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Marine microorganism derived sesterterpene Asperterpinol B derivative and synthesis method as well as application of saccharidase

A technology of disesquiterpenes and derivatives is applied in the application field of α-glucosidase inhibitor drugs, and can solve the problems of adverse reactions of hypoglycemia, weight gain of patients, inability to completely control postprandial blood sugar and the like

Active Publication Date: 2018-06-22
SOUTH CHINA NORMAL UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Drugs currently on the market for the treatment of diabetes have been developed, such as acarbose, metformin, glimepiride, and repaglinide, but these drugs have adverse reactions such as swelling, abdominal distension, flatulence, diarrhea, and intestinal air sac swelling , long-term use will lead to weight gain in patients, prone to adverse reactions of hypoglycemia (Kihara et al., 1997; Güemes et al., 2016)
Although diabetes drugs can better control fasting blood sugar levels, they cannot completely control the rise in postprandial blood sugar

Method used

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  • Marine microorganism derived sesterterpene Asperterpinol B derivative and synthesis method as well as application of saccharidase
  • Marine microorganism derived sesterterpene Asperterpinol B derivative and synthesis method as well as application of saccharidase
  • Marine microorganism derived sesterterpene Asperterpinol B derivative and synthesis method as well as application of saccharidase

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028] AsB-1:(2aS,6aS,6bS,12S,12aS,13R,13aS,Z)-2a,5,5,9,12,13a-hexamethyl-2,2a,3,4,5,6,6a, Synthesis of 6b,7,8,12,12a,13,13a-tetradecahydro-1H-cyclopenta[4,5]cycloocta[1,2-a]naphthalen-13-ol

[0029]

[0030] Experimental steps:

[0031] Weigh AsB (38.7mg, 0.103mmol, 1eq) in a 50ml round bottom flask, add 2ml of dichloromethane to dissolve, add boron trifluoride ether (mass fraction 46.5%-49.5%) dropwise into 1ml syringe (50ul, 0.135mmol , 1.3eq) in the solution, stirring at room temperature for half an hour, adding triethylamine to stop the reaction after half an hour, adjusting the pH to neutral, adding 15ml of saturated saline and dichloromethane (3×20ml) for extraction, and separating the organic phase, dried by adding anhydrous magnesium sulfate, and distilled under reduced pressure to obtain a crude product. Column chromatography of a petroleum ether / ethyl acetate system (V:V=1:10) gave 38.5 mg of a white solid with a yield of 95%.

[0032] White solid, yield 95%, m...

Embodiment 2

[0035] AsB-S 1 :(2aS,6aS,6bS,11R,12R,12aS,13R,13aS,Z)-13-hydroxy-2a,5,5,9,12,13a-hexamethyl-2,2a,3,4,5,6 ,6a,6b,7,8,10,11,12,12a,13,13a-hexadecahydro-1H-cyclopenta [4,5]cycloocta[1,2-a]naphthalen-11-yl acetate synthesis

[0036]

[0037] Experimental steps:

[0038] Weigh AsB (42.3mg, 0.11mmol, 1eq) in a 50ml two-necked round-bottom flask, add 2ml of anhydrous pyridine to dissolve, add anhydride (1.1mmol, 10eq), put it in an oil bath at 90°C to condense and reflux for reaction, and follow the reaction by TLC until The response is complete. Cool to room temperature and add 2M HCl solution to stop the reaction, adjust the pH of the solution to 2, stir for 15 minutes, add saturated brine 15ml and EA (3×15ml) to extract the organic phase, dry over anhydrous magnesium sulfate, and distill under reduced pressure to obtain the crude product, petroleum A pure white solid was obtained by column chromatography of ether ethyl acetate system (V:V=1:2).

[0039] White solid, yield 6...

