Synthesis and configuration of the cyclin-dependent kinase inhibitor roscovitine and its enantiomer

Wang, Shudong; McClue, Steven J.; Ferguson, John R.; Hull, Jonathan D.; Stokes, Steven H.; Parsons, Simon; Westwood, R.; Fischer, Peter M.

doi:10.1016/s0957-4166(01)00471-2

Cited by 37 publications

(28 citation statements)

References 12 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…23 This we were able to attribute to the optical and chemical purity of our preparation of R-roscovitine. 11 It should be noted that the increased potency of CYC202 over roscovitine is not maintained across all kinases: activity at CDK2/cyclin A is comparable to that previously published, 16 despite the fact that in our assays ATP was present at the higher concentration of 100 M. Activity at CDK1/ cyclin B is actually less than that published. The enzymes we used here were exclusively human, while Meijer et al 16 used starfish cdc2, and similarly the substrates used for many of these kinases were different: we used a GST-Rb fragment for CDK2/cyclin A, while Histone was used by Meijer et al 16 We were also able to show a selective anti-tumour effect, with an average potency against a group of human tumour cell lines of 15.2 M (range 7.9 to 30.2 M), which compared to potencies of almost 2-fold lower against non-proliferating cells (range 22.2 to Ͼ 100 M), suggesting that a therapeutic window could be achieved.…”

Section: Discussionsupporting

confidence: 57%

“…One possibility was that our material had a different optical purity to that used by other groups. 11 Improved potency of 2-R-vs. 2-S substituted purine enantiomers has previously been observed. 17,18 To test this we synthesised and assayed the Sisomer, which in our CDK2/cyclin E assay gave an IC 50 of 0.24 (Ϯ 0.02) M (n ϭ 3).…”

Section: Cyc202 Potency Against Purified Recombinant Kinasesmentioning

confidence: 99%

“…10 Compounds of this class have been shown to block proliferation of various tumour types in cell culture. [11][12][13] Our study describes the relative potency of CYC202 (R-roscovitine) against purified recombinant CDKs and relates this result to in vivo growth inhibitory properties in a panel of human cancer cell lines representative of human solid tumours, and compares its cytotoxicity in proliferating tumour cells vs. non-proliferating cells. The effects of CYC202 on cell cycle distribution in Lovo colorectal carcinoma cells is discussed.…”

mentioning

confidence: 99%

See 2 more Smart Citations

In vitro and in vivo antitumor properties of the cyclin dependent kinase inhibitor CYC202 (R‐roscovitine)

McClue

Blake

Clarke

et al. 2002

Intl Journal of Cancer

Self Cite

360

296

View full text Add to dashboard Cite

CDK2 inhibitors have been proposed as effective anti-cancer therapeutics. We show here that CYC202 (R-roscovitine) is a potent inhibitor of recombinant CDK2/cyclin E kinase activity (IC 50 ‫؍‬ 0.10 M) with an average cytotoxic IC 50 of 15.2 M in a panel of 19 human tumour cell lines, and we also demonstrate selectivity for rapidly proliferating cells over non-proliferating cells. A study of the cell cycle effects of CYC202 in Lovo colorectal carcinoma cells showed that the major effect was not the predicted arrest in one part of the cycle, but rather an induction of cell death from all compartments of the cell cycle. The maximum tolerated dose given intravenously to mice was in excess of 20 mg/kg. Doses up to 2,000 mg/kg were tolerated when administered orally in mice. Following repeated intraperitoneal administration (3 times daily for 5 days) of 100 mg/kg to nude mice bearing the Lovo human colorectal tumour, CYC202 induced a significant antitumour effect with a 45% reduction in tumour growth compared to controls. A second experiment using the human uterine xenograft MESSA-DX5 treated with orally administered CYC202 (500 mg/kg 3 times daily for 4 days) also exhibited a significant reduction in the rate of growth of the tumour (62%). These data, showing enzyme and cellular potency together with antitumour activity, confirm the potential of CDK2 inhibitors such as CYC202 as anticancer drugs. © 2002 Wiley-Liss, Inc. Key words: cyclin-dependent kinase inhibitors; CYC202; roscovitine; cell cycle; anti-tumour efficacyCyclin-dependent kinases (CDKs) are key regulators in the process of cell cycle progression. 1 These enzymes are activated by periodic formation of complexes with cyclins, which are proteins that are present only at specific stages of the cell cycle. CDK4 and CDK6, coupled with their partner cyclin D, are responsible for progression through G1, whereas CDK2 in combination with cyclin E is responsible for normal progression from G1 into S phase. CDK2/cyclin A is required for progression through S phase, and CDK1/cyclin B is necessary for mitosis to occur. 2 These CDK/ cyclin complexes are regulated in turn by stoichiometric association with small proteins, cyclin-dependent kinase inhibitors (CDKIs), such as p19, p16, p15, p21 and p27, which are members of the INK4 and WAF1/KIP1 class of CDK inhibitor. Mutation and/or deletion of some of these CDKIs has been shown in many human neoplasias. 3 Hence control of the cell cycle through CDKs, by means of small molecule CDK inhibitors, has been of great interest as a novel cancer treatment strategy. Questions remain, however, regarding the importance of CDK selectivity for this type of agent. Both CDK2 and CDK4 have been targeted for small molecule inhibitor development, and recent results suggest that CDK2 antagonists may induce apoptosis selectively in transformed cells regardless of p53 status, 4 while the function of CDK4 has now been linked to modulation of the rate of cellular growth and has been suggested to be (in Drosophila at least) dispensable for cel...

