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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
| Content Provider | MDPI |
|---|---|
| Author | Sarhan, Mona O. El-Karim, Somaia S. Abd Anwar, Manal M. Gouda, Raghda H. Zaghary, Wafaa A. Khedr, Mohammed A. |
| Copyright Year | 2021 |
| Description | 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 ΔG of –15.34 kcal/mol with an affinity of 40.05 pki. In a molecular dynamic study 2b showed an equilibrium at 0.8 Å after 3.5 ns, while flavopiridol did so at 0.5 Å after the same time (3.5 ns). 2b showed an $IC_{50}$ of 0.0136 µM, 0.015 µM, and 0.054 µM 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 $IC_{50}$ of 0.036 µM. 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.$ ^{131}$I-2b showed good in vitro stability up to 4 h. In solid tumor bearing mice, the values of tumor uptake reached a height of 5.97 ± 0.82%ID/g at 60 min p.i.$ ^{131}$I-2b can be considered as a selective radiotheranostic agent for solid tumors with promising anticancer activity. |
| Starting Page | 2273 |
| e-ISSN | 14203049 |
| DOI | 10.3390/molecules26082273 |
| Journal | Molecules |
| Issue Number | 8 |
| Volume Number | 26 |
| Language | English |
| Publisher | MDPI |
| Publisher Date | 2021-04-14 |
| Access Restriction | Open |
| Subject Keyword | Molecules Medicinal Chemistry Coumarin Synthesis Molecular Dynamics Radioiodination Cdk4 |
| Content Type | Text |
| Resource Type | Article |
