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3-Substituted-4-hydroxycoumarin as a new scaffold with potent CDK inhibition and promising anticancer effect: Synthesis,molecular modeling and QSAR studies |
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| Institution: | 1. 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;2. Chemistry Department, Faculty of Science, Taif University, Taif, Saudi Arabia;3. Pharmaceutical Chemistry Department, Faculty of Pharmacy, Helwan University, Ein Helwan, Cairo, P.O. Box 11795, Egypt;4. Research Unit, Saco Pharm. Co., 6th October City, Egypt;5. Department of pharmaceutical sciences, College of clinical pharmacy, King faisal university, Saudi Arabia;1. Department of Chemistry, The University of Sistan and Baluchestan, 98135-674 Zahedan, Islamic Republic of Iran;2. Department of Chemistry, Payame Noor University, 19395-4697 Tehran, Islamic Republic of Iran;1. Department of Chemistry, Faculty of Science, Ain Shams University, Abbassiya 11566, Cairo, Egypt;2. Department of Pharmaceutical Sciences, College of Pharmacy, AlMaarefa University, Ad Diriyah 13713, Riyadh, Saudi Arabia;3. Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City 11884, Cairo, Egypt;1. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Marmara University, Istanbul, Turkey;2. Department of Biochemistry, School of Medicine, Aydin Adnan Menderes University, Ayd?n, Turkey;1. Pharmaceutical Chemistry Department, Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt;2. Pharmaceutical Chemistry Department, Faculty of Pharmaceutical Sciences and Pharmaceutical Industries, Future University in Egypt, Cairo, Egypt;3. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, New Giza University, Newgiza, km 22 Cairo–Alexandria Desert Road, Cairo, Egypt |
| 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 = 0.35–0.88 nM). Most of them elicited considerable inhibiting effect against CDK9T1 (Ki = 3.26–23.45 nM). 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 0.23 nM, 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 10 mg/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 R2 of 0.81. |
| Keywords: | 4-Hydroxycoumarin Pyrazolines 2-Aminopyridine-3-carbonitriles CDK Anticancer Molecular docking QSAR CDK"} {"#name":"keyword" "$":{"id":"k0045"} "$$":[{"#name":"text" "_":"cyclin dependent kinase QSAR"} {"#name":"keyword" "$":{"id":"k0055"} "$$":[{"#name":"text" "_":"quantitative structure activity relationship AP-1"} {"#name":"keyword" "$":{"id":"k0065"} "$$":[{"#name":"text" "_":"activator protein-1 RMSE"} {"#name":"keyword" "$":{"id":"k0075"} "$$":[{"#name":"text" "_":"root mean square error TLC"} {"#name":"keyword" "$":{"id":"k0085"} "$$":[{"#name":"text" "_":"thin layer chromatography DMSO"} {"#name":"keyword" "$":{"id":"k0095"} "$$":[{"#name":"text" "_":"dimethylsulfoxide MOPAC"} {"#name":"keyword" "$":{"id":"k0105"} "$$":[{"#name":"text" "_":"molecular orbital PACkage |
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