 mmol, 0.20 equiv) and n-Bu3SnH (100 μL, 0.383 mmol, 2.0 equiv). Place the reaction system in a Schlenk flask, freeze it with liquid nitrogen, evacuate the gas above the sample using a vacuum pump. After repeating the freeze-pump-thaw process three times, under the protection of argon, heat it at 90 ºC and stir for 4 hours. After the reaction is completed, cool the reaction system to room temperature, and then concentrate the reaction system to obtain a crude product. The crude product is purified by silica gel column chromatography (hexanes: EtOAc 10:1 → 4:1) to obtain the colorless oily product ottensinin (2.1) (29.0 mg, with a yield of 50%).

[0042] The detection data of the obtained compound ottensinin (2.1) are as follows: Rf = 0.50 (silica gel, hexanes: EtOAc = 1: 1); [α]20 D = +8.2 (c = 0.61, CHCl3); IR (film) 2925, 2849, 1695, 1649, 1617, 1388, 1325, 1259, 1215, 836 cm –1 ; 1 1H NMR (500 MHz, CDCl3) δ 7.66 (d, J = 5.7 Hz, 1H), 7.52 (s, 1H), 6.31 (d, J = 5.7 Hz, 1H), 4.81 (s, 1H), 4.46 (s, 1H), 2.69 (d, J = 16.2 Hz, 1H), 2.48 – 2.41 (m, 1H), 2.41 – 2.35 (m, 1H), 2.04 – 1.95 (m, 2H), 1.90 – 1.86 (m, 1H), 1.77 – 1.73 (m, 1H), 1.61 – 1.57 (m, 1H), 1.55 – 1.52 (m, 1H), 1.41 – 1.32 (m, 2H), 1.22 – 1.16 (m, 3H), 0.88 (s, 3H), 0.82 (s, 3H), 0.78 (s, 3H); 13 13C NMR (126 MHz, CDCl3) δ 178.8, 154.7, 153.1, 147.9, 130.0, 116.5, 107.9, 55.7, 54.1, 42.2, 40.1, 39.2, 38.2, 33.8, 33.8, 24.5, 21.9, 19.7, 19.5, 14.5; HRMS (ESI) Calcd for C 20 H 28 NaO2 [M+Na] + : 323.1982, Found: 323.1980. Example 9: Synthesis of Compound 2.67 The synthetic route of Compound 2.67 is as follows: The specific synthetic procedure is as follows: Substrate 2.38 (500 mg, 2.30 mmol, 1.0 equiv) was dissolved in diethyl ether (3 mL), and 1.6 M n n-BuLi (2.37 mL, 3.80 mmol, 1.7 equiv) was added dropwise at -78 ºC. After addition, the mixture was stirred at this temperature for 1 h. After completion of the reaction, the reaction was quenched with saturated ammonium chloride solution (2 mL). The mixture was extracted with ethyl acetate (5 mL × 3), and the combined organic phases were washed once with saturated brine (2 mL), then dried over anhydrous Na2SO4, filtered, and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (hexanes: EtOAc 20:1→10:1) to give Compound 2.67 as a colorless oil (300 mg, yield 60%).

