title: Design, synthesis, mechanisms of action, and toxicity of novel 20(s)-sulfonylamidine derivatives of camptothecin as potent antitumor agents.
abstract: Twelve novel 20-sulfonylamidine derivatives (9a-9l) of camptothecin (1) were synthesized via a Cu-catalyzed three-component reaction. They showed similar or superior cytotoxicity compared with that of irinotecan (3) against A-549, DU-145, KB, and multidrug-resistant (MDR) KBvin tumor cell lines. Compound 9a demonstrated better cytotoxicity against MDR cells compared with that of 1 and 3. Mechanistically, 9a induced significant DNA damage by selectively inhibiting Topoisomerase (Topo) I and activating the ATM/Chk related DNA damage-response pathway. In xenograft models, 9a demonstrated significant activity without overt adverse effects at 5 and 10 mg/kg, comparable to 3 at 100 mg/kg. Notably, 9a at 300 mg/kg (i.p.) showed no overt toxicity in contrast to 1 (LD50 56.2 mg/kg, i.p.) and 3 (LD50 177.5 mg/kg, i.p.). Intact 9a inhibited Topo I activity in a cell-free assay in a manner similar to that of 1, confirming that 9a is a new class of Topo I inhibitor. 20-Sulfonylamidine 1-derivative 9a merits development as an anticancer clinical trial candidate.
authors.affiliation: School of Pharmacy, Lanzhou University , Lanzhou 730000, PR China.
authors.forename: Mei-Juan
authors.initials: MJ
authors.lastname: Wang
authors.forename: Ying-Qian
authors.initials: YQ
authors.lastname: Liu
authors.forename: Ling-Chu
authors.initials: LC
authors.lastname: Chang
authors.forename: Chih-Ya
authors.initials: CY
authors.lastname: Wang
authors.forename: Yong-Long
authors.initials: YL
authors.lastname: Zhao
authors.forename: Xiao-Bo
authors.initials: XB
authors.lastname: Zhao
authors.forename: Keduo
authors.initials: K
authors.lastname: Qian
authors.forename: Xiang
authors.initials: X
authors.lastname: Nan
authors.forename: Liu
authors.initials: L
authors.lastname: Yang
authors.forename: Xiao-Ming
authors.initials: XM
authors.lastname: Yang
authors.forename: Hsin-Yi
authors.initials: HY
authors.lastname: Hung
authors.forename: Jai-Sing
authors.initials: JS
authors.lastname: Yang
authors.forename: Daih-Huang
authors.initials: DH
authors.lastname: Kuo
authors.forename: Masuo
authors.initials: M
authors.lastname: Goto
authors.forename: Susan L
authors.initials: SL
authors.lastname: Morris-Natschke
authors.forename: Shiow-Lin
authors.initials: SL
authors.lastname: Pan
authors.forename: Che-Ming
authors.initials: CM
authors.lastname: Teng
authors.forename: Sheng-Chu
authors.initials: SC
authors.lastname: Kuo
authors.forename: Tian-Shung
authors.initials: TS
authors.lastname: Wu
authors.forename: Yang-Chang
authors.initials: YC
authors.lastname: Wu
authors.forename: Kuo-Hsiung
authors.initials: KH
authors.lastname: Lee
mesh_terms: D000578:Amidines / Q000737:chemistry*; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000737:chemistry; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004264:DNA Topoisomerases, Type I / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D005260:Female; D045325:HCT116 Cells; D006801:Humans; D007624:KB Cells; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008968:Molecular Conformation; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000473:pathology; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry*; D059004:Topoisomerase I Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000578:Amidines; D000970:Antineoplastic Agents; D013449:Sulfonamides; D059004:Topoisomerase I Inhibitors; D004264:DNA Topoisomerases, Type I; D002166:Camptothecin