ABSTRACT
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.
ABSTRACT
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.
Subject(s)
Benzimidazoles/pharmacology , Enzyme Inhibitors/pharmacology , Janus Kinase 3/antagonists & inhibitors , Purines/pharmacology , Animals , Benzimidazoles/chemical synthesis , Benzimidazoles/chemistry , Dose-Response Relationship, Drug , Drug Design , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Interferon-gamma/biosynthesis , Interleukin-2/antagonists & inhibitors , Mice , Models, Animal , Models, Molecular , Molecular Structure , Purines/chemical synthesis , Purines/chemistry , Stereoisomerism , Structure-Activity RelationshipABSTRACT
Properly substituted pyrazolo[1,5-a]pyrimidines are potent and selective CDK2 inhibitors. Compound 15j is orally available and showed efficacy in a mouse A2780 xenograft model.
Subject(s)
Cyclin-Dependent Kinase 2/antagonists & inhibitors , Pyrazoles/chemistry , Pyrazoles/pharmacology , Pyridines/chemistry , Pyridines/pharmacology , Administration, Oral , Animals , Crystallography, X-Ray , Cyclin-Dependent Kinase 2/drug effects , Dogs , Drug Screening Assays, Antitumor , Haplorhini , Mice , Models, Animal , Models, Molecular , Molecular Structure , Pyrazoles/chemical synthesis , Pyridines/chemical synthesis , Rats , Xenograft Model Antitumor AssaysABSTRACT
Synthetic investigations of ustiloxin natural products are described. The first total synthesis of ustiloxin F was completed in 15 steps via ethynyl aziridine ring-opening by a phenol derivative. The results of biological tests of synthetic ustiloxins D and F, and two analogs, O-Me-ustiloxin D and 6-Ile-ustiloxin, demonstrated that the free hydroxyl group ortho to the ether linkage is critical for activity and variations at the Val/Ala site produce changes in the biological activity suggesting the need for further perturbations at this site to more extensively study the tubulin binding.
Subject(s)
Biological Products/chemical synthesis , Biological Products/pharmacology , Peptides, Cyclic/chemical synthesis , Peptides, Cyclic/pharmacology , Biological Products/chemistry , Cell Line, Tumor , Humans , Inhibitory Concentration 50 , Molecular Structure , Mycotoxins/chemistry , Peptides, Cyclic/chemistry , Tubulin/metabolismABSTRACT
Through a systematic examination of ligand and counterion effects, new protocols for a nearly quantitative and highly selective codimerization of ethylene and various functionalized vinylarenes have been discovered. In a typical reaction, 4-bromostyrene and ethylene undergo codimerization in the presence of 0.0035 equiv each of [(allyl)NiBr]2, triphenylphosphine, and AgOTf in CH2Cl2 at -56 degrees C to give 3-(4-bromophenyl)-1-butene in >98% yield and selectivity. Corresponding reactions with [(allyl)PdX]2 are much less efficient and less selective and may require further optimization before a viable system can be identified. Another useful protocol that gives comparable yield and selectivity involves the use of a single-component catalyst prepared from allyl 2-diphenylphosphinobenzoate, Ni(COD)2, and (C6F5)3B. Recognition of a synergistic relationship between a chiral hemilabile ligand (for example, (R)-2-methoxy-2'-diphenylphosphino-1,1'-binaphthyl, MOP) and a highly dissociated counteranion (BARF or SbF6) in an enantioselective version of the Ni-catalyzed reaction raises the prospects of developing a practical route for the synthesis of 3-arylbutenes. Several pharmaceutically relevant compounds, including widely used 2-arylpropionic acids, can be synthesized from these key intermediates. This reaction appears to be quite general. Synthesis of several new 2-diphenylphosphino-1,1-binaphthyl derivatives, prepared to probe the effect of hemilabile coordination on the efficiency and selectivity of the reaction, are also described.
ABSTRACT
The total synthesis of ustiloxin D, a highly potent inhibitor of microtubule assembly, has been achieved. Notable features are the use of nucleophilic aromatic substitution (SNAr) for the construction of a chiral tertiary alkyl-aryl ether linkage, Sharpless asymmetric aminohydroxylation for the formation of the beta-hydroxytyrosine moiety, macrolactamization, and regioselective methylation.
Subject(s)
Anti-Bacterial Agents/chemical synthesis , Antibiotics, Antineoplastic/chemical synthesis , Mycotoxins/chemical synthesis , Peptides , Anti-Bacterial Agents/metabolism , Anti-Bacterial Agents/pharmacology , Antibiotics, Antineoplastic/metabolism , Antibiotics, Antineoplastic/pharmacology , Fungi/chemistry , Mycotoxins/metabolism , Mycotoxins/pharmacology , Peptides, Cyclic , Stereoisomerism , Structure-Activity Relationship , Tubulin/metabolismABSTRACT
Only a limited number of ligands have been successfully employed for the Ni-catalyzed asymmetric hydrovinylation reaction. Diarylphosphonites prepared from readily available carbohydrates in conjunction with a highly dissociated counterion ([3,5-(CF3)2-C6H3)4B]- or SbF6-) effect the hydrovinylation of 4-bromostyrene or 4-isobutylstyrene under ambient pressure of ethylene with the best overall selectivities reported to date for these important substrates. In a prototypical synthesis of a 2-arylpropionic acid, 3-(4-bromophenyl)-1-butene (prepared in 98% isolated yield and 89% ee from 4-bromostyrene) has been transformed into (R)-ibuprofen by Ni-catalyzed cross-coupling with i-BuMgBr, ozonolysis, and subsequent oxidation of the resulting aldehyde.
