Design, synthesis, mechanisms of action, and toxicity of novel 20(s)-sulfonylamidine derivatives of camptothecin as potent antitumor agents
Journal
Journal of Medicinal Chemistry
Journal Volume
57
Journal Issue
14
Pages
6008-6018
Date Issued
2014
Author(s)
CHE-MING TENG
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. ? 2014 American Chemical Society.
SDGs
Other Subjects
antineoplastic agent; camptothecin derivative; irinotecan; animal experiment; animal model; antineoplastic activity; antiproliferative activity; apoptosis; article; cancer cell line; controlled study; cytotoxicity; DNA damage; drug design; drug mechanism; drug synthesis; human; human cell; male; mouse; nonhuman; structure activity relation; Amidines; Animals; Antineoplastic Agents; Apoptosis; Camptothecin; Cell Cycle; Cell Line, Tumor; Cell Proliferation; DNA Topoisomerases, Type I; Dose-Response Relationship, Drug; Drug Design; Drug Screening Assays, Antitumor; Female; HCT116 Cells; Humans; KB Cells; Mice; Mice, Inbred BALB C; Mice, Nude; Molecular Conformation; Neoplasms, Experimental; Structure-Activity Relationship; Sulfonamides; Topoisomerase I Inhibitors
Type
journal article