Shahin, Afnan, I Zaraei, Seyed-Omar AlKubaisi, Bilal O. Ullah, Saif Anbar, Hanan S. El-Gamal, Randa Menon, Varsha Abdel-Maksoud, Mohammed S. Oh, Chang-Hyun El-Awady, Raafat Gelsleichter, Nicolly Espindola Pelletier, Julie Sevigny, Jean Iqbal, Jamshed Al-Tel, Taleb H. El-Gamal, Mohammed, I 2024-01-19T10:31:14Z 2024-01-19T10:31:14Z 2023-01-13 2023-01 0223-5234 https://pubs.kist.re.kr/handle/201004/114156 A series of adamantyl carboxamide derivatives containing sulfonate or sulfonamide moiety were designed as multitargeted inhibitors of ectonucleotide pyrophosphatases/phosphodiesterases (NPPs) and carbonic anhydrases (CAs). The target compounds were investigated for their antiproliferative activity against NCI-60 cancer cell lines panel. Three main series composed of 3- and 4-aminophenol, 4-aminoaniline, and 5-hydroxyindole scaffolds were designed based on a lead compound (A). Compounds 1e (benzenesulfonyl) and 1i (4-fluorobenzenesulfonyl) of 4-aminophenol backbone exhibited the most promising antiproliferative activity. Both compounds exhibited a broad-spectrum and potent inhibition against all the nine tested cancer subtypes. Both compounds showed nanomolar IC50 values over several cancer cell lines that belong to leukemia and colon cancer such as K-562, RPMI-8226, SR, COLO 205, HCT-116, HCT-15, HT29, KM12, and SW-620 cell lines. Compounds 1e and 1i induced apoptosis in K-562 leukemia cells in a dose-dependent manner. Compound 1i showed the highest cytotoxic activity with IC50 value of 200 nM against HT29 cell line. In addition, compounds 1e and 1i were tested against normal breast cells (HME1) and normal skin fibroblast cells (F180) and the results revealed that the compounds are safe toward normal cells compared to cancers cells. Enzymatic assays against NPP1-3 and carbonic anhydrases II, IX, and XII were performed to investigate the possible molecular target(s) of compounds 1e and 1i. Furthermore, a molecular docking study was performed to predict the binding modes of compounds 1e and 1i in the active site of the most sensitive enzymes subtypes. English Elsevier BV Design and synthesis of new adamantyl derivatives as promising antiproliferative agents Article 10.1016/j.ejmech.2022.114958 1 European Journal of Medicinal Chemistry, v.246 European Journal of Medicinal Chemistry 246 N scie scopus 000901866400004 2-s2.0-85143371464 Chemistry, Medicinal Pharmacology & Pharmacy Article CARBONIC-ANHYDRASE-IX PHOSPHODIESTERASE-I CANCER EXPRESSION NUCLEOTIDE INHIBITORS DISCOVERY HYPOXIA MARKER CELLS Adamantyl carboxamide Anticancer Ectonucleotide pyrophosphatases Phosphodiesterases (NPPs) Carbonic anhydrases Sulfonamide Sulfonate