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  3. Design and synthesis of new adamantyl derivatives as promising antiproliferative agents

Design and synthesis of new adamantyl derivatives as promising antiproliferative agents

  • Eur J Med Chem. 2023 Jan 15:246:114958. doi: 10.1016/j.ejmech.2022.114958.
Afnan I Shahin 1,  Seyed-Omar Zaraei 1,  Bilal O AlKubaisi 1,  Saif Ullah 2,  Hanan S Anbar 3,  Randa El-Gamal 4,  Varsha Menon 1,  Mohammed S Abdel-Maksoud 5,  Chang-Hyun Oh 6,  Raafat El-Awady 7,  Nicolly Espindola Gelsleichter 8,  Julie Pelletier 9,  Jean Sévigny 8,  Jamshed Iqbal 10,  Taleb H Al-Tel 11,  Mohammed I El-Gamal 12
Affiliations

Affiliations

  • 1 Sharjah Institute for Medical Research, University of Sharjah, Sharjah, 27272, United Arab Emirates.
  • 2 Centre for Advanced Drug Research, COMSATS University Islamabad, Abbottabad Campus, Abbottabad, 22060, Pakistan.
  • 3 Department of Clinical Pharmacy and Pharmacotherapeutics, Dubai Pharmacy College for Girls, Dubai, 19099, United Arab Emirates.
  • 4 Department of Medical Biochemistry, Faculty of Medicine, Mansoura University, Mansoura, 35516, Egypt.
  • 5 Medicinal & Pharmaceutical Chemistry Department, Pharmaceutical and Drug Industries Research Institute, National Research Centre NRC (ID: 60014618), Dokki, Giza, 12622, Egypt.
  • 6 Center for Biomaterials, Korea Institute of Science and Technology, PO Box 131, Cheongryang, Seoul, 130-650, Republic of Korea; Department of Biomolecular Science, Korea University of Science and Technology, 113 Gwahangno, Yuseong-gu, Daejeon, 305-333, Republic of Korea.
  • 7 Sharjah Institute for Medical Research, University of Sharjah, Sharjah, 27272, United Arab Emirates; Department of Pharmacy Practice and Pharmacotherapeutics, College of Pharmacy, University of Sharjah, Sharjah, 27272, United Arab Emirates.
  • 8 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.
  • 9 Centre de Recherche du CHU de Québec - Université Laval, Québec, QC, G1V 4G2, Canada.
  • 10 Centre for Advanced Drug Research, COMSATS University Islamabad, Abbottabad Campus, Abbottabad, 22060, Pakistan. Electronic address: drjamshed@cuiatd.edu.pk.
  • 11 Sharjah Institute for Medical Research, University of Sharjah, Sharjah, 27272, United Arab Emirates; Department of Medicinal Chemistry, College of Pharmacy, University of Sharjah, Sharjah, 27272, United Arab Emirates. Electronic address: taltal@sharjah.ac.ae.
  • 12 Sharjah Institute for Medical Research, University of Sharjah, Sharjah, 27272, United Arab Emirates; Department of Medicinal Chemistry, College of Pharmacy, University of Sharjah, Sharjah, 27272, United Arab Emirates; Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt. Electronic address: drmelgamal2002@gmail.com.
PMID: 36470105 DOI: 10.1016/j.ejmech.2022.114958
Abstract

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.

Keywords

Adamantyl carboxamide; Anticancer; Carbonic anhydrases; Ectonucleotide pyrophosphatases; Phosphodiesterases (NPPs); Sulfonamide; Sulfonate.

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