ABSTRACT
Herein we report the discovery of pyrazolocarboxamides as novel, potent, and kinase selective inhibitors of receptor interacting protein 2 kinase (RIP2). Fragment based screening and design principles led to the identification of the inhibitor series, and X-ray crystallography was used to inform key structural changes. Through key substitutions about the N1 and C5 N positions on the pyrazole ring significant kinase selectivity and potency were achieved. Bridged bicyclic pyrazolocarboxamide 11 represents a selective and potent inhibitor of RIP2 and will allow for a more detailed investigation of RIP2 inhibition as a therapeutic target for autoinflammatory disorders.
ABSTRACT
Efforts to develop therapeutic agents that inhibit HIV-1 entry have led to the identification of several small molecule leads. One of the most promising is the NBD series, which binds within a conserved gp120 cavity and possesses para-halogen substituted aromatic rings, a central oxalamide linker, and a tetramethylpiperidine moiety. In this study, we characterized structurally the interactions of four NBD analogues containing meta-fluoro substitution on the aromatic ring and various heterocyclic ring replacements of the tetramethylpiperidine group. The addition of a meta-fluorine to the aromatic ring improved surface complementarity and did not alter the position of the analogue relative to gp120. By contrast, heterocyclic ring replacements of the tetramethylpiperidine moiety exhibited diverse positioning and interactions with the vestibule of the gp120 cavity. Overall, the biological profile of NBD-congeners was modulated by ligand interactions with the gp120-cavity vestibule. Herein, six co-crystal structures of NBD-analogues with gp120 provide a structural framework for continued small molecule-entry inhibitor optimization.
Subject(s)
CD4 Antigens/chemistry , CD4 Antigens/metabolism , HIV Envelope Protein gp120/chemistry , HIV Envelope Protein gp120/metabolism , Binding Sites , Crystallography, X-Ray , Humans , Oxalates/chemistry , Piperidines/chemistry , Protein BindingABSTRACT
Structure-activity studies were employed to investigate the stabilization of DNA-topoisomerases I and II covalent binary complexes by topopyrone analogues. The synthesis of five new topopyrone derivatives and study of their ability to stabilize DNA-topoisomerase I and DNA-topoisomerase II covalent binary complexes are described. The biochemical assays suggest that the orientation of the fused 1,4-pyrone ring and halogen substituents contribute importantly to the overall potency of the topopyrones as topoisomerase poisons.
Subject(s)
DNA Topoisomerases, Type II/metabolism , DNA Topoisomerases, Type I/metabolism , Pyrones/chemical synthesis , Pyrones/pharmacology , Topoisomerase I Inhibitors/chemical synthesis , Topoisomerase I Inhibitors/pharmacology , Topoisomerase II Inhibitors/chemical synthesis , Topoisomerase II Inhibitors/pharmacology , Anthraquinones/chemistry , Humans , Molecular Structure , Pyrones/chemistry , Structure-Activity Relationship , Topoisomerase I Inhibitors/chemistry , Topoisomerase II Inhibitors/chemistryABSTRACT
The low-molecular-weight compound JRC-II-191 inhibits infection of HIV-1 by blocking the binding of the HIV-1 envelope glycoprotein gp120 to the CD4 receptor and is therefore an important lead in the development of a potent viral entry inhibitor. Reported here is the use of two orthogonal screening methods, gold docking and ROCS shape-based similarity searching, to identify amine-building blocks that, when conjugated to the core scaffold, yield novel analogs that maintain similar affinity for gp120. Use of this computational approach to expand SAR produced analogs of equal inhibitory activity but with diverse capacity to enhance viral infection. The novel analogs provide additional lead scaffolds for the development of HIV-1 entry inhibitors that employ protein-ligand interactions in the vestibule of gp120 Phe 43 cavity.
Subject(s)
Anti-HIV Agents/pharmacology , CD4 Antigens/metabolism , HIV Envelope Protein gp120/antagonists & inhibitors , Drug Design , HIV Envelope Protein gp120/metabolism , Membrane Fusion/drug effects , Models, Molecular , Protein Binding , Structure-Activity RelationshipABSTRACT
The topopyrones are fungal natural products shown previously to act as poisons of human DNA topoisomerase I. Recent total syntheses of the four known naturally occurring members of this class of compounds have enabled more detailed biochemical characterization. Presently it is shown that in addition to topoisomerase I, topopyrones A-D also act as poisons of human DNA topoisomerase II. The topopyrones thus represent a rare example of molecules capable of interacting effectively with more than one DNA topoisomerase.
Subject(s)
Anthraquinones/pharmacology , DNA-Binding Proteins/antagonists & inhibitors , Enzyme Inhibitors/pharmacology , Pyrones/pharmacology , Topoisomerase I Inhibitors , Topoisomerase II Inhibitors , Anthraquinones/chemistry , Antigens, Neoplasm/metabolism , Base Sequence , DNA/metabolism , DNA Topoisomerases, Type I/metabolism , DNA Topoisomerases, Type II/metabolism , DNA-Binding Proteins/metabolism , Enzyme Inhibitors/chemistry , Humans , Pyrones/chemistryABSTRACT
The topopyrones represent a new class of highly cytotoxic topoisomerase I poisons. Efficient total syntheses of all four naturally occurring members of this class have been accomplished. Key elements of the syntheses include Diels-Alder reactions employing two novel dienes and a titanium-mediated ortho-directed Friedel-Crafts acylation. Additionally, the syntheses of two chlorinated analogues accessible from an advanced intermediate are described.
Subject(s)
Enzyme Inhibitors/chemical synthesis , Pyrones/chemical synthesis , Topoisomerase I Inhibitors , Benzoquinones/chemical synthesis , Benzoquinones/chemistry , Biological Products/chemistry , DNA Topoisomerases, Type I/metabolism , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/classification , Enzyme Inhibitors/pharmacology , Hydrocarbons, Chlorinated/chemical synthesis , Hydrocarbons, Chlorinated/chemistry , Molecular Structure , Pyrones/chemistry , Pyrones/classification , Pyrones/pharmacologyABSTRACT
Described herein is the first total synthesis and structural confirmation of cepharadione A, a naturally occurring DNA damaging agent. Also reported is the synthesis of cepharadione B, a closely related natural product, as well as the biological evaluation of both natural products. Finally, the preparation and biological evaluation of novel dioxoaporphine analogues is described.
Subject(s)
Antineoplastic Agents/pharmacology , Aporphines/chemical synthesis , Aporphines/pharmacology , Cell Survival/drug effects , Isoquinolines/chemical synthesis , Isoquinolines/pharmacology , Porphyrins/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Biological Products/pharmacology , Drug Evaluation, Preclinical , Humans , Models, Molecular , Molecular Conformation , Molecular Structure , Porphyrins/chemical synthesis , Porphyrins/chemistry , Structure-Activity RelationshipABSTRACT
[reaction: see text] 10,11-Methylenedioxy-14-azacamptothecin, a potent analogue of the antitumor agent camptothecin (CPT), has been prepared via a key condensation between AB and DE ring precursors. The biological testing of this compound validated a strategy for modulation of the off-rate of camptothecin analogues from the topoisomerase-DNA-CPT ternary complex via structural modification.
