title: Synthesis and biological evaluation of novel homocamptothecins conjugating with dihydropyrimidine derivatives as potent topoisomerase I inhibitors.
abstract: Homocamptothecin (hCPT) is a camptothecin (CPT) homologue with the insertion of a methylene (CH₂) spacer between the alcohol moiety and carbonyl group of the classical six-membered α-hydroxylactone ring. This modification provides higher lactone stability and did not impair its activity against topoisomerase I (Topo I), but rather appears to improve it compared to CPT. In an attempt to improve the antitumor activity of homocamptothecins, a series of novel hCPT derivatives conjugating with dihydropyrimidine (DHPM) derivatives was designed and synthesized based on a synthetic route which couples 7-formylhomocamptothecin with different dihydropyrimidine derivates. Most of the synthesized compounds exhibited good antiproliferative activity on tumor cell lines A549, MDA-MB-435 and HCT116. Furthermore, this class of compounds showed superior Topo I inhibition activity comparable to or higher than CPT.
authors.affiliation: School of Pharmacy, Second Military Medical University, Shanghai, P. R. China.
authors.forename: Lingjian
authors.initials: L
authors.lastname: Zhu
authors.forename: Pengfei
authors.initials: P
authors.lastname: Cheng
authors.forename: Ning
authors.initials: N
authors.lastname: Lei
authors.forename: Jianzhong
authors.initials: J
authors.lastname: Yao
authors.forename: Chunquan
authors.initials: C
authors.lastname: Sheng
authors.forename: Chunlin
authors.initials: C
authors.lastname: Zhuang
authors.forename: Wei
authors.initials: W
authors.lastname: Guo
authors.forename: Wenfeng
authors.initials: W
authors.lastname: Liu
authors.forename: Yongqiang
authors.initials: Y
authors.lastname: Zhang
authors.forename: Guoqiang
authors.initials: G
authors.lastname: Dong
authors.forename: Shengzhang
authors.initials: S
authors.lastname: Wang
authors.forename: Zhenyuan
authors.initials: Z
authors.lastname: Miao
authors.forename: Wannian
authors.initials: W
authors.lastname: Zhang
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004264:DNA Topoisomerases, Type I / Q000187:drug effects* / Q000378:metabolism; D045325:HCT116 Cells; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy / Q000473:pathology; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D059004:Topoisomerase I Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D011743:Pyrimidines; D059004:Topoisomerase I Inhibitors; C120029:homocamptothecin; D004264:DNA Topoisomerases, Type I; D002166:Camptothecin