[0043] The detection data of the obtained Compound 2.67 are as follows: Rf Rf = 0.8 (silica gel, hexanes: EtOAc = 10: 1); [α]22.5 D = +25.2 ( c c = 1.0, CH2Cl2); {[α]25 D = +47.6 ( c c = 0.2, CHCl3)} IR (film) 2923, 2865, 1672, 1610, 1459, 1375, 892, 754 cm –1 ; 1 1H NMR (500 MHz, CDCl3) δ 10.03 (s, 1H), 2.57 – 2.52 (m, 1H), 2.28 –2.22 (m, 2H), 2.01 (s, 3H), 1.73 – 1.56 (m, 2H), 1.49 – 1.36 (m, 3H), 1.17(s, 3H), 1.16 – 1.14 (m, 1H), 1.07 (dd, J J = 2.0, 12.6 Hz, 1H), 1.01 – 0.92(m, 1H), 0.88 (s, 3H), 0.84 (s, 3H); 13 13C NMR (125 MHz, CDCl3) δ 192.77, 153.78, 143.83, 51.69, 41.73,37.68, 36.70, 36.35, 33.55, 33.44, 21.77, 20.27, 19.28, 19.01, 18.42; HRMS (ESI) calcd for C 15 H 25 O + [M+H] + 221.1900, found 221.1895. Example 10: Synthesis of Compound 2.68 The synthetic route of Compound 2.68 is as follows: The specific synthesis process is as follows: Dissolve 3-iodo-4 H -pyran-4-one 2.24 (75.3 mg, 0.339 mmol, 1.5 equiv) in diethyl ether (1 mL), and dropwise add 1.6 M n-BuLi (0.240 mL, 0.384 mmol, 1.7 equiv). After addition, stir at this temperature for 1 hour. Dissolve substrate 2.67 (50 mg, 0.226 mmol, 1.0 equiv) in diethyl ether (1 mL) and add dropwise to the reaction system. Stir at -95 ºC for 1 hour. After the reaction is complete, quench the reaction by adding saturated ammonium chloride solution (2 mL). Extract with ethyl acetate (5 mL × 3). Wash the combined organic phases once with saturated brine (2 mL), then dry over anhydrous Na2SO4, filter, and concentrate to obtain the crude product. Purify the crude product by silica gel column chromatography (hexanes: EtOAc 4:1) to obtain the colorless solid product 2.68 (33.6 mg, yield 47%).

[0044] The detection data of the obtained compound 2.68 are as follows: Rf = 0.50 (silica gel, hexanes: EtOAc = 1: 1); m.p. (hexane / DCM): 153 - 154 ºC; [α]22.5 D= +59.1 ( c = 1.0, CH2Cl2); IR (film) 3385, 3303, 2928, 2858, 1643, 1592, 1320, 734 cm –1 ; 1 1H NMR (500 MHz, CDCl3) δ 7.78 (dd, J = 1.0, 5.7 Hz, 1H), 7.57 (s,1H), 6.40 (d, J = 5.7 Hz, 1H), 5.54 (s, 1H), 4.85 (s, 1H), 2.10 – 1.99 (m,3H), 1.74 – 1.69 (m, 1H), 1.65 (s, 3H), 1.63 – 1.52 (m, 2H), 1.47 – 1.31 (m,3H), 1.27 – 1.23 (m, 1H), 1.22 – 1.15 (m, 1H), 0.91 (s, 3H), 0.90 (s, 3H),0.84 (s, 3H); 1313C NMR (125 MHz, CDCl3) δ 180.96, 155.89, 153.78, 137.22, 130.76, 117.16, 65.53, 52.12, 41.46, 38.95, 36.41, 34.78, 33.43, 22.92, 22.58, 21.77, 20.78, 19.20, 19.01; HRMS (ESI) calcd for C 20 H 29 O3 + [M+H] + 317.2111, found 317.2101. Example 11: Synthesis of Compound 2.7 The synthetic route of Compound 2.7 is as follows: The specific synthesis process is as follows: At 0 °C, DMDH (3.9 g, 40.0 mmol, 2.0 equiv) was dissolved in dichloromethane (40 mL), and 2.0 M Me3Al (22 mL, 44.0 mmol, 2.2 equiv) was added dropwise. After the addition was complete, the mixture was stirred at room temperature for 2 hours. The substrate sclareolide (2.6) (5.0 g, 20.0 mmol, 1.0 equiv) was dissolved in dichloromethane (40 mL) and stirred at room temperature for 2 hours. After the reaction was complete, it was quenched with 2 M H2SO4, extracted with dichloromethane (200 mL × 3), and the combined organic phases were washed once with saturated brine (50 mL), then dried over anhydrous Na2SO4, filtered, and concentrated to obtain a crude product. This crude product was purified by silica gel column chromatography (hexanes: EtOAc 1:1 → 2:3) to obtain the white solid product 2.7 (6.05 g, yield 97%).

