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Novel gossypol derivatives, and preparation method and antineoplastic application thereof

A derivative, the technology of gossypol, applied in the field of novel gossypol derivatives and their preparation, anti-tumor applications, can solve the problems such as the inability to exert the maximum biological activity of the compound, the reduction of antiviral biological activity, the influence of antiviral activity, etc., and achieve excellent Biological activity, resolving toxic aldehyde groups, simple post-processing effects

Active Publication Date: 2015-08-05
江苏度未生物工程科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] Experiments have confirmed that the 6, 7 or 6', 7' phenolic hydroxyl groups are necessary for antiviral and other biological activities. If the phenolic hydroxyl is replaced, the antiviral and other biological activities will be reduced or lost (V.T.Dao, C.Gaspard, M. Mayer, G.H.Werner, S.N.Nguyen, R.J.Michelot, Eur.J.Med.Chem.2000, 35, 805-813.), but the phenolic hydroxyl tautomers at the 7 and 7′ positions of such gossypol modification products are carbonyl groups, The antiviral activity is affected, and the maximum biological activity of this type of compound cannot be exerted
Therefore, it is a challenge for the field of organic synthesis to obtain a modified product that can not only retain the phenolic hydroxyl group of gossypol activity to the greatest extent, but also modify the toxic aldehyde group of gossypol.

Method used

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  • Novel gossypol derivatives, and preparation method and antineoplastic application thereof
  • Novel gossypol derivatives, and preparation method and antineoplastic application thereof
  • Novel gossypol derivatives, and preparation method and antineoplastic application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] Example 1: 2,2'-(1,1',6,6',7,7'-hexahydroxy-5,5'-diisopropyl-3,3'-dimethyl-[2, Preparation of 2'-binaphthyl]-8,8'-diyl)bis(N-benzyl-2-oxoacetamide)

[0031] Take (346mg, 0.6mmol, 1.0eq) gossypol acetate and place it in a 10mL single-necked round-bottomed flask, add 2.5mL of ethanol and 100uL of water, and add (2.2eq) of isocyanide 1( ), the addition was completed, the reflux condenser was installed, and the temperature was slowly raised to 80°C. After 24 hours, the TCL detection reaction was basically complete. After standing still, the solid was precipitated, filtered with suction, and the filter residue was washed 3 times with ethanol to obtain a yellow solid with a yield of 53%.

[0032]

[0033] 1 H NMR (400MHz, CDCl 3 )δ=13.60(s,1H),9.73(d,J=12.2,1H),7.95(s,1H),7.59(s,1H),7.38–7.27(m,5H),5.59(s,1H) ,4.67(d,J=4.3,2H),3.81–3.65(m,1H),2.11(s,3H),1.52(dd,J=6.8,4.8,6H). 13 C NMR (100MHz, CDCl 3 )δ=172.98,163.00,149.04,147.12,136.24,132.01,129.07,128.24,127.60,...

Embodiment 2

[0034] Example 2: 2,2'-(1,1',6,6',7,7'-hexahydroxy-5,5'-diisopropyl-3,3'-dimethyl-[2, Preparation of 2'-binaphthyl]-8,8'-diyl)bis(N-cyclohexyl-2-oxoacetamide)

[0035] Take (346mg, 0.6mmol, 1.0eq) gossypol acetate and place it in a 10mL single-necked round-bottomed flask, add 2.5mL of ethanol and 100uL of water, and add (2.2eq) of isonitrile 2( ), the addition was completed, the reflux condenser was installed, and the temperature was slowly raised to 80°C. After 24 hours, the TCL detection reaction was basically complete. After standing still, the solid was precipitated, filtered with suction, and the filter residue was washed 3 times with ethanol to obtain a yellow solid with a yield of 66%.

