Oxindole-Based Inhibitors of Cyclin-Dependent Kinase 2 (CDK2):  Design, Synthesis, Enzymatic Activities, and X-ray Crystallographic Analysis

Rathos

Molecular Cancer Therapeutics

et al. 2007

116

Cyclin-dependent kinases (Cdk) and their associated pathways represent some of the most attractive targets for the development of anticancer therapeutics. Based on antitumor activity in animal models, a variety of Cdk inhibitors are undergoing clinical evaluation either as a single agent or in combination with other approved drugs. In our anticancer drug discovery program, a novel series of flavones have been synthesized for evaluation against the activity of Cdk4-D1. This enzyme catalyzes the phosphorylation of retinoblastoma protein, thus inhibiting its function. We have identified a series of potent Cdk4-D1 inhibitors with IC 50 below 250 nmol/L. In this report, we have described the properties of one of the best compound,

Section: Introductionmentioning

confidence: 99%

In vitro antitumor properties of a novel cyclin-dependent kinase inhibitor, P276-00

Rathos

Molecular Cancer Therapeutics

et al. 2007

116

Molecular Cancer Therapeutics

“…One of these compounds, R-roscovitine (13), is now undergoing evaluation in phase II clinical trials. In addition, more selective inhibitors of CDK2 are being investigated (14,15).…”

Section: Introductionmentioning

confidence: 99%

The cellular phenotype of AZ703, a novel selective imidazo[1,2-a]pyridine cyclin-dependent kinase inhibitor

Byth

Geh

Forder

et al. 2006

Because the majority of cancers exhibit direct or indirect deregulation of cyclin-dependent kinase (CDK) function, members of the CDK family are attractive targets for the development of anticancer agents. As part of an ongoing program, novel imidazopyridines were identified and developed as potent and selective CDK inhibitors. Here, we describe data on the in vitro biological activities of one of these compounds, AZ703. The selectivity profile of AZ703 was investigated in kinase assays against a range of CDK enzymes as well as a panel of protein kinases in vitro. IC 50 s were assessed against different tumor cell lines in vitro. The mechanism of action of AZ703 was determined by observing changes in phosphorylation of CDK substrates and cell cycle effects on tumor and normal cells. In vitro studies revealed that AZ703 is a selective inhibitor of CDK1 and CDK2 and displays a mode of action consistent with the induction of G 1 -, S-, and G 2 -M-phase arrest. AZ703 also showed potent antiproliferative activity across a wide range of tumor cell lines in vitro. Moreover, AZ703 induced reversible blockade of normal cells while causing tumor cells to undergo apoptosis. We have identified AZ703 as a novel selective imidazo[1,2-a]pyridine CDK inhibitor that shows promising antitumor properties in vitro. [Mol Cancer Ther 2006;5(3):655 -64]

European Journal of Medicinal Chemistry

“…Unfortunately, due to purification problems the coupling/deprotection sequence was performed in only 29% yield of pure isolated 3. Accordingly, we decided to attempt another approach for the preparation of the bromo-analogue 6, involving the 5-bromo-3-ethoxymethyleneindolin-2-one (5) instead of the dimethylaminomethylene intermediate [7]. 5-Bromoindolin-2-one (4) was obtained by bromination of the corresponding indolin-2-one as previously described [15].…”

Section: Chemistrymentioning

confidence: 99%

“…As part of our ongoing studies concerning the preparation of potential biologically active compounds, we were interested in the synthesis of indolin-2-one derivatives [1] and [2]. Since various kinases are involved in the growth of microorganisms and because many oxindoles are kinases' inhibitors [3], [4], [5], [6], [7] and [8], these compounds could exert antibacterial activities as it was shown previously for several oxindole derivatives ( Fig. 1) [9], [10] and [11].…”

Section: Introductionmentioning

confidence: 99%

Synthesis and biological evaluation of diversely substituted indolin-2-ones

Bouchikhi

Rossignol

Sancelme

et al. 2008

The synthesis of indolin-2-one derivatives substituted in the 3-position by an aminomethylene group bearing either an ornithine or a lysine residue is described. The inhibitory activities of these compounds toward a panel of eight kinases were examined. Furthermore, the antibacterial activities of the prepared compounds were tested against two Gram-positive bacteria Bacillus cereus and Streptomyces chartreusis, a Gram-negative bacterium Escherichia coli and a yeast Candida albicans.