title: 3-Substituted-4-hydroxycoumarin as a new scaffold with potent CDK inhibition and promising anticancer effect: Synthesis, molecular modeling and QSAR studies.
abstract: A new series of 3-substituted-4-hydroxycoumarin derivatives was designed, synthesized, and evaluated for CDK inhibiting and anticancer activities. All the synthesized target compounds showed remarkably high affinity and selectivity towards CDK1B, compared to flavopiridol, with Ki values in the low nanomolar range (Ki=0.35-0.88nM). Most of them elicited considerable inhibiting effect against CDK9T1 (Ki=3.26-23.45nM). Moreover, all the target compounds were tested in vitro against eighteen types of human tumor cell lines. The hydrazone 3a, N-phenylpyrazoline derivative 6b and 2-aminopyridyl-3-carbonitrile derivative 8c were the most potent anticancer agents against MCF-7 breast cancer cell line (IC50=0.21, 0.21 and 0.23nM, respectively). The target compounds 3a, 6b and 8c were further evaluated in MCF-7 breast cancer mouse xenograft model and showed in vivo efficacy at 10mg/kg dose. The docking study confirmed a unique binding mode in the active site of CDK1B with better score than flavopiridol. Quantitative structure activity relationship study was done and revealed a highly predictive power R(2) of 0.81.
authors.affiliation: Chemistry of Natural Compounds Department, Pharmaceutical Industries Division, National Research Center, 33 El Bohouth St. (Former El Tahrir St.), Dokki, Giza, P.O. Box 12622, Egypt; Chemistry Department, Faculty of Science, Taif University, Taif, Saudi Arabia. Electronic address: nehad_km@yahoo.com.
authors.forename: Nehad A
authors.initials: NA
authors.lastname: Abdel Latif
authors.affiliation: Chemistry of Natural Compounds Department, Pharmaceutical Industries Division, National Research Center, 33 El Bohouth St. (Former El Tahrir St.), Dokki, Giza, P.O. Box 12622, Egypt.
authors.forename: Rasha Z
authors.initials: RZ
authors.lastname: Batran
authors.affiliation: Pharmaceutical Chemistry Department, Faculty of Pharmacy, Helwan University, Ein Helwan, Cairo, P.O. Box 11795, Egypt; Department of pharmaceutical sciences, College of clinical pharmacy, King faisal university, Saudi Arabia.
authors.forename: Mohammed A
authors.initials: MA
authors.lastname: Khedr
authors.affiliation: Research Unit, Saco Pharm. Co., 6th October City, Egypt.
authors.forename: Mohamed M
authors.initials: MM
authors.lastname: Abdalla
mesh_terms: D015110:4-Hydroxycoumarins / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D008958:Models, Molecular; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D021281:Quantitative Structure-Activity Relationship
chemical_list: D015110:4-Hydroxycoumarins; D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D018844:Cyclin-Dependent Kinases; C068805:4-hydroxycoumarin
keywords: 2-Aminopyridine-3-carbonitriles; 4-Hydroxycoumarin; Anticancer; CDK; Molecular docking; Pyrazolines; QSAR