RESUMEN
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.
RESUMEN
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.
Asunto(s)
Antígenos CD4/química , Antígenos CD4/metabolismo , Proteína gp120 de Envoltorio del VIH/química , Proteína gp120 de Envoltorio del VIH/metabolismo , Sitios de Unión , Cristalografía por Rayos X , Humanos , Oxalatos/química , Piperidinas/química , Unión ProteicaRESUMEN
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.
Asunto(s)
ADN-Topoisomerasas de Tipo II/metabolismo , ADN-Topoisomerasas de Tipo I/metabolismo , Pironas/síntesis química , Pironas/farmacología , Inhibidores de Topoisomerasa I/síntesis química , Inhibidores de Topoisomerasa I/farmacología , Inhibidores de Topoisomerasa II/síntesis química , Inhibidores de Topoisomerasa II/farmacología , Antraquinonas/química , Humanos , Estructura Molecular , Pironas/química , Relación Estructura-Actividad , Inhibidores de Topoisomerasa I/química , Inhibidores de Topoisomerasa II/químicaRESUMEN
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.
Asunto(s)
Fármacos Anti-VIH/farmacología , Antígenos CD4/metabolismo , Proteína gp120 de Envoltorio del VIH/antagonistas & inhibidores , Diseño de Fármacos , Proteína gp120 de Envoltorio del VIH/metabolismo , Fusión de Membrana/efectos de los fármacos , Modelos Moleculares , Unión Proteica , Relación Estructura-ActividadRESUMEN
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.
Asunto(s)
Antraquinonas/farmacología , Proteínas de Unión al ADN/antagonistas & inhibidores , Inhibidores Enzimáticos/farmacología , Pironas/farmacología , Inhibidores de Topoisomerasa I , Inhibidores de Topoisomerasa II , Antraquinonas/química , Antígenos de Neoplasias/metabolismo , Secuencia de Bases , ADN/metabolismo , ADN-Topoisomerasas de Tipo I/metabolismo , ADN-Topoisomerasas de Tipo II/metabolismo , Proteínas de Unión al ADN/metabolismo , Inhibidores Enzimáticos/química , Humanos , Pironas/químicaRESUMEN
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.
Asunto(s)
Inhibidores Enzimáticos/síntesis química , Pironas/síntesis química , Inhibidores de Topoisomerasa I , Benzoquinonas/síntesis química , Benzoquinonas/química , Productos Biológicos/química , ADN-Topoisomerasas de Tipo I/metabolismo , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/clasificación , Inhibidores Enzimáticos/farmacología , Hidrocarburos Clorados/síntesis química , Hidrocarburos Clorados/química , Estructura Molecular , Pironas/química , Pironas/clasificación , Pironas/farmacologíaRESUMEN
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.
Asunto(s)
Antineoplásicos/farmacología , Aporfinas/síntesis química , Aporfinas/farmacología , Supervivencia Celular/efectos de los fármacos , Isoquinolinas/síntesis química , Isoquinolinas/farmacología , Porfirinas/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Productos Biológicos/farmacología , Evaluación Preclínica de Medicamentos , Humanos , Modelos Moleculares , Conformación Molecular , Estructura Molecular , Porfirinas/síntesis química , Porfirinas/química , Relación Estructura-ActividadRESUMEN
[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.