Synthesis,Bioactivity And Structure-activity Relationship Studies Of Natural Product Gossypol And Its Derivatives

Gossypol,a polyhydroxy dinaphthaldehyde natural product,has drawn extensive attention due to its broad spectrum of biological activity.A current synthetic strategy to obtain varied gossypol derivatives is mainly based on semisynthesis approach.Among the reported gossypol derivatives,only a few of the known derivatives have been tested their medicinal activities.Gossypol is a part of a plant's defense system against pathogenic fungi and insects,however,the structure-activity relationships(SAR)in the pesticide field have never been reported.Therefore,how to obtain the target products with variety of structures as well as controllable biological activities via appropriate chemical approaches is the research direction for the botanical pesticide—gossypol.This dissertation is associated with the diverted total synthesis of gossypol and its novel derivatives,and synthesis of four series of gossypol derivatives together with their exploration in the field of pesticide science.The main contributions of this dissertation are as follows:1.DDQ/TFA and air/NO~+oxidative systems for the construction of phenanthrenes from 1,2-diphenyl ethene have been developed,and the air/NO~+oxidative system was further extended to the intermolecular oxidative homocoupling reaction to form biaryls.This provides a probable synthetic strategy for the construction of binaphthyl framework of gossypol.It should be noted that the coupling reaction of benzylic C(sp~3)-H and benzene C(sp~2)-H proceeded when the substrate was substituted benzyl cyanide.2.A practical and scalable route for the total synthesis of gossypol was developed.Hemigossypol,the biosynthetic precursor of gossypol,was synthesized on a gram scale by using Stobbe condensation,electrophilic cyclization,and Michael addition of ortho-quinone methide as key steps from commercially available carvacrol and dimethyl succinate,which was further converted to gossypol via a biosynthetic process in a nonenzymatic condition.More importantly,the intermediates could be used to synthesize gossypol or hemigossypol derivatives with structural diversity.3.To reduce the toxicity of gossypol and enhance rigidity of plane structure formed by the naphthalene ring and pseudo six-membered ring linked by hydrogen bonds,a series of aromatic gossypol Schiff bases were prepared.The results of bioassays indicated that most of these derivatives exhibited excellent anti-TMV activity,in which o-trifluoromethylaniline Schiff base(5-17)displayed the best antiviral activity,which showed equivalent activity at a concentration of 100?g/m L to gossypol at 500?g/m L,thus emerged as potential inhibitor of plant virus.These compounds also exhibited good fungicidal activities against 14 kinds of plant fungi in vitro.Compared with gossypol,these aromatic gossypol Schiff bases were benefit to the inhibitory activities against Fusarium graminearum,Phytophthora capsici,Sclerotinia sclerotiorum and Fusarium oxysporium f.sp.Cucumeris.4.In order to increase the solubility of gossypol derivatives,study the influence of tautomeric forms of gossypol Schiff bases,and maintain the rigidity of plane structure mentioned above,a series of gossypol Schiff bases with aliphatic amine,oxime,and hydrazine were synthesized.The results of bioassays showed that most of the compounds exhibited better solubility than aromatic gossypol Schiff bases and better anti-TMV activity than the parent compound—gossypol.The introduction of some functional groups in the alkyl chain can greatly adjust antiviral activity levels.Especially,Gossypol Schiff base of taurine(6-18)and aminomethanesulfonic acid(6-26)showed the best activities and are equivalent to NK-007.They also displayed fungicidal and insecticidal activities.Gossypol Schiff base of prop-2-en-1-amine(6-9)had 100%mortality against oriental armyworm,cotton bollworm and corn borer at600?g/m L.Gossypol Schiff base of pyridin-3-ylmethanamine(6-13)showed 40%mortality against mosquito larvae at 0.5?g/m L.5.In order to explore the effect of intramolecular hydrogen bonding and dihedral angle of dinaphthalene on the biological activities,several compounds were synthesized by modification of the hydroxyl groups or simultaneous modification of the hydroxyl groups and aldehyde groups.Further studies indicated that the presence of partial hydroxyl groups is benefit to the anti-TMV activity,and the compound 7-11showed the best activities.Most of the compounds also displayed fungicidal and insecticidal activities.Especially,7-12 showed 60%mortality against mosquito larvae at 0.25?g/m L.6.Hemigossypol was bioassayed and found to display a better anti-TMV and fungicidal activity level than gossypol.In order to improve the stability of hemigossypol,enhance its biological activity and investigate the necessity of the two symmetrical parts of gossypol to the biological activities,a series of hemigossypol and vergosin derivatives were designed,synthesized and bioassayed.The results indicated that the planar structure of the naphthalene can keep the stability of their biological activities.The larger plane of the naphthalene owns,the more improvement of the biological activities show.Hemigossylic acid lactone(8-7)not only displayed better activity against TMV than NK-007,but also showed 60%mortality against mosquito larvae at 0.25?g/m L.Hemigossypol exhibited excellent fungicidal activities against 14 kinds of plant fungi in vitro.The derivatives 8-2,8-3,8-7 and8-11 displayed similar activities as hemigossypol,however,the stabilities of them are greatly higher than it.7.The derivatives were evaluated for their anticancer activities and compounds6-17,6-19 and 7-5 showed better activities than gossypol.