Aromatase inhibition by 2-methyl indole hydrazone derivatives evaluated via molecular docking and in vitro activity
Senem Ozcan-Sezer1, Elif Ince1, Atilla Akdemir2
1a Faculty of Pharmacy, Department of Pharmaceutical Toxicology , Ege University , Izmir , Turkey.
Abstract:
A causal association is reported between prolonged exposures to elevated levels of estrogen and breast cancer. Therefore inhibiting aromatase (CYP19A), which catalyses the conversion of androgens to estrogens, is an important approach in prevention and treatment of estrogen receptor positive (ER+) breast cancer. Melatonin, a natural indolic hormone, is reported to prevent free radical induced carcinogenesis and block local estrogen synthesis in breast tissue via aromatase inhibition. However several features of melatonin limit its therapeutic use. In the present study aromatase inhibiting potential of 2-methyl indole hydrazones are investigated, and compared with melatonin, by two in vitro models; a cell-free assay using a fluorescence substrate and a cell-based assay where cell proliferation was determined in ER + human breast cancer cells (MCF-7 BUS) in the absence of estrogen and the presence of testosterone. Aromatase inhibitory effect is also explored by molecular modelling studies. In biological activity assays monochloro substituted indole hydrazones were found to have stronger aromatase inhibitory activity among all tested derivatives and were more active than melatonin. This finding is further confirmed by molecular modelling. These results may be useful in the design and synthesis of novel melatonin analogues with higher inhibitory potency against aromatase.
Insights
New indole hydrazones show stronger aromatase inhibition than melatonin, offering potential for novel breast cancer therapies. These compounds may lead to improved treatments for estrogen receptor-positive breast cancer by blocking estrogen synthesis.
Area of Science:
- Biochemistry
- Pharmacology
- Oncology
Background:
- Elevated estrogen levels are linked to breast cancer, necessitating aromatase inhibition.
- Aromatase (CYP19A) inhibitors are crucial for treating estrogen receptor-positive (ER+) breast cancer.
- Melatonin inhibits aromatase but has therapeutic limitations.
Purpose of the Study:
- To investigate the aromatase-inhibiting potential of 2-methyl indole hydrazones.
- To compare the efficacy of these novel compounds with melatonin.
- To explore the molecular mechanisms of aromatase inhibition.
Main Methods:
- In vitro assays: cell-free fluorescence substrate assay and cell-based assay using ER+ MCF-7 BUS cells.
- Assessed cell proliferation in the absence of estrogen and presence of testosterone.
- Molecular modeling studies to explore aromatase inhibition.
Main Results:
- Monochloro-substituted indole hydrazones exhibited the strongest aromatase inhibitory activity.
- These derivatives were more potent inhibitors than melatonin.
- Molecular modeling confirmed the enhanced inhibitory effects.
Conclusions:
- 2-methyl indole hydrazones, particularly monochloro derivatives, are potent aromatase inhibitors.
- These compounds represent promising candidates for developing new melatonin analogues.
- Findings support the design of novel therapeutics for ER+ breast cancer.
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