Synthesis Of Derivatives Of Staurosporine Aglycon At C-7 And Carbazole Nirogen Position

Due to the good antibacterial,antifungal,antitumor activity,indolepyrrole carbazole alkaloids are widely studied,including the total synthesis of indole carbazole pyrrole alkaloids on natural sources,synthesis of the nucleus,and the compound structural modification and structure-activity relationship research.In this work,a series of C(7)derivatives of K252 c were synthesized,the antiproliferative activities of these compounds against four cancer cell lines were tested.The synthetic route of K252 c is explored in order to simplify the sugar ring structure of K252 a.14 simplified K252 a derivatives was synthesized,and a series of 6 derivatives of K252 c which was modified at C(7)position were synthesized.This thesis mainly includes the following two parts:1.The synthetic route which utilizes indole as starting material and a sequential transformation reactions such as oxalyl chloride acylation reaction,esterification,adol condensation,oxidative coupling,and addition reaction,finally etherification,to give 18K252 c derivatives modified at C(7)position and a kind of 3,9-diromide K252 c through halogenations reaction.The addition reaction,etherification and halogenating reaction conditions were studied.1)Compared to utilizing Grignard reagent as reaction reagent,the yield of addition reaction is almost 20% higher with organic lithium reagent and The yield showed no significant differrence when component solvent THF/HMPA or THF were used.2)Etherification reaction under acidic condition results in a mess of product,while a good yield of etherification reaction can be achieved under strong basic condition at 80℃.3)Halogenation of additive product at 3,9 position and etherification of hydroxyl group can be achieved with NBS by using methanol as solvent,and chlorination with NCS causes a mess of product.The antiproliferative activities of nineteen K252 c derivatives was tested in vitro against four cell lines(human non-small-cell lung carcinoma cell line A549,henrietta lacks strain of cancer cells,human gastric carcinoma cell line SGC-7901,human breast cancer cell line MCF-7),most of the derivatives showed moderate anti-cytotoxicity activity.It also showed that the cytotoxicity of these compounds were affected by C(7)group size,the bromides at 3,9 position show positive effect on the cytotoxicity.2.Four synthetic routes designed for indole carbazole pyrrole nucleus were explored:1)we tried to use tryptamine as starting material to synthesize K252 c through a sequential transformation such as amino acylation,oxidation reaction,deprotection,and indole condensation,intramolecular adol reaction,the desired product could not be synthesized.2)we tried to use 4,5-dichlorine phthalic anhydride as starting materials,a series of condensation,amination reaction,oxidative coupling reaction were explored,but the efforts were failed.3)Almost the same with the second route,we replaced aniline with o-chloroaniline in the second step,then tried the palladium-catalyzed coupling reaction to get the target molecule in the third step,but a product with dechlorination was obtained.4)Iodoaniline as starting material was tested,2,2’-biindoles were synthesized through four steps.2,2’-Biindoles then react with the intermediate synthesized by another route to give K252 c modified at amide nitrogen atom.The reaction condition of the forth route was optimized.Fourteen derivatives of these simplified K252 a with product(K252c with a group at amide nitrogen)obtained in the forth route were synthesized in three steps,as well as 6 derivatives modified at carbazole nitrogen of C(7)derivatives of K252 c.The synthesis of these derivatives makes the material foundation for the study of structure-activity relationships and the screening of the leading compounds.