title: Total synthesis of 7-ethyl-10-hydroxycamptothecin (SN38) and its application to the development of C18-functionalized camptothecin derivatives.
abstract: A new chemical synthesis of SN38, the active metabolite of the camptothecin prodrug irinotecan, has been achieved in 12 steps from simple, commercially available starting materials. A mild and efficient FeCl(3)-catalyzed Friedländer condensation was successfully applied to construct the AB ring system. Functionalization of the C ring was accomplished by a vinylogous Mukaiyama reaction of an in situ generated N-acyliminium intermediate with a silyl enol ether. An intramolecular oxa Diels-Alder reaction efficiently constructed the D and E rings in one step. Successive asymmetric dihydroxylation and I(2) -based hemiacetal oxidation furnished the stereochemistry of SN38 with high enantiopurity. Utilizing the ABC-ring intermediate and a functionalized silyl enol ether permitted the synthesis of a number of new C18-functionalized SN38 derivatives. Several of the novel SN38 derivatives that bore a C10 methoxy group were found to exhibit comparable or more potent inhibitory activity against the proliferation of cancer cells relative to SN38.
authors.affiliation: State Key Laboratory of Coordination Chemistry, Institute of Chemical Biology and Drug Innovation, School of Chemistry and Chemical Engineering, Nanjing University, 22 Hankou Road, Nanjing, Jiangsu 210093, P. R. China.
authors.forename: Yuan-Shan
authors.initials: YS
authors.lastname: Yao
authors.forename: Jia-Li
authors.initials: JL
authors.lastname: Liu
authors.forename: Jie
authors.initials: J
authors.lastname: Xi
authors.forename: Bukeyan
authors.initials: B
authors.lastname: Miu
authors.forename: Guai-Sai
authors.initials: GS
authors.lastname: Liu
authors.forename: Shaozhong
authors.initials: S
authors.lastname: Wang
authors.forename: Linghua
authors.initials: L
authors.lastname: Meng
authors.forename: Zhu-Jun
authors.initials: ZJ
authors.lastname: Yao
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D005260:Female; D045325:HCT116 Cells; D006367:HeLa Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D000077146:Irinotecan; D015394:Molecular Structure; D011355:Prodrugs / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D011355:Prodrugs; D000077146:Irinotecan; D002166:Camptothecin