Synthesis and SAR studies of novel 1,2,4-oxadiazole-sulfonamide based compounds as potential anticancer agents for colorectal cancer therapy
| Autor: | Meher Rizvi, Mohammad Abid, Bushra Zeya, Sandeep Rana, Farheen Shamsi, Jered C. Garrison, Parvez Khan, Phool Hasan, Muhammad Zahid, Hannah M. King, Mohamed F. Alajmi, Imtaiyaz Hassan, Aarfa Queen, Afzal Hussain |
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| Rok vydání: | 2019 |
| Předmět: |
Drug
Colorectal cancer media_common.quotation_subject Oxadiazole Antineoplastic Agents 01 natural sciences Biochemistry chemistry.chemical_compound Structure-Activity Relationship Drug Discovery medicine Tumor Cells Cultured Potency Humans Doxorubicin Thiazole Molecular Biology media_common Cell Proliferation Oxadiazoles Sulfonamides Dose-Response Relationship Drug Molecular Structure 010405 organic chemistry Chemistry Organic Chemistry Sulfonamide (medicine) medicine.disease 0104 chemical sciences Molecular Docking Simulation 010404 medicinal & biomolecular chemistry Apoptosis Cancer research Drug Screening Assays Antitumor Colorectal Neoplasms medicine.drug |
| Zdroj: | Bioorganic chemistry. 98 |
| ISSN: | 1090-2120 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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