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

Jung Ho Jun, Vineet Kumar, Thomas S. Dexheimer, Iwona Wedlich, Marc C. Nicklaus, Yves Pommier, Sanjay V. Malhotra

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

Abstract

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 μM 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 GI50 = 1.88 μM for COLO-205 and maximum GI50 = 11.1 μM for SW-620 cells. These newly synthesized sulfamides were also screening for their Tdp1 inhibition activity. Compound 18 (NSC 750706) showed significant inhibition of Tdp1 with IC50 = 23.7 μM. Molecular-docking studies showed that 18 bind to Tdp1 in its binding pocket similar to a known Tdp1 inhibitor.

Original languageEnglish (US)
Pages (from-to)337-348
Number of pages12
JournalEuropean Journal of Pharmaceutical Sciences
Volume111
DOIs
StatePublished - Jan 1 2018
Externally publishedYes

Keywords

  • Anti-cancer
  • Biological activity
  • Piperidinyl sulfamides
  • Synthesis
  • Tyrosyl-DNA phosphodiesterase 1 (Tdp1)

ASJC Scopus subject areas

  • Pharmaceutical Science

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