Discovery of New Coumarin-Based Lead with Potential Anticancer, CDK4 Inhibition and Selective Radiotheranostic Effect: Synthesis, 2D & 3D QSAR, Molecular Dynamics, In Vitro Cytotoxicity, Radioiodination, and Biodistribution Studies

Novel 6-bromo-coumarin-ethylidene-hydrazonyl-thiazolyl and 6-bromo-coumarin-thiazolyl-based derivatives were synthesized. A quantitative structure activity relationship (QSAR) model with high predictive power r(2) = 0.92, and RMSE = 0.44 predicted five compounds; 2b, 3b, 5a, 9a and 9i to have potential anticancer activities. Compound 2b achieved the best Delta G of -15.34 kcal/mol with an affinity of 40.05 pki. In a molecular dynamic study 2b showed an equilibrium at 0.8 angstrom after 3.5 ns, while flavopiridol did so at 0.5 angstrom after the same time (3.5 ns). 2b showed an IC50 of 0.0136 mu M, 0.015 mu M, and 0.054 mu M against MCF-7, A-549, and CHO-K1 cell lines, respectively. The CDK4 enzyme assay revealed the significant CDK4 inhibitory activity of compound 2b with IC50 of 0.036 mu M. The selectivity of the newly discovered lead compound 2b toward localization in tumor cells was confirmed by a radioiodination biological assay that was done via electrophilic substitution reaction utilizing the oxidative effect of chloramine-t. I-131-2b showed good in vitro stability up to 4 h. In solid tumor bearing mice, the values of tumor uptake reached a height of 5.97 +/- 0.82%ID/g at 60 min p.i. I-131-2b can be considered as a selective radiotheranostic agent for solid tumors with promising anticancer activity.

Automated summary

The newly synthesized 6-bromo-coumarin-ethylidene-hydrazonyl-thiazolyl compound 2b showed potential anticancer activity against multiple cancer cell lines, with good stability and selective targeting of tumor cells demonstrated in molecular dynamic studies. It can be considered as a promising radiotheranostic agent for solid tumors.