2. Academic Validation
  3. Synthesis and SAR studies of novel 1,2,4-oxadiazole-sulfonamide based compounds as potential anticancer agents for colorectal cancer therapy

Synthesis and SAR studies of novel 1,2,4-oxadiazole-sulfonamide based compounds as potential anticancer agents for colorectal cancer therapy

  • Bioorg Chem. 2020 May;98:103754. doi: 10.1016/j.bioorg.2020.103754.
Farheen Shamsi 1,  Phool Hasan 2,  Aarfa Queen 3,  Afzal Hussain 4,  Parvez Khan 3,  Bushra Zeya 5,  Hannah M King 6,  Sandeep Rana 6,  Jered Garrison 7,  Mohamed F Alajmi 4,  M Moshahid Alam Rizvi 5,  Muhammad Zahid 8,  Md Imtaiyaz Hassan 3,  Mohammad Abid 9
Affiliations

Affiliations

  • 1 Medicinal Chemistry Laboratory, Department of Biosciences, Jamia Millia Islamia, New Delhi 110025, India; Genome Biology Laboratory, Department of Biosciences, Jamia Millia Islamia, New Delhi 110025, India.
  • 2 Medicinal Chemistry Laboratory, Department of Biosciences, Jamia Millia Islamia, New Delhi 110025, India.
  • 3 Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi 110025, India.
  • 4 Department of Pharmacognosy, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia.
  • 5 Genome Biology Laboratory, Department of Biosciences, Jamia Millia Islamia, New Delhi 110025, India.
  • 6 Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska 68198-6805, USA.
  • 7 Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, Nebraska 68198-6805, USA.
  • 8 Department of Environmental, Agricultural and Occupational Health, University of Nebraska Medical Center, Omaha, Nebraska 68198-6805, USA.
  • 9 Medicinal Chemistry Laboratory, Department of Biosciences, Jamia Millia Islamia, New Delhi 110025, India. Electronic address: [email protected].
PMID: 32200329 DOI: 10.1016/j.bioorg.2020.103754
Abstract

A diverse series of 1,2,4-oxadiazoles based substituted compounds were designed, synthesized and evaluated as Anticancer agents targeting Carbonic Anhydrase IX (CAIX). Initial structure-activity analysis suggested that the thiazole/thiophene-sulfonamide conjugates of 1,2,4-oxadiazoles exhibited potent Anticancer activities with low μM potencies. Compound OX12 exhibited antiproliferative activity (IC50 = 11.1 µM) along with appreciable inhibition potential for tumor-associated CAIX (IC50 = 4.23 µM) isoform. Therefore, OX12 was structurally optimized and its SAR oriented derivatives (OX17-27) were synthesized and evaluated. This iteration resulted in compound OX27 with an almost two-fold increase in antiproliferative effect (IC50 = 6.0 µM) comparable to the clinical drug doxorubicin and significantly higher potency against CAIX (IC50 = 0.74 µM). Additionally, OX27 treatment decreases the expression of CAIX, induces Apoptosis and ROS production, inhibited colony formation and migration of colon Cancer cells. Our studies provide preclinical rational for the further optimization of identified OX27 as a suitable lead for the possible treatment of CRC.

Keywords

1,2,4-Oxadiazoles; Apoptosis; Colorectal cancer; Inhibitors; Sulfonamides.

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