We recently reported the discovery of AM-8553 (1), a potent and selective piperidinone inhibitor of the MDM2-p53 interaction. Continued research investigation of the N-alkyl substituent of this series, focused in particular on a previously underutilized interaction in a shallow cleft on the MDM2 surface, led to the discovery of a one-carbon tethered sulfone which gave rise to substantial improvements in biochemical and cellular potency. Further investigation produced AMG 232 (2), which is currently being evaluated in human clinical trials for the treatment of cancer. Compound 2 is an extremely potent MDM2 inhibitor (SPR KD = 0.045 nM, SJSA-1 EdU IC50 = 9.1 nM), with remarkable pharmacokinetic properties and in vivo antitumor activity in the SJSA-1 osteosarcoma xenograft model (ED50 = 9.1 mg/kg).
Structure-based rational design led to the discovery of novel inhibitors of the MDM2-p53 protein-protein interaction. The affinity of these compounds for MDM2 was improved through conformational control of both the piperidinone ring and the appended N-alkyl substituent. Optimization afforded 29 (AM-8553), a potent and selective MDM2 inhibitor with excellent pharmacokinetic properties and in vivo efficacy.
The design of heterojunction with superior performance of light absorption and appropriate conduction band and valence band potentials is a promising approach for the applications in efficient environmental remediation and the solar energy storage. In recent years, many studies have been devoted to the applications of graphitic carbon nitride (g-CN)-based heterojunction photoactive nanomaterials under visible light irradiation due to its excellent physical, optical, and electrical properties, which inspired us to compile this review. Although many reviews demonstrated about the syntheses and applications of g-CN composites, a targeted review on the systematic application and photocatalytic mechanisms of g-CN-based heterojunction, in which components are in intimate linkage with each other rather than a physical mixture, is still absent. In this review, the applications of g-CN-based heterojunction photoactive nanomaterials in environmental remediation and solar energy storage, such as photocatalytic treatment of persistent organic pollutants, heavy-metal-ion redox, oxidative decomposition of pathogens, water splitting for H evolution, and CO reduction, are systematically discussed. In addition, some emerging applications, such as solar cells and biosensors, are also introduced. Meanwhile, a comprehensive assessment on the basis of first-principles calculations and the thermodynamics and kinetics of surface catalytic reaction for the electronic structure and photocatalytic properties of g-CN-based heterojunction are valued by this review. In the end, a brief summary and perspectives in designing practical heterojunction photoactive nanomaterials also showed the bright future of g-CN-based heterojunction. Altogether, this review systematically complements the information that previous reviews have frequently ignored and points out the future development trends of g-CN-based heterojunction, which expected to provide important references and right directions for the development and practical applications of g-CN-based heterojunction photoactive nanomaterials.
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