RESUMO
The DNA damage response (DDR) is a DNA damage surveillance and repair mechanism that can limit the effectiveness of radiotherapy and DNA-damaging chemotherapy, commonly used treatment modalities in cancer. Two related kinases, ataxia telangiectasia mutated (ATM) and ATM and Rad3-related kinase (ATR), work together as apical proteins in the DDR to maintain genome stability and cell survival in the face of potentially lethal forms of DNA damage. However, compromised ATM signaling is a common characteristic of tumor cells, which places greater reliance on ATR to mediate the DDR. In such circumstances, ATR inhibition has been shown to enhance the toxicity of DNA damaging chemotherapy to many cancer cells in multiple preclinical studies, while healthy tissue with functional ATM can tolerate ATR inhibition. ATR therefore represents a very attractive anticancer target. Herein we describe the discovery of VX-970/M6620, the first ATR inhibitor to enter clinical studies, which is based on a 2-aminopyrazine core first reported by Charrier ( J. Med. Chem. 2011 , 54 , 2320 - 2330 , DOI: 10.1021/jm101488z ).
Assuntos
Proteínas Mutadas de Ataxia Telangiectasia/antagonistas & inibidores , Desenho de Fármacos , Isoxazóis/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Pirazinas/farmacologia , Animais , Proteínas Mutadas de Ataxia Telangiectasia/química , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Linhagem Celular , Isoxazóis/farmacocinética , Masculino , Modelos Moleculares , Conformação Proteica , Inibidores de Proteínas Quinases/farmacocinética , Pirazinas/farmacocinética , Ratos , Ratos Sprague-DawleyRESUMO
The first enantioselective synthesis of a chamigrane sesquiterpene, (+)-majusculone, has been completed. The quaternary center was generated asymmetrically by alkylidene carbene insertion, with retention of absolute configuration, from a diastereomerically pure ketal.
Assuntos
Sesquiterpenos/síntese química , Modelos Moleculares , Conformação Molecular , Estrutura Molecular , Sesquiterpenos/química , EstereoisomerismoRESUMO
The preparation of an advanced intermediate toward the enantioselective synthesis of tetrodotoxin is outlined. The enantiomerically pure cyclopentene 15 was generated from ketone 14 by alkylidene carbene insertion with retention of absolute configuration. An ozonolysis/aldol sequence first produced the trans cyclohexenone, which upon epimerization gave the more stable cis enone 18.
Assuntos
Cicloexanonas/síntese química , Metano/análogos & derivados , Tetrodotoxina/síntese química , Hidrocarbonetos , Metano/química , Ozônio/química , Estereoisomerismo , Tetrodotoxina/químicaRESUMO
A one-pot preparation of unsymmetrical 1,4-alkynediols such as 2a by the coupling of trimethylsilylacetylene and two different aldehydes or ketones is reported. The dilithiated species 5 is generated by the sequential addition of the first aldehyde or ketone 1b to a solution of lithium trimethylsilylacetylide, followed by the addition of methyllithium, which removes the trimethylsilyl protecting group. Addition of the second aldehyde or ketone then leads to the unsymmetrical 1,4-alkynediol 2a.