title: New homocamptothecins: synthesis, antitumor activity, and molecular modeling.
abstract: Homocamptothecins (hCPTs) represent a class of new emerging antitumor agents, which contains a seven-membered beta-hydroxylactone in place of the conventional six-membered alpha-hydroxylactone ring (E ring) of camptothecins. Some novel 7-substituted hCPTs were designed and synthesized based on a newly developed synthetic route which couples ring A with ring C, E and D. Most of the synthesized compounds exhibit very high cytotoxic activity on tumor cell line A549. Some compounds, such as 9b, 9l, and 9y, show broad in vitro antitumor spectrum and are more potent than topotecan. Three-dimensional quantitative structure-activity relationship (3D-QSAR) methods, CoMFA and CoMSIA, were applied to explain the structure-activity relationship (SAR) of the synthesized compounds. Furthermore, molecular docking was used to clarify the binding mode of the synthesized compounds to human DNA topoisomerase I. The important hydrophobic, base-pair stacking, and hydrogen-bonding interactions were observed between the hCPT derivatives and their receptor. The results from molecular modeling will guide the design of novel hCPTs with higher antitumor activity.
authors.affiliation: School of Pharmacy, Military Key Laboratory of Medicinal Chemistry, Second Military Medical University, 325 Guohe Road, Shanghai 200433, People's Republic of China.
authors.forename: Zhenyuan
authors.initials: Z
authors.lastname: Miao
authors.forename: Chunquan
authors.initials: C
authors.lastname: Sheng
authors.forename: Wannian
authors.initials: W
authors.lastname: Zhang
authors.forename: Haitao
authors.initials: H
authors.lastname: Ji
authors.forename: Jing
authors.initials: J
authors.lastname: Zhang
authors.forename: Lücheng
authors.initials: L
authors.lastname: Shao
authors.forename: Liang
authors.initials: L
authors.lastname: You
authors.forename: Min
authors.initials: M
authors.lastname: Zhang
authors.forename: Jianzhong
authors.initials: J
authors.lastname: Yao
authors.forename: Xiaoyin
authors.initials: X
authors.lastname: Che
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004264:DNA Topoisomerases, Type I / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D021621:Imaging, Three-Dimensional; D007097:Imines / Q000737:chemistry; D008745:Methylation; D008958:Models, Molecular; D015394:Molecular Structure; D011485:Protein Binding; D011725:Pyridines / Q000737:chemistry; D021281:Quantitative Structure-Activity Relationship; D012995:Solubility; D014867:Water
chemical_list: D000970:Antineoplastic Agents; D007097:Imines; D011725:Pyridines; D014867:Water; C120029:homocamptothecin; D004264:DNA Topoisomerases, Type I; C023666:pyridine; D002166:Camptothecin