Synthesis, anti-cancer screening and tyrosyl-DNA phosphodiesterase 1 (Tdp1) inhibition activity of novel piperidinyl sulfamides

Novel piperidinyl-based sulfamide derivatives were designed and synthesized through various synthetic routes. Anticancer activities of these sulfamides were evaluated by phenotypic screening on National Cancer Institute's 60 human tumor cell lines (NCI-60). Preliminary screening at 10 mu M concentration showed that piperidinyl sulfamide aminoester 26 (NSC 749204) was sensitive to most of the cell lines in the panel. Further dose-response studies showed that 26 was highly selective for inhibition of colon cancer cell lines with minimum GI(50) = 1.88 mu M for COLO-205 and maximum GI(50) = 11.1 mu M for SW-620 cells. These newly synthesized sulfamides were also screening for their Tdpl inhibition activity. Compound 18 (NSC 750706) showed significant inhibition of Tdpl with IC50 = 23.7 mu M. Molecular-docking studies showed that 18 bind to Tdpl in its binding pocket similar to a known Tdpl inhibitor.