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

doi:10.1016/j.ejps.2017.10.017

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 journal › Article › peer-review

12 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 language	English (US)
Pages (from-to)	337-348
Number of pages	12
Journal	European Journal of Pharmaceutical Sciences
Volume	111
DOIs	https://doi.org/10.1016/j.ejps.2017.10.017
State	Published - Jan 1 2018
Externally published	Yes

Keywords

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

ASJC Scopus subject areas

Pharmaceutical Science

Access to Document

10.1016/j.ejps.2017.10.017

Cite this

@article{da8cff6b2f214f19adacaa12cb4ee10e,

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

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.",

keywords = "Anti-cancer, Biological activity, Piperidinyl sulfamides, Synthesis, Tyrosyl-DNA phosphodiesterase 1 (Tdp1)",

author = "Jun, {Jung Ho} and Vineet Kumar and Dexheimer, {Thomas S.} and Iwona Wedlich and Nicklaus, {Marc C.} and Yves Pommier and Malhotra, {Sanjay V.}",

note = "Publisher Copyright: {\textcopyright} 2017",

year = "2018",

month = jan,

day = "1",

doi = "10.1016/j.ejps.2017.10.017",

language = "English (US)",

volume = "111",

pages = "337--348",

journal = "European Journal of Pharmaceutical Sciences",

issn = "0928-0987",

publisher = "Elsevier",

}

TY - JOUR

T1 - Synthesis, anti-cancer screening and tyrosyl-DNA phosphodiesterase 1 (Tdp1) inhibition activity of novel piperidinyl sulfamides

AU - Jun, Jung Ho

AU - Kumar, Vineet

AU - Dexheimer, Thomas S.

AU - Wedlich, Iwona

AU - Nicklaus, Marc C.

AU - Pommier, Yves

AU - Malhotra, Sanjay V.

PY - 2018/1/1

Y1 - 2018/1/1

N2 - 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.

AB - 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.

KW - Anti-cancer

KW - Biological activity

KW - Piperidinyl sulfamides

KW - Synthesis

KW - Tyrosyl-DNA phosphodiesterase 1 (Tdp1)

UR - http://www.scopus.com/inward/record.url?scp=85032859442&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85032859442&partnerID=8YFLogxK

U2 - 10.1016/j.ejps.2017.10.017

DO - 10.1016/j.ejps.2017.10.017

M3 - Article

C2 - 29037996

AN - SCOPUS:85032859442

SN - 0928-0987

VL - 111

SP - 337

EP - 348

JO - European Journal of Pharmaceutical Sciences

JF - European Journal of Pharmaceutical Sciences

ER -

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

Abstract

Keywords

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this