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

• Published in: Molecules (Basel, Switzerland) Vol. 26; no. 8; p. 2273
• Main Authors: Sarhan, Mona O, Abd El-Karim, Somaia S, Anwar, Manal M, Gouda, Raghda H, Zaghary, Wafaa A, Khedr, Mohammed A
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 14.04.2021; MDPI
• Subjects: A549 Cells; Amino Acid Sequence; Animals; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Antitumor activity; Cancer therapies; CDK4; Cell cycle; Cell Death - drug effects; Chloramine-T; CHO Cells; Coumarin; Coumarins - chemistry; Coumarins - pharmacology; Cricetulus; Cyclin-Dependent Kinase 2 - chemistry; Cyclin-dependent kinase 4; Cyclin-Dependent Kinase 4 - antagonists & inhibitors; Cyclin-Dependent Kinase 4 - chemistry; Cyclin-Dependent Kinase 4 - metabolism; Cyclin-dependent kinases; Cytotoxicity; Drug Design; Drug Discovery; Drugs; Flavopiridol; Humans; Inhibitory Concentration 50; Iodine Radioisotopes - chemistry; Kinases; Lead compounds; Localization; MCF-7 Cells; Molecular Docking Simulation; Molecular dynamics; Molecular Dynamics Simulation; Quantitative Structure-Activity Relationship; Radioiodination; Selectivity; Solid tumors; Structure-activity relationships; Substitution reactions; synthesis; Tissue Distribution - drug effects; Tumor cells; Tumors; synthesis; radioiodination; molecular dynamics; CDK4; coumarin
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules26082273

Novel 6-bromo-coumarin-ethylidene-hydrazonyl-thiazolyl and 6-bromo-coumarin-thiazolyl-based derivatives were synthesized. A quantitative structure activity relationship ( model with high predictive power r = 0.92, and RMSE = 0.44 predicted five compounds; , , , and to have potential anticancer activities. Compound achieved the best ΔG of -15.34 kcal/mol with an affinity of 40.05 pki. In a molecular dynamic study 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). showed an IC 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 with IC of 0.036 µM. The selectivity of the newly discovered lead compound 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. 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. can be considered as a selective radiotheranostic agent for solid tumors with promising anticancer activity.