Embodiment 3

[0042] AsB-S 2 :(2aS,6aS,6bS,11R,12R,12aS,13R,13aS,Z)-13-hydroxy-2a,5,5,9,12,13a-h examethyl-2,2a,3,4,5, Synthesis of 6,6a,6b,7,8,10,11,12,12a,13,13a-hexadecahydro-1H-cyclopenta[4,5]cycloocta[1,2-a]naphthalen-11-yl butyrate

[0043]

[0044] Experimental procedure: with embodiment 2

[0045] White solid, yield 72.04%, m.p.51.7-54.7℃. 1 H NMR (500MHz, CDCl 3 )δ4.75 (d, J = 6.5Hz, 1H), 4.57 (d, J = 10.7Hz, 1H), 3.01 (d, J = 1.8Hz, 1H), 2.78 (dd, J = 17.8, 6.5Hz, 1H), 2.62(t, J=14.8Hz, 1H), 2.22(ddd, J=18.3, 14.3, 7.0Hz, 4H), 1.73–1.65(m, 3H), 1.64(d, J=0.5Hz, 1H ),1.63(s,3H),1.62–1.49(m,2H),1.43–1.36(m,2H),1.35–1.24(m,6H),1.19–1.09(m,3H),1.08(s,3H ),0.97–0.92(m, 3H),0.91(s,3H),0.88(d,J=6.8Hz,6H),0.77(s,3H).

[0046] HRMS(ESI)for[M+Na] + :calcd for C 29 h 48 o 3 Na: 467.34957. Found: 467.3492.

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Abstract

The invention discloses a marine microorganism derived sesterterpene Asperterpinol B derivative and a synthesis method as well as application of saccharidase. The marine microorganism derived sesterterpene Asperterpinol B derivative is an ester type derivative with a chemical formula shown as a structural formula I, an amide type derivative shown as a structural formula II, a five-membered ring dehydrated derivative shown as a structural formula III or an eight-membered ring dehydrated derivative shown as a structural formula IV, or pharmaceutically acceptable salts or stereoisomers thereof ora prodrug molecule thereof: the formula I, the formula II, the formula III and the formula IV are shown in the description, wherein R0 is X-substituted alkane, alkene, alkyne, cycloalkane or phenyl with the carbon atom number of 1 to 10, ; X is H, Cl, Br, F, I, CN, NO2, CF3, OH, OCH3, COOH or COOCH3; R1 and R2 are alkane, alkene, alkyne, cycloalkane, N / O / S heterocycle or phenyl with the carbon atom number of 1 to 10; X is H, Cl, Br, F, I, CN, NO2, CF3, OH, OCH3, COOH or COOCH3. According to the marine microorganism derived sesterterpene Asperterpinol B derivative provided by the invention, anAsperterpinol B structure is modified to obtain a series of compounds with very good alpha-glucosidase activity and a new candidate drug molecule is provided for clinical treatment of diabetes mellitus.

Description

technical field [0001] The present invention relates to the field of medicinal chemistry, in particular, to the preparation of sesquiterpene Asperterpinol B (Ze'en et al., 2013) derivatives derived from marine microorganisms and the use of derivatives thereof in α-glucosidase inhibitor drugs Applications. Background technique [0002] Diabetes mellitus (DM) is a metabolic disease associated with abnormal insulin production and action and characterized by hyperglycemia. Diabetes is mainly divided into two categories: type 1 diabetes, which is mainly caused by absolute insulin deficiency, and type Ⅱ diabetes, which is mainly caused by relative insulin deficiency and insulin resistance. With the improvement of people's living standards, diabetes mellitus (DM) is becoming more and more serious to human health and has become a global public health problem. According to relevant statistics from the International Diabetes Federation (IDF), there were about 415 million people with...

Claims

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Application Information

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IPC IPC(8): C07J63/00A61K31/56A61P3/10
CPCC07J63/00
Inventor 龙玉华李婷妹佘志刚范炜隆温世彤颜樟元郭惠娴黄翠莹蒋腊生
Owner SOUTH CHINA NORMAL UNIVERSITY
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