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  3. Aromatase inhibitors and apoptotic inducers: Design, synthesis, anticancer activity and molecular modeling studies of novel phenothiazine derivatives carrying sulfonamide moiety as hybrid molecules

Aromatase inhibitors and apoptotic inducers: Design, synthesis, anticancer activity and molecular modeling studies of novel phenothiazine derivatives carrying sulfonamide moiety as hybrid molecules

  • Eur J Med Chem. 2017 Jul 7:134:304-315. doi: 10.1016/j.ejmech.2017.04.028.
Mostafa M Ghorab 1,  Mansour S Alsaid 2,  Nermin Samir 3,  Ghada A Abdel-Latif 4,  Aiten M Soliman 5,  Fatma A Ragab 6,  Dalal A Abou El Ella 7
Affiliations

Affiliations

  • 1 Department of Pharmacognosy, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia; Department of Drug Radiation Research, National Center for Radiation Research and Technology, Egyptian Atomic Energy Authority, Cairo 113701, Egypt. Electronic address: mmsghorab@yahoo.com.
  • 2 Department of Pharmacognosy, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia.
  • 3 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Ain Shams University, Cairo 11566, Egypt.
  • 4 Department of Pharmacology, Faculty of Pharmacy, Misr International University, Cairo, Egypt.
  • 5 Department of Drug Radiation Research, National Center for Radiation Research and Technology, Egyptian Atomic Energy Authority, Cairo 113701, Egypt.
  • 6 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Cairo, Egypt.
  • 7 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Ain Shams University, Cairo 11566, Egypt; Faculty of Pharmacy, Nahda University, 62511 New Beni Suef (NUB), Egypt.
PMID: 28427017 DOI: 10.1016/j.ejmech.2017.04.028
Abstract

Hybrid molecules are used as Anticancer agents to improve effectiveness and diminish drug resistance. So, the current study aimed to introduce twenty novel phenothiazine sulfonamide hybrids 5-22, 24 and 25 of promising Anticancer activity. Compounds 11 and 13 revealed more potent Anticancer properties (IC50 8.1 and 8.8 μM) than that of the reference drug (doxorubicin, IC50 = 9.8 μM) against human breast Cancer cell line (T47D). To determine the mechanism of their Anticancer activity, compounds 5, 6, 7, 11, 13, 14, 16, 17, 19 and 22 that showed promising activity on T47D, were evaluated for their aromatase inhibitory effect. The study results disclose that the most potent aromatase inhibitors 11 and 13 showed the lowest IC50 (5.67 μM and 6.7 μM), respectively on the target Enzyme. Accordingly, the apoptotic effect of the most potent compound 11 was extensively investigated and showed a marked increase in Bax level up to 55,000 folds, and down-regulation in Bcl2 to 5.24*10-4 folds, in comparison to the control. Furthermore, the effect of compound 11 on caspases 3, 8 and 9 was evaluated and was found to increase their levels by 20, 34, and 8.9 folds, respectively, which indicates the activation of both intrinsic and extrinsic pathways. Also, the effect of compound 11 on the cell cycle and its cytotoxic effect were examined. Moreover, a molecular docking and computer aided ADMET studies were adopted to confirm their mechanism of action.

Keywords

Anticancer; Apoptosis; Aromatase inhibitors; Benzenesulfonamide; Phenothiazine.

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