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Coculture-Based Screening Revealed Selective Cytostatic Effects of Pyrazol-Azepinoindoles
Dmitry A Skvortsov1, Irina V Zhirkina1, Daria A Ipatova1
1Chemistry Department and AN Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Leninskie Gory, Building 1/3 GSP-1, Moscow, 119991, Russian Federation.
Abstract:
This work focuses on the search for new small molecules for anticancer therapy using the fluorescent cells cocultivation test (FCCT). This method allows the control of the specificity of the action of compounds from the earliest stages of drug development. For the FCCT, labeled MCF7' breast cancer cells and noncancerous breast MCF10A cells are cocultured. Screening of 2025 compounds in the above system and previously developed coculture of A549 with VA13 yields 16 selectively cytotoxic molecules. The results are confirmed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay for seven of these molecules. Few are known as potential antitumor agents: angelicin, coumarin, and colchicine derivatives. However, the structures of macrocycle 1, pyrazole-azepinoindole derivative 2, and complex heterocyclic derivative 3 are not described as anticancer compounds according to the PubChem and SciFinder databases. Structure-activity relationships are investigated for 2 and its derivatives. The indole with a caprolactam ring (tetrahydro-azepinoindolone core) together with the pyrazolyl at the third position is the key element of the pharmacophore. The optimized pyrazole-azepinoindole derivative 23 shows SI = 18 for HCT116 versus VA-13 on the expanded array of cell lines. Its effect is mainly mediated by the G1 arrest of the cell cycle.
Insights
Researchers identified 16 novel selectively cytotoxic molecules for anticancer therapy using a fluorescent cells cocultivation test (FCCT). Optimized pyrazole-azepinoindole derivative 23 demonstrated significant efficacy and cell cycle arrest.
Area of Science:
- Drug Discovery and Development
- Medicinal Chemistry
- Cancer Biology
Background:
- The search for novel anticancer agents is crucial for effective cancer therapy.
- Early-stage screening methods are vital for identifying compounds with specific cytotoxic activity.
- Existing drug discovery pipelines require innovative approaches to identify new molecular entities.
Purpose of the Study:
- To identify novel small molecules with selective anticancer activity.
- To utilize the fluorescent cells cocultivation test (FCCT) for early-stage drug development.
- To investigate structure-activity relationships of promising anticancer compound scaffolds.
Main Methods:
- Screening of 2025 compounds using the fluorescent cells cocultivation test (FCCT) with breast cancer (MCF7) and noncancerous (MCF10A) cells.
- Confirmation of cytotoxicity using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay.
- Structure-activity relationship (SAR) analysis of pyrazole-azepinoindole derivatives.
Main Results:
- Identification of 16 selectively cytotoxic molecules, including known agents and novel compounds like macrocycle 1, pyrazole-azepinoindole derivative 2, and complex heterocyclic derivative 3.
- Confirmation of anticancer potential for seven compounds via MTT assay.
- An optimized pyrazole-azepinoindole derivative (23) exhibited a selectivity index (SI) of 18 against HCT116 versus VA-13 cells.
Conclusions:
- The FCCT is an effective method for identifying selectively cytotoxic anticancer compounds early in development.
- Novel chemical scaffolds, particularly pyrazole-azepinoindole derivatives, show significant potential for anticancer therapy.
- The identified compounds, especially derivative 23, warrant further investigation for their therapeutic efficacy, with effects mediated by G1 cell cycle arrest.
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