2. Academic Validation
  3. Mitigating the resistance of MCF-7 cancer cells to Doxorubicin under hypoxic conditions with novel coumarin based carbonic anhydrase IX and XII inhibitors

Mitigating the resistance of MCF-7 cancer cells to Doxorubicin under hypoxic conditions with novel coumarin based carbonic anhydrase IX and XII inhibitors

  • Bioorg Chem. 2024 Nov:152:107759. doi: 10.1016/j.bioorg.2024.107759.
Hend I Abdelaal 1,  Abdalla R Mohamed 2,  Mahmoud F Abo-Ashour 3,  Simone Giovannuzzi 4,  Samar H Fahim 5,  Hatem A Abdel-Aziz 6,  Claudiu T Supuran 7,  Sahar M Abou-Seri 8
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Egyptian Russian University, Badr City, Cairo 11829, Egypt.
  • 2 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Egyptian Russian University, Badr City, Cairo 11829, Egypt. Electronic address: abdallaharafa@eru.edu.eg.
  • 3 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, El Saleheya El Gadida University, El Saleheya El Gadida, 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, Cairo University, Kasr El-Aini Street, Cairo 11562, Egypt. Electronic address: samer.mohamed@pharma.cu.edu.eg.
  • 6 Department of Applied Organic Chemistry, National Research Center, Dokki, Cairo 12622, Egypt; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Pahros University in Alexandria, Canal El Mahmoudia Street, Alexandria 21648, Egypt.
  • 7 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.
  • 8 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Kasr El-Aini Street, Cairo 11562, Egypt.
PMID: 39213797 DOI: 10.1016/j.bioorg.2024.107759
Abstract

In the present study, the design and synthesis of novel coumarin derivatives 8a-h, 11a-d and 16a-c as potential selective inhibitors for the tumor associated human Carbonic Anhydrase isoforms (hCA IX and XII) was reported. All the newly synthesized derivatives showed potent to mild activity against the targeted CA IX (KI = 0.08-9.57 µM), with selectivity indices over CA I (SI = 2.0-21.9) and over CA II (SI = 1.1-15.7). They showed similar activities against CA XII (KI = 0.06-9.48 µM) with selectivity indices over CA I (SI = 1.4-21.2) and CA II (SI = 0.9-15.5). Compound 16b featuring sulfonamide function possessed promising inhibitory activities against the targeted isoforms CA IX and XII with KI values of 0.08 and 0.06 µM, respectively. Interestingly, it was found that using compound 16b at a nontoxic concentration as an Adjuvant with Doxorubicin against MCF-7 cells enhanced the cytotoxicity under hypoxia by almost 3.5 folds; IC50 decreased from 25.74 to 7.43 µM. Therefore, compound 16b restored the cytotoxicity of Doxorubicin against MCF-7 cells under hypoxia, almost as normoxia. Furthermore, flow cytometry analysis of a combination treatment of compound 16b and Doxorubicin to the MCF7 cell line revealed an increase in cell cycle arrest at the G2/M phase and a more efficient apoptotic effect than Doxorubicin alone. Furthermore, compound 16b showed no cytotoxicity against normal breast MCF-10A cell line (IC50 = 296.25 µM).

Keywords

Adjuvant; Anticancer sensitization; Carbonic anhydrase; Coumarins.

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