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Aromatase inhibitors and apoptotic inducers: Design, synthesis, anticancer activity and molecular modeling studies of novel phenothiazine derivatives carrying sulfonamide moiety as hybrid molecules
- Source :
- European Journal of Medicinal Chemistry. 134:304-315
- Publication Year :
- 2017
- Publisher :
- Elsevier BV, 2017.
-
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 (IC 50 8.1 and 8.8 μM) than that of the reference drug (doxorubicin, IC 50 = 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 IC 50 (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.
- Subjects :
- Models, Molecular
Molecular model
Antineoplastic Agents
Apoptosis
Breast Neoplasms
Pharmacology
01 natural sciences
Structure-Activity Relationship
03 medical and health sciences
chemistry.chemical_compound
Aromatase
0302 clinical medicine
Phenothiazines
Cell Line, Tumor
Phenothiazine
Drug Discovery
medicine
Humans
Doxorubicin
Breast
Caspase
chemistry.chemical_classification
Sulfonamides
biology
Aromatase Inhibitors
010405 organic chemistry
Organic Chemistry
General Medicine
0104 chemical sciences
Molecular Docking Simulation
Enzyme
chemistry
Mechanism of action
030220 oncology & carcinogenesis
biology.protein
Female
Drug Screening Assays, Antitumor
medicine.symptom
medicine.drug
Subjects
Details
- ISSN :
- 02235234
- Volume :
- 134
- Database :
- OpenAIRE
- Journal :
- European Journal of Medicinal Chemistry
- Accession number :
- edsair.doi.dedup.....ed1cd5d0f2af971040c925b906eed173