2. Academic Validation
  3. Design and synthesis of 6-arylpyridine-tethered sulfonamides as novel selective inhibitors of carbonic anhydrase IX with promising antitumor features toward the human colorectal cancer

Design and synthesis of 6-arylpyridine-tethered sulfonamides as novel selective inhibitors of carbonic anhydrase IX with promising antitumor features toward the human colorectal cancer

  • Eur J Med Chem. 2023 Oct 5;258:115538. doi: 10.1016/j.ejmech.2023.115538.
Wagdy M Eldehna 1,  Eslam E Mohammed 2,  Ghada H Al-Ansary 3,  Emanuela Berrino 4,  Mostafa M Elbadawi 5,  Tamer M Ibrahim 5,  Maiy Y Jaballah 3,  Sara T Al-Rashood 6,  Faizah A Binjubair 6,  Meltem Celik 2,  Alessio Nocentini 4,  Fawzy A Elbarbry 7,  Fikrettin Sahin 2,  Hatem A Abdel-Aziz 8,  Claudiu T Supuran 9,  Mohamed Fares 10
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh, P.O. Box 33516, Egypt. Electronic address: wagdy2000@gmail.com.
  • 2 Department of Genetics and Bioengineering, Faculty of Engineering, Yeditepe University, 26 Ağustos Campus, Kayisdagi Cad, Ataşehir, TR-34755, Istanbul, Turkey.
  • 3 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Ain Shams University, Cairo, Abbassia, Egypt.
  • 4 Department of NEUROFARBA, Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, Polo Scientifico, Via U. Schiff 6, 50019, Sesto Fiorentino, Firenze, Italy.
  • 5 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh, P.O. Box 33516, Egypt.
  • 6 Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh, 11451, Saudi Arabia.
  • 7 School of Pharmacy, Pacific University Oregon, Hillsboro, OR, 97123, USA.
  • 8 Department of Applied Organic Chemistry, National Research Center, Dokki, Giza, P.O. Box 12622, Egypt.
  • 9 Department of NEUROFARBA, Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, Polo Scientifico, Via U. Schiff 6, 50019, Sesto Fiorentino, Firenze, Italy. Electronic address: claudiu.supuran@unifi.it.
  • 10 School of Pharmacy, The University of Sydney, Sydney, NSW, 2006, Australia; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Egyptian Russian University, Badr City, Cairo, 11829, Egypt.
PMID: 37321108 DOI: 10.1016/j.ejmech.2023.115538
Abstract

Hypoxia, a characteristic feature of solid tumors, develops as a result of excessive cell proliferation and rapid tumor growth exceeding the oxygen supply, and can result in angiogenesis activation, increased invasiveness, aggressiveness, and metastasis, leading to improved tumor survival and suppression of Anticancer drug therapeutic impact. SLC-0111, a ureido benzenesulfonamide, is a selective human Carbonic Anhydrase (hCA) IX inhibitor in clinical trials for the treatment of hypoxic malignancies. Herein, we describe the design and synthesis of novel 6-arylpyridines 8a-l and 9a-d as structural analogues of SLC-0111, in the aim of exploring new selective inhibitors for the cancer-associated hCA IX isoform. The para-fluorophenyl tail in SLC-0111 was replaced by the privileged 6-arylpyridine motif. Moreover, both ortho- and meta-sulfonamide regioisomers, as well as an ethylene extended analogous were developed. All 6-arylpyridine-based SLC-0111 analogues were screened in vitro for their inhibitory potential against a panel of hCAs (hCA I, II, IV and IX isoforms) using stopped-flow CO2 hydrase assay. In addition, the Anticancer activity was firstly explored against a panel of 57 Cancer cell lines at the USA NCI-Developmental Therapeutic Program. Compound 8g emerged as the best anti-proliferative candidate with mean GI% value equals 44. Accordingly, a cell viability assay (MTS) for 8g was applied on colorectal HCT-116 and HT-29 Cancer cell lines as well as on the healthy HUVEC cells. Thereafter, Annexin V-FITC Apoptosis detection, cell cycle, TUNEL, and qRT-PCR, colony formation, and wound healing assays were applied to gain mechanistic insights and to understand the behavior of colorectal Cancer cells upon the treatment of compound 8g. Also, a molecular docking analysis was conducted to provide in silico insights into the reported hCA IX inhibitory activity and selectivity.

Keywords

Anticancer agents; Hypoxic tumors; Pyridine; SLC-0111; Tail approach.

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