show abstract

Section: Discussionsupporting

confidence: 57%

Section: Cyc202 Potency Against Purified Recombinant Kinasesmentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

In vitro and in vivo antitumor properties of the cyclin dependent kinase inhibitor CYC202 (R‐roscovitine)

McClue

Blake

Clarke

et al. 2002

Intl Journal of Cancer

Self Cite

360

296

View full text Add to dashboard Cite

show abstract

“…We have synthesised (R)-roscovitine (CYC202) and its (S)-enantiomer [98] and molecular structure of the produced CYC202 was determined unambiguously by X-ray diffraction. Briefly, compound 2,6-dichloropurine (1) was converted into N-benzyl-2-chloro-9H-purin-6-amine (2) up on heating with benzylamine in the presence of triethylamine in n-butanol for a period of 3 hours.…”

Section: Chemical Synthesis and Physicochemical Properties Of Roscovimentioning

confidence: 99%

From Roscovitine to CYC202 to Seliciclib – from bench to bedside: discovery and development

Zhelev

Trifonov²,

Wang³

et al. 2013

Biodiscovery

Self Cite

View full text Add to dashboard Cite

This monograph reviews the discovery and development of the cyclindependent kinase inhibitor roscovitine (R-roscovitine, CYC202, Seliciclib). The authors summarise the in vitro and in vivo data that have formed the basis for clinical investigation of Seliciclib as an anti-cancer drug. Kinase selectivity, cellular effects and the pharmacological properties of the drug are discussed in addition to the clinical results of Seliciclib being reviewed. Novel results on the effect of the drug in cardiac hypertrophy are summarized and potential applications of Seliciclib in other therapeutic areas, including, inflammation, virology, glomerulonephritis and polycystic kidney disease, are discussed. Finally the authors argue that optimisation of the therapeutic effect of kinase inhibitors such as Seliciclib can be enhanced using a systems biology approach involving mathematical modelling of the molecular pathways regulating cell growth and division. Seliciclib -discovery and developmentBioDiscovery 2 December 2013 | Issue 10 | 1

show abstract

“…[9][10][11][12][13] In the process of designing novel class PLK1 inhibitors we prepared and evaluated the biological activity of ON 01910 and several derivatives. The structure activity relationship established has provided guidance for us to rapidly progress our drug discovery programme.…”

Section: Sodiummentioning

confidence: 99%

Synthesis and biological evaluation of benzyl styrylsulfonyl derivatives as potent anticancer mitotic inhibitors

Chahrour

Abdalla

Lam

et al. 2011

Bioorganic & Medicinal Chemistry Letters

Self Cite

View full text Add to dashboard Cite

Synthesis and configuration of the cyclin-dependent kinase inhibitor roscovitine and its enantiomer

Cited by 37 publications

References 12 publications

In vitro and in vivo antitumor properties of the cyclin dependent kinase inhibitor CYC202 (R‐roscovitine)

In vitro and in vivo antitumor properties of the cyclin dependent kinase inhibitor CYC202 (R‐roscovitine)

From Roscovitine to CYC202 to Seliciclib – from bench to bedside: discovery and development

Synthesis and biological evaluation of benzyl styrylsulfonyl derivatives as potent anticancer mitotic inhibitors

Contact Info

Product

Resources

About