2. Academic Validation
  3. Synthesis of coumarin-sulfonamide derivatives and determination of their cytotoxicity, carbonic anhydrase inhibitory and molecular docking studies

Synthesis of coumarin-sulfonamide derivatives and determination of their cytotoxicity, carbonic anhydrase inhibitory and molecular docking studies

  • Eur J Med Chem. 2019 Dec 1:183:111702. doi: 10.1016/j.ejmech.2019.111702.
Belma Zengin Kurt 1,  Fatih Sonmez 2,  Dilek Ozturk 3,  Atilla Akdemir 4,  Andrea Angeli 5,  Claudiu T Supuran 5
Affiliations

Affiliations

  • 1 Bezmialem Vakif University, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, 34093, Istanbul, Turkey. Electronic address: bzengin@bezmialem.edu.tr.
  • 2 Sakarya University of Applied Sciences, Pamukova Vocational School, 54055, Sakarya, Turkey.
  • 3 Bezmialem Vakif University, Faculty of Pharmacy, Department of Pharmacology, 34093, Istanbul, Turkey.
  • 4 Bezmialem Vakif University, Faculty of Pharmacy, Department of Pharmacology, Computer-aided drug discovery laboratory, 34093, Istanbul, Turkey.
  • 5 Università degli Studi di Firenze, Dipartimento Neurofarba, Sezione di Scienze Farmaceutiche e Nutraceutiche, Via U. Schiff 6, 50019, Sesto Fiorentino, Florence, Italy.
PMID: 31542715 DOI: 10.1016/j.ejmech.2019.111702
Abstract

Carbonic anhydrases isoforms CA IX, and XII are known to be highly expressed in various human tissues and malignancies. CA IX is a prominent target for especially colorectal cancers, because it is overexpressed in colorectal Cancer and this overexpression leads poor prognosis. Inhibition of CA IX activity by small molecule CA inhibitors like sulfonamides, sulfonamide derivative or Coumarins leads to inhibition of tumorigenesis. Novel twenty-seven compounds in three series (sulfonamide-based imines (6a-6i), coumarin-based aldehydes (7a-7i), and coumarin-sulfonamide-based target molecules (8a-8i)) were synthesized and characterized by means of IR, NMR, and mass spectra. All compounds were tested for their ability to inhibit CA I, CA II, CA IX, and CA XII isoforms. 4-((((2-((1-(3-((2-oxo-2H-chromen-7-yl)oxy)propyl)-1H-1,2,3-triazol-4-yl)methoxy)naphthalen-1-yl)-methylene)amino)methyl)benzenesulfonamide (8i) exhibited the highest hCA IX inhibition with the Ki of 45.5 nM. In addition, 8i was found to be potent in inhibiting Cancer cell proliferation as selective (IC50 = 17.01 ± 1.35 μM for HT-29, IC50 = 118.73 ± 1.19 μM for HEK293T). This novel compound inhibited the CA IX and CA XII protein expression in HT-29 cells. These findings indicate that 8i can inhibit cellular proliferation in human colon Cancer cells by specifically targeting the CA IX and CA XII expression.

Keywords

Carbonic anhydrase; Coumarin; Cytotoxicity; Enzyme inhibition; Molecular docking; Sulfonamide.

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