title: Quantitative structure-activity relationship studies on indenoisoquinoline topoisomerase I inhibitors as anticancer agents in human renal cell carcinoma cell line SN12C.
abstract: Topoisomerase I is important for DNA replication and cell division, making it an attractive drug target for anticancer therapy. A series of indenoisoquinolines displaying potent Top1 inhibitory activity in human renal cell carcinoma cell line SN12C were selected to establish 3D-QSAR models using CoMFA and CoMSIA methods. Internal and external cross-validation techniques were investigated, as well as some measures taken, including region focusing, bootstrapping and the "leave-group-out" cross-validation method. The satisfactory CoMFA model predicted a q(2) value of 0.659 and an r(2) value of 0.949, indicating that electrostatic and steric properties play a significant role in potency. The best CoMSIA model, based on a combination of steric, electrostatic and H-bond acceptor descriptors, predicted a q(2) value of 0.523 and an r(2) value of 0.902. The models were graphically interpreted by contour plots which provided insight into the structural requirements for increasing the activity of a compound, providing a solid basis for future rational design of more active anticancer agents.
authors: Urology Center, Southwest Hospital, Third Military Medical University, Chongqing 400038, China.
authors: Yi
authors: Y
authors: Zhi
authors: Department of Cell Biology, Third Military Medical University, Chongqing 400038, China.
authors: Jin
authors: J
authors: Yang
authors: Urology Center, Southwest Hospital, Third Military Medical University, Chongqing 400038, China.
authors: Shengchao
authors: S
authors: Tian
authors: Urology Center, Southwest Hospital, Third Military Medical University, Chongqing 400038, China.
authors: Fang
authors: F
authors: Yuan
authors: Urology Center, Southwest Hospital, Third Military Medical University, Chongqing 400038, China.
authors: Yang
authors: Y
authors: Liu
authors: Department of Cell Biology, Third Military Medical University, Chongqing 400038, China.
authors: Yi
authors: Y
authors: Zhang
authors: Guangdong Province Key Laboratory of Pharmacodynamic Constituents of Traditional Chinese Medicine and New Drugs Research, College of Pharmacy, Jinan University, Guangzhou 510632, China.
authors: Pinghua
authors: P
authors: Sun
authors: Urology Center, Southwest Hospital, Third Military Medical University, Chongqing 400038, China.
authors: Bo
authors: B
authors: Song
authors: Urology Center, Southwest Hospital, Third Military Medical University, Chongqing 400038, China.
authors: Zhiwen
authors: Z
authors: Chen
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D006801:Humans; D007192:Indenes / Q000138:chemical synthesis* / Q000494:pharmacology; D007546:Isoquinolines / Q000138:chemical synthesis* / Q000494:pharmacology; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008958:Models, Molecular; D011412:Propanolamines / Q000138:chemical synthesis* / Q000494:pharmacology; D021281:Quantitative Structure-Activity Relationship; D055672:Static Electricity; D059004:Topoisomerase I Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D007192:Indenes; D007546:Isoquinolines; D011412:Propanolamines; D059004:Topoisomerase I Inhibitors; C002989:indenolol