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Novel, Selective CDK9 Inhibitors for the Treatment of HIV Infection

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Cyclin Dependent Kinases (CDKs) are important regulators of cell cycle and gene expression. Since an up-todate review about the pharmacological inhibitors of CDK family (CDK1-10) is not available; therefore in the present paper we briefly summarize the most relevant inhibitors and point out the low number of selective inhibitors. Among CDKs, CDK9 is a validated pathological target in HIV infection, inflammation and cardiac hypertrophy; however selective CDK9 inhibitors are still not available. We present a selective inhibitor family of CDK9 based on the 4-phenylamino-6- phenylpyrimidine nucleus. We show a convenient synthetic method to prepare a useful intermediate and its derivatisation resulting in novel compounds. The CDK9 inhibitory activity of the derivatives was measured in specific kinase assay and the CDK inhibitory profile of the best ones (IC50 > 100nM) was determined. The most selective compounds had high selectivity over CDK1, 2, 3, 5, 6, 7 and showed at least one order of magnitude higher inhibitory activity over CDK4 inhibition. The most selective molecules were examined in cytotoxicity assays and their ability to inhibit HIV-1 replication was determined in cellular assays.





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Keywords: 4-aminophenyl-6-phenyl-pyrimidine; ATP-binding; Alzheimer's disease; CDK9; Flavopiridol; HIV; Herpes Simplex Virus; RNA polymerase; Sulfone groups; alsterpaullone; aminophenyl ring; boronic acids; cancer cells; carbazoles; cardiology; cell-division cycle; chloro-pyrimidines; chloropyrimidine; co-crystallization; colorectal tumours; cyclin-dependent kinases; docking; ephosphorylation; flavopiridol; hydrolysis; hypertension; inflammatory diseases; intermediate; kinase inhibitor; ligands; mitosis; nucleotide analogue; oncology; oxygen concentration; pathologic cellular; pharmacophore points; phosphorylates retinoblastoma1 protein; phosphorylation; selectivity; staurosporin; synthesis; trifocal complex; viral transcription; virology; xylocydine

Document Type: Research Article

Publication date: 2011-01-01

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  • Current Medicinal Chemistry covers all the latest and outstanding developments in medicinal chemistry and rational drug design. Each issue contains a series of timely in-depth reviews written by leaders in the field covering a range of the current topics in medicinal chemistry. Current Medicinal Chemistry is an essential journal for every medicinal chemist who wishes to be kept informed and up-to-date with the latest and most important developments.
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