[0045] The detection data of the obtained Compound 2.7 are as follows: Rf = 0.30 (silica gel, hexanes: EtOAc = 1: 1); m.p. (hexane / DCM): 122 - 124 °C; [α]22 D = +35.6 ( c = 1.0, CHCl3); lit {[α]23 D = +36.7( c = 1.63 in CHCl3)} IR (film) 3245, 2921, 1775, 1644, 1458, 1382, 1096, 1000 cm –1 ; 1 1H NMR (500 MHz, CDCl3) δ 3.70 (s, 3H), 3.16 (s, 3H), 2.61 – 2.39 (m, 3H), 1.99 – 1.88 (m, 2H), 1.70 – 1.61 (m, 1H), 1.61 – 1.53 (m, 1H), 1.52 – 1.46 (m, 1H), 1.46 – 1.37 (m, 2H), 1.37 – 1.30 (m, 1H), 1.30 – 1.20 (m, 1H), 1.13 (s, 3H), 1.04 – 0.92 (m, 2H), 0.85 (s, 3H), 0.80 (s, 3H), 0.77 (s, 3H); 13 13C NMR (125 MHz, CDCl3) δ 176.37,, 72.97, 61.33, 56.34, 55.97, 44.61, 41.85, 39.25, 38.69, 33.45, 33.35, 32.71, 26.98, 23.40, 21.50, 20.66, 18.56, 15.89; HRMS (ESI) calcd for C 18 H 33 NaNO3 + [M+Na] + 334.2353, found 334.2344. Example 12: Synthesis of Compound 2.29 The synthetic route of Compound 2.29 is as follows: The specific synthesis process is as follows: Compound 2.7 (5.0 g, 16.1 mmol, 1.0 equiv) was dissolved in dichloromethane (100 mL). At -78 ºC, pyridine (13.0 mL, 161 mmol, 10.0 equiv) and thionyl chloride (5.84 mL, 80.5 mmol, 5.0 equiv) were added successively. The mixture was stirred at this temperature for 2 hours. After the reaction was completed, saturated sodium bicarbonate solution (20 mL) was added to quench the reaction. The mixture was extracted with dichloromethane (200 mL × 3). The combined organic phases were washed once with saturated brine (100 mL), then dried over anhydrous Na2SO4, filtered, and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (hexanes: EtOAc = 10:1 → 5:1) to give the colorless oily product 2.29 (4.5 g, yield 95%).

[0046] The detection data of the obtained compound 2.29 are as follows: Rf = 0.5 (silica gel, hexanes: EtOAc = 2:1); m.p. (hexane / DCM): 89 - 92 ºC; [α]22 D = –37.8 ( c = 1.0, CHCl3); lit {[α]23 D = +45.7 ( c = 0.94 in CHCl3)} IR (film) 2933, 2867, 2843, 1667, 1644, 1459, 1440, 1382 cm –1 ; 1 1H NMR (300 MHz, CDCl3) δ 4.71 (s, 1H), 4.41 (s, 1H), 3.70 (s, 3H), 3.13 (s, 3H), 2.67 (t, J = 13.5 Hz, 1H), 2.48 (d, J= 9.6 Hz, 1H), 2.41 – 2.32 (m, 2H), 2.16 – 2.07 (m, 1H), 1.76 – 1.65 (m, 1H), 1.59 – 1.41 (m, 4H), 1.41 – 1.28 (m, 2H), 1.31 – 1.06 (m, 3H), 0.86 (s, 3H), 0.79 (s, 3H), 0.71 (s, 3H); 13 C NMR (75 MHz, CDCl3) δ 174.80, 149.74, 105.88, 61.36, 55.09, 51.68, 42.10, 38.98, 38.92, 37.67, 33.64, 33.56, 32.54, 27.24, 24.10, 21.82, 19.37, 14.80; HRMS (ESI) calcd for C 18 H 32 NO2 + [M+H] + 294.2428, found 294.2428. Example 13: Synthesis of Compound 2.17 The synthetic route of Compound 2.17 is as follows: Dissolve substrate 2.29 (1.0 g, 3.41 mmol, 1.0 equiv) in tetrahydrofuran. At -40 °C, add lithium aluminum hydride (259 mg, 6.82 mmol, 2.0 equiv) successively, and stir at this temperature for 3 hours. After the reaction is completed, at 0 °C, add saturated sodium potassium tartrate solution (20 mL) and stir for half an hour to quench the reaction. Then extract with ethyl acetate (200 mL × 3), wash the combined organic phases once with saturated brine (50 mL), and then dry over anhydrous Na2SO4, filter, and concentrate to obtain the crude product. The crude product is purified by silica gel column chromatography (hexanes: EtOAc 100:1 → 50:1) to obtain the yellow oily product 2.17 (666 mg, yield 83%).

