Synthesis And Anticancer Activity Of Longifolene-based Tetralin-1,2,4-triazolesulfonamide And Thiazole-amide Compounds

Turpentine oil is the dominant forest non-wood biomass resource in China,and Guangxi province is one of the main production areas.However,due to the increase in labor cost,the annual output of turpentine oil has been gradually reduced from about 10-15 ten thousand tons to about 8-10 ten thousand tons.Therefore,the value-added application of turpentine oil is a problem that we are facing now.Heavy turpentine oil is a by-product in the production of turpentine oil,accounting for 17%-20%of the total amount of turpentine oil.At present,heavy turpentine oil was mostly used as boiler fuel,and a small amount of it is used as a felt binder and mineral processing flotation agent.Therefore,the application value of heavy turpentine oil is low.Longifolene is the main component of heavy turpentine oil,accounting for more than 40%.Consequently,the high value-added application of longifolene is worth studying.Longifolene,a tricyclic sesquiterpene compound,can undergo the reaction of isomerization-aromatization to give 7-isopropyl-1,1-dimethyl-1,2,3,4-tetrahydronaphthalene（called as longifolene-based tetralin in this thesis）.Based on the performance of tetralin derivatives in the anticancer activity,two types of thirty-seven novel tetralin derivatives with potential anticancer activity including longifolene-based tetralin-1,2,4-triazole-sulfonamides and longifolene-based tetralin-thiazole-amides were designed and synthesized by fusing the pharmacophores used in the construction of bioactive molecules including 1,2,4-triazole,sulfonamide,thiazole,and amide pharmacophores into the longifolene-based tetralin framework.This work can provide the experimental and theoretical basis for the high value-added application of naturally renewable forest biomass resource longifolene and for the development of novel anticancer drugs.In this thesis,longifolene-based tetralin 2 was prepared by isomerization-aromatization reaction of longifolene,and further oxidized and brominated to give longifolene-based bromotetralinone 4.Then compound 4 reacted with 5-amino-3-mercapto-1,2,4-triazole to afford compound longifolene-based tetralin-1,2,4-triazole 5.Finally,seventeen novel target compound longifolene-based tetralin-1,2,4-triazole-sulfonamides 6a-6q were synthesized by the N-sulfonation reaction of compound 5 with a series of sulfonyl chlorides.Besides,compound longifolene-based tetralin-thiazole 7 was prepared by the cyclization reaction of longifolene-based bromotetralinone 4 with thiourea.Then twenty novel longifolene-based tetralin-thiazole-amides 8a-8t were synthesized by the N-acylation reaction with a series of acyl chlorides.The synthetic condition and purification method for the target compounds were explored preliminarily.In addition,the structures of target compounds were confirmed by GC,FT-IR,ESI-MS,and NMR（including 1D-NMR and 2D-NMR）.The in vitro cytotoxicity for the compounds 6a-6q and 2-5 were evaluated by standard MTT assay against T-24 human bladder cancer cell,MCF-7 human breast cancer cell,Hep G2 human liver cancer cell,A549 human lung adenocarcinoma cell,and HT-29 human colon cancer cell.In addition,the in vitro cytotoxicity for the compounds 7 and 8a-8t were evaluated by standard MTT assay against SKOV-3 human ovarian cancer cell line,T-24 human bladder cancer cell,MCF-7 human breast cancer cell,Hep G2 human liver cancer cell,and A549 human lung adenocarcinoma cell.As a result,compounds 6g,6h,7,8a,8b,and 8c exhibited better and more broad-spectrum anticancer activity against almost all the tested cancer cell lines than that of the positive control 5-FU,which were leading compounds worthy of further study.According to the antitumor activity test results,the obvious contrast on antitumor activity between disubstituted target compound 6h（R=3’-NO₂-4’-Cl）and its corresponding monosubstituted compound 6k（R=3’-NO₂）and 6j（R=4’-Cl）were found.At the same time,the antitumor activities of monosubstituted compounds were also significant differences due to their different substituent positions,such as 8a（R=2’-NO₂ Ph）、8b（R=3’-NO₂Ph）,and 8p（R=4’-NO₂Ph）.To find out the difference in the structure for these compounds,the front molecular orbital,electrostatic potential（ESP）and dipole moment of triazole compounds 6h,6k,6j and thiazole compounds 8a,8b,8p were calculated by the method of DFT/B3LYP/6-31G（d,p）in Gaussian 09 package.It was found that the molecular orbital,electrostatic potential,and dipole moment of triazole compounds 6h,6k,6j and thiazole compounds 8a,8b,8p were different in a way.In particular,the LUMO phases of the triazole compounds 6h,6k,6j and thiazole compounds 8a,8b,8p showed significant differences,which was maybe the main reason for resulting in the differences in antitumor activities.It can provide useful information for further study of these compounds,especially the leading compound 6h.