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1.
J Am Chem Soc ; 142(25): 11306-11313, 2020 06 24.
Artículo en Inglés | MEDLINE | ID: mdl-32539357

RESUMEN

Hydroboration of alkenes is a classical reaction in organic synthesis in which alkenes react with boranes to give alkylboranes with subsequent oxidation resulting in alcohols. The double bond (π-bond) of alkenes can be readily reacted with boranes owing to its high reactivity. However, the single bond (σ-bond) of alkanes has never been reacted. To pursue the development of σ-bond cleavage, we selected cyclopropanes as model substrates since they present a relatively weak σ-bond. Herein, we describe an iridium-catalyzed hydroboration of cyclopropanes, resulting in ß-methyl alkylboronates. These unusually branched boronates can be derivatized by oxidation or cross-coupling chemistry, accessing "designer" products that are desired by practitioners of natural product synthesis and medicinal chemistry. Furthermore, mechanistic investigations and theoretical studies revealed the enabling role of the catalyst.

2.
Bioorg Med Chem ; 26(3): 775-785, 2018 02 01.
Artículo en Inglés | MEDLINE | ID: mdl-29331452

RESUMEN

Lysine-specific demethylase 1 (LSD1) is an attractive molecular target for cancer therapy. We have previously reported potent LSD1-selective inhibitors (i.e., NCD18, NCD38, and their analogs) consisting of trans-2-phenylcyclopropylamine (PCPA) or trans-2-arylcyclopropylamine (ACPA) and a lysine moiety that could form a γ-turn structure in the active site of LSD1. Herein we report the design, synthesis and evaluation of γ-turn mimetic compounds for further improvement of LSD1 inhibitory activity and anticancer activity. Among a series of γ-turn mimetic compounds synthesized by a Mitsunobu-reaction-based amination strategy, we identified 1n as a potent and selective LSD1 inhibitor. Compound 1n induced cell cycle arrest and apoptosis through histone methylation in human lung cancer cells. The γ-turn mimetics approach should offer new insights into drug design for LSD1-selective inhibitors.


Asunto(s)
Ciclopropanos/farmacología , Diseño de Fármacos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Histona Demetilasas/antagonistas & inhibidores , Antineoplásicos/síntesis química , Antineoplásicos/química , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Dominio Catalítico , Puntos de Control del Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Ciclopropanos/síntesis química , Ciclopropanos/química , Pruebas de Enzimas , Inhibidores Enzimáticos/química , Histona Demetilasas/metabolismo , Humanos , Monoaminooxidasa/química , Monoaminooxidasa/metabolismo
3.
Org Biomol Chem ; 14(36): 8576-85, 2016 Sep 28.
Artículo en Inglés | MEDLINE | ID: mdl-27548471

RESUMEN

We describe the structure-activity relationship of various arylcyclopropylamines (ACPAs), which are potent LSD1 inhibitors. More than 45 ACPAs were synthesized rapidly by an unconventional method that we have recently developed, consisting of a C-H borylation and cross-coupling sequence starting from cyclopropylamine. We also generated NCD38 derivatives, which are known as LSD1 selective inhibitors, and discovered a more effective inhibitor compared to the original NCD38.


Asunto(s)
Aminas/farmacología , Ciclopropanos/farmacología , Inhibidores Enzimáticos/farmacología , Histona Demetilasas/antagonistas & inhibidores , Aminas/química , Apoptosis/efectos de los fármacos , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Ciclopropanos/química , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/química , Histona Demetilasas/metabolismo , Humanos , Conformación Molecular , Relación Estructura-Actividad
4.
Angew Chem Int Ed Engl ; 54(3): 846-51, 2015 Jan 12.
Artículo en Inglés | MEDLINE | ID: mdl-25348582

RESUMEN

A step-economical and stereodivergent synthesis of privileged 2-arylcyclopropylamines (ACPAs) through a C(sp(3))-H borylation and Suzuki-Miyaura coupling sequence has been developed. The iridium-catalyzed C-H borylation of N-cyclopropylpivalamide proceeds with cis selectivity. The subsequent B-cyclopropyl Suzuki-Miyaura coupling catalyzed by [PdCl2(dppf)]/Ag2O proceeds with retention of configuration at the carbon center bearing the Bpin group, while epimerization at the nitrogen-bound carbon atoms of both the starting materials and products is observed under the reaction conditions. This epimerization is, however, suppressed in the presence of O2. The present new ACPA synthesis results in not only a significant reduction in the steps required for making ACPA derivatives, but also the ability to access either isomer (cis or trans) by simply changing the atmosphere (N2 or O2) in the coupling stage.


Asunto(s)
Boro/química , Ciclopropanos/química , Carbono/química , Catálisis , Cristalografía por Rayos X , Ciclopropanos/síntesis química , Hidrógeno/química , Iridio/química , Conformación Molecular , Estereoisomerismo
5.
ACS Med Chem Lett ; 13(10): 1591-1597, 2022 Oct 13.
Artículo en Inglés | MEDLINE | ID: mdl-36262388

RESUMEN

Fragment-based ligand discovery was successfully applied to histone deacetylase HDAC2. In addition to the anticipated hydroxamic acid- and benzamide-based fragment screening hits, a low affinity (∼1 mM) α-amino-amide zinc binding fragment was identified, as well as fragments binding to other regions of the catalytic site. This alternative zinc-binding fragment was further optimized, guided by the structural information from protein-ligand complex X-ray structures, into a sub-µM, brain penetrant, HDAC2 inhibitor (17) capable of modulating histone acetylation levels in vivo.

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