[0047] The detection data of the obtained Compound 2.17 are as follows: Rf = 0.80 (silica gel, hexanes: EtOAc = 5: 1); [α]23 D = –27.0 (c = 1.0, CHCl3); {[α]25 D = –25.2 ( c = 0.76 in CHCl3)} IR (film) 3344, 2924, 2867, 2846, 1708, 1644, 1459, 969 cm –1 ; 1 H NMR (500 MHz, CDCl3) δ 9.62 (s, 1H), 4.80 (s, 1H), 4.38 (s, 1H), 2.50 – 2.43 (m, 2H), 2.42 – 2.38 (m, 1H), 2.35 (dd, J = 4.3, 10.3 Hz, 1H), 2.15 – 2.01 (m, 1H), 1.77 – 1.72 (m, 1H), 1.58 – 1.53 (m, 2H), 1.53 – 1.44 (m, 1H), 1.44 – 1.37 (m, 1H), 1.34 (dd, J = 4.4, 13.0 Hz, 1H), 1.20 (dd, J = 2.8, 12.7 Hz, 2H), 1.13 – 1.04 (m, 1H), 0.89 (s, 3H), 0.81 (s, 3H), 0.70 (s, 3H); 13 C NMR (125 MHz, CDCl3) δ 203.61, 148.64, 108.12, 55.36, 51.08, 42.11, 39.94, 39.48, 39.02, 37.60, 33.65, 33.63, 24.01, 21.82, 19.34, 14.70; HRMS (ESI) calcd for C 16 H 26 Na + [M+Na] + 257.1876, found 257.1871. Example 14: Synthesis of Compound 2.34 The synthetic route of Compound 2.34 is as follows: The specific synthesis process is as follows: 3-Iodo-4 H-Pyran-4-one (2.24 g, 143 mg, 3.46 mmol, 1.5 equiv) was dissolved in diethyl ether (3 mL). At -95 °C, 2.5 M n -BuLi (0.292 mL, 0.729 mmol, 1.7 equiv) was added dropwise. After the addition, the mixture was stirred at this temperature for 1 h. Substrate 2.17 (100 mg, 0.429 mmol, 1.0 equiv) was dissolved in diethyl ether (3 mL) and added dropwise to the reaction system. The mixture was stirred at -95 °C for 1 h. After the reaction was completed, saturated ammonium chloride solution (2 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (5 mL × 3). The combined organic phases were washed once with saturated brine (2 mL), then dried over anhydrous Na2SO4, filtered, and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (hexanes: EtOAc 10:1 → 4:1) to obtain a colorless oily product 2.34 (66 mg, yield 47%).

