Synthesis Of Cryptolepine Analogue And Saccharide Derivatives

The west African climbing shrub Cryptolepis sanguinolenta ( family Periplocaceae ) is widely used in west African countries in traditional medicine for the treatment of malaria as well as for a number of other diseases. cryptolepine ( 5-methyl- 10H– indolo[3,2-b]quinoline ) is the major alkaloid of many quindoline alkaloids found in the plant. Previous work has shown that cryptolepine has in vitro potent anti- plasmodial activity, but this alkaloid also has cytotoxic properties that are likely due to its abilities to intercalate into DNA and inhibit topoisomerase II as well as DNA synthesis; some derivatives of cryptolepine can induce and stabilize G-Quadruplex and they are potential inhibitors of telomerase. It can be drawn a conclusion that cryptolepine is a developing anticancer agent.In view of the progress in this field, some analogues of cryptolepine with saccharide were designed and synthesized in this dissertation. Substituted anilines reacted with 2-(2–chloro-acetamido) benzoic acid (8) to afford condensation intermediate agents, then the agents were cyclized by PPA (poly phosphoric acid ) to afford 9-methyl- 5H-indolo[3,2-b]quinolin-11(10H)-one(11),9-methoxy-5H-indolo [3,2-b]quindolin-11(10H)-one ( 13),methyl 11-oxo-10,11- dihydro-5H-indolo[3,2-b]quinoline-9-carboxylate (16)and 11-oxo-10,11–dihydro -5H-indolo[3,2-b] quinoline -7-carboxylic acid (21).(13)is a key intermediate in the synthesis of jusbetonin, which is the the first and by far the sole indolo [3,2-b] quinoline alkaloid glycoside from Cryptolepis sanguinolenta natural plant. (13) was chlorinated to afford 11-chloro-9-methoxy -10H-indolo[3,2-b]quinoline (14).(16) was converted to methyl 11-chloro-10H- indolo[3,2-b]quinoline-9-carboxylate(17),11-oxo-10,11-dihydro-5H-indolo[3,2-b] quinoline-9-carboxylic acid (18) and 11-chloro-10H-indolo[3,2-b]quinoline-9- carboxylic acid(19). (21)was converted to acyl chloride form, then reacted with 1,3,4,6-tetra-O-acetyl-2–deoxy-2- amino glucose(4)and 2,3,4,6-tetra-O-acetyl-2- deoxy-2-amino glucose (7)to afford N-(1', 3', 4', 6'-tetra-O-acetyl-β-D-pyran glucosyl)-11-chloro-10H-indolo[3,2-b] quinoline-7-carboxamide (23)and N-(2', 3', 4', 6'-tetra-O-acetyl-β-D-pyranglucosyl)-11-chloro-10H-indolo[3,2-b]quinoline-7- carboxamide(25), (23)and(25)then dechlorinated to afford N-(1', 3', 4', 6'-tetra-O- acetyl-β-D-pyran glucosyl) -10H-indolo [3,2-b]quinoline-7-carboxamide (24)and N-(2', 3', 4', 6'-tetra-O-acetyl-β-D-pyranglucosyl)-10H-indolo[3,2-b]quinoline -7-carboxamide (26).(21),(18) and (19) reacted with (4) catalyzed by EDCI and HOBt to afford 3 saccharide derivatives (23),(27)and (28).29 compounds are synthesized in this dissertation , 18 compounds have not been reported . 14 Cryptolepine analogues and Saccharide Derivatives in all were attained , but (21)is synthesized by others in our lab. most of the compounds were confirmed by 1H NMR,13C NMR ESI-MS,and screening of their bioactivities are underway.