[0036]

[0037] 1 H NMR (400MHz, CDCl 3 )δ=13.40(s,1H),9.72(d,J=7.7,1H),8.04(s,1H),7.59(s,1H),5.64(s,1H),3.86–3.64(m,1H) ,3.48–3.28(m,1H),2.12(s,3H),2.00(m,2H),1.85–1.75(m,2H),1.66–1.57(m,2H),1.54–1.48(m,7H) ,1.39–1.23(m,3H). 13 C NMR (100MHz, CDCl 3)δ=172.12, 160.88, 148.90,...

Embodiment 3

[0038] Example 3: 2,2'-(1,1',6,6',7,7'-hexahydroxy-5,5'-diisopropyl-3,3'-dimethyl-[2, Preparation of 2'-binaphthyl]-8,8'-diyl)bis(N-(1-adamantyl)-2-oxoacetamide)

[0039] Take (346mg, 0.6mmol, 1.0eq) gossypol acetate and place it in a 10mL single-necked round-bottomed flask, add 2.5mL of ethanol and 100uL of water, and add (2.2eq) of isonitrile 3( ), the addition was completed, the reflux condenser was installed, and the temperature was slowly raised to 80°C. After 24 hours, the TCL detection reaction was basically complete. After standing still, the solid was precipitated, filtered with suction, and the filter residue was washed 3 times with ethanol to obtain a gray-yellow solid with a yield of 70%.

[0040]

[0041] 1 H NMR (400MHz, CDCl 3 )δ=13.57(d,J=15.0,1H),9.80(d,J=12.5,1H),7.61(s,1H),5.60(brs,1H),3.79–3.66(m,1H),2.17( m,3H),2.12(s,3H),1.94(m,5H),1.82–1.62(m,7H),1.57–1.49(m,6H). 13 C NMR (100MHz, CDCl 3 )δ=171.77, 158.07, 148.84, 147.30, 131.49, 128.87, 126.94...

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Abstract

The invention specifically discloses novel gossypol derivatives, and a preparation method and application thereof, belonging to the technical field of organic synthesis. According to the method, gossypol and isonitrile are used as raw materials and undergo a stirring reaction in a polar solvent at 70 to 80 DEG C for 24 and 36 h, then simple filtering and separating are carried out, and thus, a series of the gossypol derivative with modified aldehyde groups are prepared through one-step reaction. The preparation method and post-treatment are simple; a reaction system is mild; and the synthesized novel gossypol derivatives retain all the active phenolic hydroxyl groups unique to gossypol to a greatest extent, and it is estimated that all the excellent biological activities of gossypol are retatined and the problem of toxic aldehyde groups carried by gossypol is overcome. Most of the gossypol derivatives prepared in the invention have good anti-prostatic cancer activity and can be applied in the antineoplastic field.

Description

technical field [0001] The invention belongs to the field of organic synthesis and medicine, and relates to a novel gossypol derivative, its preparation method and anti-tumor application. Background technique [0002] Gossypol is a yellow polyphenolic compound that occurs naturally in certain plants in the Malvaceae family. Gossypol as a toxic natural product has received little attention until its antineoplastic (Jaroszewski, J.W.; Kaplan, O.; Cohen, J.S. Cancer Res. 1990, 50, 6936-6943) and antifertility (Waller, D.P.; Zaneveld, L.J.; Fong,H.H.Contraception 1980,22,183–187) was discovered, and recent studies have shown that gossypol also has antimalarial properties (Deck,L.M.,R.E.Royer,B.B.Chamblee,V.M.Hernandez,R.R.Malone,J.E.Torres,L.A.Hunsaker,R.C. Piper, M.T. Makler, and D.L. Vander Jagt, J.Med.Chem.1998, 41, 3879-3887), antiparasitic (Montamat, E.E.; Burgos, C.; Gerez de Burgos, N.M.; Rovai, L.E.; Blanco, A.; Segura, E.L.Science 1982,218,288-289) and antiviral (Dors...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C235/80C07C231/10C07D307/52C07C323/59C07C319/20C07D317/58A61P35/00
Inventor 王巍卢育智李长浩杨剑周海兵
Owner 江苏度未生物工程科技有限公司
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