[0048] The detection data of the obtained compound 2.34 are as follows: Rf = 0.50 (silica gel, hexanes: EtOAc = 2: 1); [α]22 D = +32.9 ( c = 1.0, CHCl3); IR (film) 2924, 2866, 2845, 1647, 1600, 1436, 1142, 837 cm –1 ; 1 1H NMR (500 MHz, CDCl3) δ 7.77 (s, 1H), 7.74 (d, J = 5.8 Hz, 1H), 6.35(d, J = 5.7 Hz, 1H), 4.87 (d, J = 1.6 Hz, 1H), 4.64 (s, 1H), 4.53 (dd, J =2.3, 10.2 Hz, 1H), 2.44 – 2.37 (m, 1H), 2.11 (d, J = 11.2 Hz, 1H), 2.09 –2.00 (m, 1H), 1.92 (dd, J= 10.2, 14.2 Hz, 1H), 1.78 – 1.69 (m, 3H), 1.59 –1.43 (m, 2H), 1.41 – 1.30 (m, 2H), 1.26 – 1.16 (m, 2H), 1.13 – 1.06 (m, 1H),0.87 (s, 3H), 0.79 (s, 3H), 0.66 (s, 3H); 13 C NMR (125 MHz, CDCl3) δ 179.08, 155.47, 151.86, 148.91, 132.54,117.50, 106.87, 67.79, 55.55, 52.29, 42.22, 39.45, 39.09, 38.39, 33.73,30.76, 24.49, 21.81, 19.43, 14.77; HRMS (ESI) calcd for C 21 H 30 NaO3 + [M+Na] + 353.2087, found 353.2086. Example 15: Synthesis of Compound 2.33 The synthetic route of Compound 2.33 is as follows: The specific synthesis process is as follows: Dissolve the substrate 2.34 (200 mg, 0.606 mmol, 1.0 equiv) in tetrahydrofuran (2 mL). At -78 °C, sequentially add 1.0 M NaHMDS (0.60 mL, 1.21 mmol, 2.0 equiv) and CS2 (727 μL, 12.1 mmol, 20.0 equiv), and stir at this temperature for 1 hour. Then, add methyl iodide (755 μL, 12.1 mmol, 20.0 equiv), and stir at this temperature for 1 hour. After the reaction is complete, quench the reaction with saturated ammonium chloride solution (2 mL). Extract with ethyl acetate (5 mL × 3), wash the combined organic phase once with saturated brine (5 mL), and then dry over anhydrous Na2SO4, filter, and concentrate to obtain the crude product. Dissolve the crude product in toluene (2 mL), add AIBN (19.8 mg, 0.121 mmol, 0.20 equiv) and n-Bu3SnH (325 μL, 1.21 mmol, 2.0 equiv). The reaction system was placed in a Schlenk flask, frozen with liquid nitrogen, and the gas above the sample was evacuated using a vacuum pump. After repeating the freeze-pump-thaw process three times, the reaction was stirred under argon protection at 90 ºC for 4 hours until completion. The reaction system was cooled to room temperature, and the reaction mixture was concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (hexanes: EtOAc 10:1 → 4:1) to give a colorless oil product 2.33 (114 mg, yield 63%).

[0049] The detection data of the obtained compound 2.33 are as follows: Rf = 0.80 (silica gel, hexanes: EtOAc = 2: 1); [α]23 D= +27.1 ( c = 1.0, CHCl3); IR (film) 3358, 2960, 2919, 2848, 1647, 1437, 1260, 796 cm –1 ; 1 1H NMR (500 MHz, CDCl3) δ 7.68 (d, J = 5.8 Hz, 1H), 7.59 (s, 1H), 6.30(d, J = 5.8 Hz, 1H), 4.85 (d, J = 2.0 Hz, 1H), 4.64 (d, J = 2.0 Hz, 1H), 2.59– 2.48 (m, 1H), 2.40 – 2.34 (m, 1H), 2.13 – 2.01 (m, 1H), 1.98 – 1.90 (m,1H), 1.76 – 1.65 (m, 3H), 1.60 (d, J = 11.7 Hz, 1H), 1.57 – 1.40 (m, 2H),1.37 – 1.33 (m, 1H), 1.30 (dd, J = 4.2, 13.0 Hz, 1H), 1.15 (dd, J = 4.2, 13.5Hz, 1H), 1.05 (dd, J= 2.8, 12.6 Hz, 1H), 0.99 – 0.88 (m, 2H), 0.84 (s, 3H), 0.77 (s, 3H), 0.64 (s, 3H); 13 C NMR (125 MHz, CDCl3) δ 178.63, 155.11, 151.90, 148.20, 131.10, 116.80, 106.83, 56.59, 55.61, 42.21, 39.72, 39.10, 38.40, 33.69, 33.65, 25.08, 24.50, 22.03, 21.80, 19.41, 14.58; HRMS (ESI) calcd for C 21 H 30 NaO2 + [M+Na] + 337.2138, found 337.2140. Experiment 1: Cytotoxicity Detection of Different Compounds To explore the antitumor effects of the compounds obtained in the present invention, the following detections were respectively carried out using human colon cancer cells as experimental subjects in this example: Cell culture: HCT-116 (human colon cancer cells, purchased from Shanghai Institute of Life Sciences, Chinese Academy of Sciences) cells were cultured at 37°C in an environment of 5% CO2. The culture medium was high-glucose Dulbecco’s Modified Eagle Medium (DMEM) (purchased from: Gibco, product number: C11995500BT), which was supplemented with 10% fetal bovine serum (FBS) (purchased from: Vazyme, product number: F101-01) and 1% penicillin-streptomycin solution (purchased from: Biosharp, product number: BL505A). When the cells were cultured to 70 - 80% confluence, subculture operations were performed, and the experimental generations were within five generations.

