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Eur J Med Chem. 2019 Jul 25;181:111560. doi: 10.1016/j.ejmech.2019.07.063. [Epub ahead of print]

Synthesis, biological evaluation, and docking studies of new raloxifene sulfonate or sulfamate derivatives as inhibitors of nucleotide pyrophosphatase/phosphodiesterase.

Author information

1
College of Pharmacy, University of Sharjah, Sharjah, 27272, United Arab Emirates; Sharjah Institute for Medical Research, University of Sharjah, Sharjah, 27272, United Arab Emirates; Faculty of Pharmacy, University of Mansoura, Mansoura, 35516, Egypt. Electronic address: drmelgamal2002@gmail.com.
2
Centre for Advanced Drug Research, COMSATS University Islamabad, Abbottabad Campus, Abbottabad, 22060, Pakistan.
3
Sharjah Institute for Medical Research, University of Sharjah, Sharjah, 27272, United Arab Emirates.
4
College of Pharmacy, University of Sharjah, Sharjah, 27272, United Arab Emirates; Sharjah Institute for Medical Research, University of Sharjah, Sharjah, 27272, United Arab Emirates; Faculty of Pharmacy, Beni-Suef University, Beni-Suef 62514, Egypt.
5
Faculty of Pharmacy, University of Mansoura, Mansoura, 35516, Egypt.
6
Centre de Recherche du CHU de Québec - Université Laval, Québec, QC, G1V 4G2, Canada.
7
Centre de Recherche du CHU de Québec - Université Laval, Québec, QC, G1V 4G2, Canada; Département de microbiologie-infectiologie et d'immunologie, Faculté de Médecine, Université Laval, Québec, QC, G1V 0A6, Canada.
8
Centre for Advanced Drug Research, COMSATS University Islamabad, Abbottabad Campus, Abbottabad, 22060, Pakistan. Electronic address: drjamshed@cuiatd.edu.pk.

Abstract

A new series of raloxifene sulfonate/sulfamate derivatives were designed and synthesized. The target compounds were tested for inhibitory effect against nucleotide pyrophosphatase/phosphodiesterase-1 and -3 (NPP1 and NPP3) enzymes. Furthermore, all the ten target compounds were subjected to cytotoxic studies on various cancer cell lines, and the most potent derivatives were explored for their potency against these cancer cell lines as well as F180 fibroblasts to investigate the selectivity indexes. Compound 1f exerted the highest potency against HT-29 colon cancer cell line (IC50 = 1.4 μM) with 8.43-fold selectivity towards HT-29 than F180 fibroblasts. Compound 1f exerted sub-micromolar IC50 values against NPP1 and NPP3 (IC50 = 0.29 μM and 0.71 μM, respectively). The most potent inhibitors were docked in developed homology model of NPP1 and crystal structure of NPP3. All the docked analogues manifested remarkable interactions within the active pocket of NPP1 and NPP3.

KEYWORDS:

Cytotoxic studies; Docking studies; Homology model; Nucleotide pyrophosphatase/phosphodiesterase; Raloxifene derivatives

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