Design Synthesis Mechanismsof Action and Toxicityof Novel 20(S)-Sulfonylamidine Derivativesof Camptothecin as Potent Antitumor Agents

摘要

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.