[0050] Cell treatment: Select the cells in the above logarithmic growth phase, count the cell suspension using a cell counter, and adjust its concentration to 5×10 4 cells / mL. The cell suspension was inoculated into a 96-well culture plate, with a volume of 100 μL per well, and cultured overnight to ensure that the cells adhered well. Subsequently, the original culture medium was replaced with fresh culture medium containing different final concentrations of the compound, and the cells were continuously cultured for 72 hours.

[0051] Cell viability detection: Add 10 μL of MTT reagent to each well of a 96-well culture plate and incubate at 37 °C for 2 hours. Measure the optical density (OD) value of each well at a wavelength of 450 nm using a microplate reader. The formula for calculating cell viability is as follows: Viability (%) = (OD value of the drug-treated group - OD value of the blank control) / (OD value of the untreated control group - OD value of the blank control group) × 100.

[0052] The formula for calculating the cell growth inhibition rate is as follows: Cell growth inhibition rate (%) = 1 - (absorbance of the drug group / absorbance of the control group) × 100%.

[0053] The statistical results of cell viability are shown in Figure 6 . As Figure 6 shown, some treatment groups showed obvious cytotoxic effects on HCT-116 cells. The viability was less than 20% at a final concentration of 100 mM of the compounds, including compounds 2.64a, 2.64b, 2.66, 2.68, 2.33, 2.34, ottensinin. The above results indicate that compounds 2.64a, 2.64b, 2.66, 2.68, 2.33, 2.34, ottensinin have certain abilities to inhibit anti-tumor cell proliferation in vitro.

[0054] The effects of each compound on cell activity are shown in Figure 7 . As Figure 7 shown, all 6 Ottensinin derivatives have the ability to inhibit HCT116 cells, and with the increase of the compound concentration, the inhibitory effect on HCT116 cells becomes more obvious. The highest inhibition rate of each compound on HCT116 cells can reach 91.87% (100 mM). In addition, due to different functional groups, their cytotoxicities are also different.

[0055] The half-inhibitory concentration IC 50 of each compound on HCT 116 cells. The statistical results are shown in Table 1. As shown in Table 1, after different functional groupizations of ottensinin, the corresponding Ottensinin derivatives are obtained. After detection, the IC 50 of this type of Ottensinin derivative changes. When the oxidation state increases, IC decreases. When the double bond is isomerized, IC 50 increases. Extending the length of the C9 carbon chain will increase the IC 50 value, reducing its cytotoxicity.

[0056] Table 1 IC 50 The above are only the preferred embodiments of the present invention, and do not impose any form of limitation on the present invention. Although the present invention has been disclosed above with the preferred embodiments, it is not intended to limit the present invention. Any person skilled in the art can make some changes or modifications to equivalent embodiments by using the methods and technical contents disclosed above within the scope of the technical solution of the present invention. However, as long as it does not depart from the content of the technical solution of the present invention, any simple modification, equivalent change and modification made to the above embodiments according to the technical essence of the present invention still fall within the scope of the technical solution of the present invention.

Claims

1. A compound of formula I or II or a pharmaceutically acceptable salt thereof: Among them, R represents α-OH, β-OH or OCSSMe; n is 0 or 1.

2. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that, The compound represented by Formula I is any of the following compounds: 。 3. A pharmaceutical composition, characterized in that, The pharmaceutical composition comprises: (1) a compound of formula I as claimed in claim 1 or 2 or a pharmaceutically acceptable salt thereof, and (2) a pharmaceutically acceptable excipient.

4. Use of a compound of formula I as claimed in claim 1 or 2 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as claimed in claim 3 in the manufacture of a medicament for the treatment and / or prevention of a disease associated with abnormal cell activity.

5. The application according to claim 4, wherein The disease associated with abnormal cell activity is selected from tumors.

6. The application according to claim 5, wherein The tumor is colon cancer.

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