Molecular pharmacology and antitumor activity of Zalypsis® in several human cancer cell lines

摘要: Abstract Zalypsis® is a new synthetic alkaloid tetrahydroisoquinoline antibiotic that has reactive carbinolamine group. This functionality can lead to the formation of covalent bond with amino group selected guanines in DNA double helix, both absence and presence methylated cytosines. The resulting complex additionally stabilized by establishment one or more hydrogen bonds adjacent nucleotides opposite strand as well van der Waals interactions within minor groove. Fluorescence-based thermal denaturation experiments demonstrated most favorable triplets for adduct are AGG, GGC, AGC, CGG TGG, these preferences could be rationalized on basis molecular modeling results. Zalypsis®–DNA adducts eventually give rise double-strand breaks, triggering S-phase accumulation apoptotic cell death. potent cytotoxic activity was ascertained 24 line panel. mean IC50 value 7 nM leukemia stomach tumor lines were amongst sensitive. administration four murine xenograft models human cancer demonstrates significant growth inhibition highest Hs746t gastric no weight loss treated animals. Taken together, results indicate antitumor supports its current development clinic an anticancer agent.