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...

Narrow graphene nanoribbons exhibit substantial electronic bandgaps and optical properties fundamentally different from those of graphene. Unlike graphene-which shows a wavelength-independent absorbance for visible light-the electronic bandgap, and therefore the optical response, of graphene nanoribbons changes with ribbon width. Here we report on the optical properties of armchair graphene nanoribbons of width N ¼ 7 grown on metal surfaces. Reflectance difference spectroscopy in combination with ab initio calculations show that ultranarrow graphene nanoribbons have fully anisotropic optical properties dominated by excitonic effects that sensitively depend on the exact atomic structure. For N ¼ 7 armchair graphene nanoribbons, the optical response is dominated by absorption features at 2.1, 2.3 and 4.2 eV, in excellent agreement with ab initio calculations, which also reveal an absorbance of more than twice the one of graphene for linearly polarized light in the visible range of wavelengths.

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Following the identification through virtual screening of 4-(2,4-dimethyl-thiazol-5-yl)pyrimidin-2-ylamines as moderately potent inhibitors of cyclin-dependent kinase-2 (CDK2), a CDK inhibitor analogue program was initiated. The first aims were to optimize potency and to evaluate the cellular mode of action of lead candidate molecules. Here the synthetic chemistry, the structure-guided design approach, and the structure-activity relationships (SARs) that led to the discovery of 2-anilino-4-(thiazol-5-yl)pyrimidine ATP-antagonistic CDK2 inhibitors, many with very low nM K(i)s against CDK2, are reported. Furthermore, X-ray crystal structures of four representative analogues from our chemical series in complex with CDK2 are presented, and these structures are used to rationalize the observed biochemical SARs. Finally results are reported that show, using the most potent CDK2 inhibitor compound from the current series, that the observed antiproliferative and proapoptotic effects are consistent with cellular CDK2 and CDK9 inhibition.