Highly Potent, Selective, and Orally Bioavailable 4-Thiazol-N-(pyridin-2-yl)pyrimidin-2-amine Cyclin-Dependent Kinases 4 and 6 Inhibitors as Anticancer Drug Candidates: Design, Synthesis, and Evaluation

Abstract

Cyclin D dependent kinases (CDK4 and CDK6) regulate entry into S phase of the cell cycle and are validated targets for anticancer drug discovery. Herein we detail the discovery of a novel series of 4-thiazol-N-(pyridin-2-yl)pyrimidin-2-amine derivatives as highly potent and selective inhibitors of CDK4 and CDK6. Medicinal chemistry optimization resulted in 83, an orally bioavailable inhibitor molecule with remarkable selectivity. Repeated oral administration of 83 caused marked inhibition of tumor growth in MV4-11 acute myeloid leukemia mouse xenografts without having a negative effect on body weight and showing any sign of clinical toxicity. The data merit 83 as a clinical development candidate.

Neurolocomotor Behavior and Oxidative Stress Markers of Thiazole and Thiazolidinedione Derivatives against Nauphoeta cinerea

“…The derivatives of thiazolidines, thiazoles and thiazolidinediones are molecules recognized in the literature for presenting a series of relevant pharmacological activities [ 1 , 2 , 3 ]. Among these activities are antimicrobial [ 3 , 4 ], antiviral [ 1 , 2 ], neurodegenerative [ 5 ], antitumor [ 6 , 7 ] and antioxidant [ 8 ] activities.…”

Fluorine‐Containing sp3‐Enriched Building Blocks for the Multigram Synthesis of Fluorinated Pyrazoles and Pyrimidines with (Hetero)aliphatic Substituents

“…Column chromatography was performed using Kieselgel Merck 60 (230-400 mesh) as the stationary phase. 1 H and 13 C{ 1 H} NMR spectra were recorded on a Bruker 170 Avance 500 spectrometer (at 500 MHz for 1 H NMR, 126 MHz for 13 C{ 1 H} NMR, and 470 MHz for 19 F{ 1 H} NMR), Agilent ProPulse 600 spectrometer (at 600 MHz for 1 H NMR and 151 MHz for 13 C{ 1 H} NMR), and Varian Unity Plus 400 spectrometer (at 400 MHz for 1 H NMR, 101 MHz for 13 C{ 1 H} NMR, and 376 MHz for 19 F{ 1 H} NMR). NMR chemical shifts are reported in ppm downfield from TMS as an internal standard and are referenced using residual NMR solvent peaks at 7.26 and 77.16 ppm for 1 H and 13 C{ 1 H} in CDCl 3 , 2.50 and 39.52 ppm for 1 H and 13 C{ 1 H} in DMSO-d 6 .…”

“…13 C{ 1 H} NMR (151 MHz, DMSO-d 6 ) δ 159.1 (q, J = 33.6 Hz), 147.2 (d, J = 241.9 Hz), 134.3, 117.6, 117.0 (q, J = 296.4 Hz), 50.8, 27.2 (d, J = 3.4 Hz). 19…”

Antiproliferative Effects of Alkaloids from the Bulbs of Crinum abyscinicum Hochst. ExA. Rich

“…Apoptotic induction test was performed as described previously [ 20 ]. Cells were seeded at 8 × 10 4 cells per well using a 6-well plate and incubated overnight at 37°C, 5% CO 2 .…”