High throughput screening identified 2-acetamido-thiazolylthio acetic ester 1 as an inhibitor of cyclin-dependent kinase 2 (CDK2). Because this compound is inactive in cells and unstable in plasma, we have stabilized it to metabolic hydrolysis by replacing the ester moiety with a 5-ethyl-substituted oxazole as in compound 14. Combinatorial and parallel synthesis provided a rapid analysis of the structure-activity relationship (SAR) for these inhibitors of CDK2, and over 100 analogues with IC(50) values in the 1-10 nM range were rapidly prepared. The X-ray crystallographic data of the inhibitors bound to the active site of CDK2 protein provided insight into the binding modes of these inhibitors, and the SAR of this series of analogues was rationalized. Many of these analogues displayed potent and broad spectrum antiproliferative activity across a panel of tumor cell lines in vitro. In addition, A2780 ovarian carcinoma cells undergo rapid apoptosis following exposure to CDK2 inhibitors of this class. Mechanism of action studies have confirmed that the phosphorylation of CDK2 substrates such as RB, histone H1, and DNA polymerase alpha (p70 subunit) is reduced in the presence of compound 14. Further optimization led to compounds such as water soluble 45, which possesses a favorable pharmacokinetic profile in mice and demonstrates significant antitumor activity in vivo in several murine and human models, including an engineered murine mammary tumor that overexpresses cyclin E, the coactivator of CDK2.

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Incorporating metal nanocrystals with semiconductor photoanodes significantly enhances the efficiency of the energy conversion in the visible range during water splitting due to the excitation of hot electrons. While extensively studied on ensemble samples, hot electron response of metal nanocrystals in a photoelectrochemical cell remains unexploited at the single-particle level. Herein, we systematically investigate hot electron response of individual single-crystalline gold nanocrystals (AuNCs) on a TiO2 photoanode during water splitting. We directly correlate the morphology of the AuNC and its plasmonic property to the efficiencies involving hot electrons with the help of single-particle dark-field microscopy and photocurrent mapping. Our results show that the efficiencies of individual AuNCs are dependent on a variety of factors including interface condition, applied bias, excitation power, incident angle, and AuNC size. Our research may shed light on optimizing the light-harvesting capability of metal/semiconductor photoanodes by providing insights into the photocatalytic processes.

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