Haengsoon Park

Discovery of Dinaciclib (SCH 727965): A Potent and Selective Inhibitor of Cyclin-Dependent Kinases

Inhibition of cyclin-dependent kinases (CDKs) has emerged as an attractive strategy for the development of novel oncology therapeutics. Herein is described the utilization of an in vivo screening approach with integrated efficacy and tolerability parameters to identify candidate CDK inhibitors with a suitable balance of activity and tolerability. This approach has resulted in the identification of SCH 727965, a potent and selective CDK inhibitor that is currently undergoing clinical evaluation.

Hydrovinylation and Related Reactions: New Protocols and Control Elements in Search of Greater Synthetic Efficiency and Selectivity

New reaction conditions and stereochemical control elements for heterodimerization between ethylene (or propylene) and functionalized vinyl arenes are highlighted (see equation). For example, an enantioselective version of the hydrovinylation reaction uses [{(allyl)NiBr}2], a noncoordinating counter anion, (bis-CF3−C6H3)4B−, and a hemilabile ligand such as MOP. Other applications include intramolecular cyclization of 1,6-dienes and heterodimerization of norbornene and ethylene.

Ligand Tuning as a Tool for the Discovery of New Catalytic Asymmetric Processes

In this era of heightened environmental awareness and ever-increasing demand for higher efficiency from chemical processes, one of the major challenges facing organic synthesis is the utilization of abundantly available carbon sources as precursors for more advanced intermediates. The dual problems of activation of thermodynamically stable precursors and their stereoselective incorporation pose new challenges, solutions of which may have broader implications in asymmetric catalysis. This review summarizes our recent efforts to discover broadly applicable control elements in key enantioselective carbon-carbon and carbon-hydrogen bondforming reactions. Transition metal complexes of 1,2-diol phosphinites derived from readily available monosaccharides catalyze a variety of asymmetric reactions of prochiral olefins including Markovnikov addition of HCN to vinyl arenes and hydrogenation of dehydroamino acids. Enantioselectivities of these reactions can be optimized through steric and electronic tuning of the bis-phosphinite ligand system. Both R and S enantiomers of the precursors of protoptypical 2-arylpropionic acids and of various α-amino acids can be prepared by these routes. We have also discovered new protocols for a nearly quantitative and highly selective codimerization of ethylene or propylene, and various functionalized vinylarenes and strained olefins. Various strategies for stereochemical control in an enantioselective version of this reaction will be discussed. These include design and synthesis of new ligands and applications of the ‘hemi-labile ligand concept’. During these investigations important synergistic relationships between such ligands and coordinating properties of various counter ions were also uncovered. These discoveries may contribute to the discovery of more selective homogeneous catalysts. Dedicated to Professor Henri B. Kagan in recognition of his seminal contributions to catalytic asymmetric synthesis *Address correspondence to this author at the Department of Chemistry, The Ohio State University, 100 W. 18 Avenue, Columbus, Ohio 43210, USA; Tel: 614-688-3543; Fax: 614-292-1685; E mail:rajanbabu.1@osu.edu *Current Address: 1. The DuPont Company; 2. Aventis Pharmaceuticals; 3. Nagoya University; Japan; 4. Smith-Kline-Beckmann Pharmaceuticals; 5. Pharmacopeia

2-Benzimidazolyl-9-(chroman-4-yl)-purinone derivatives as JAK3 inhibitors.

A novel class of Janus tyrosine kinase 3 (JAK3) inhibitors based on a 2-benzimidazoylpurinone core structure is described. Through substitution of the benzimidazoyl moiety and optimization of the N-9 substituent of the purinone, compound 24 was identified incorporating a chroman-based functional group. Compound 24 shows excellent kinase activity, good oral bioavailability and demonstrates efficacy in an acute mechanistic mouse model through inhibition of interleukin-2 (IL-2) induced interferon-gamma (INF-gamma) production.