149744-27-4Relevant articles and documents
Synthesis and Assay of SIRT1-Activating Compounds
Dai,Ellis,Sinclair,Hubbard
, p. 213 - 244 (2018/05/04)
The NAD+-dependent deacetylase SIRT1 plays key roles in numerous cellular processes including DNA repair, gene transcription, cell differentiation, and metabolism. Overexpression of SIRT1 protects against a number of age-related diseases including diabetes, cancer, and Alzheimer's disease. Moreover, overexpression of SIRT1 in the murine brain extends lifespan. A number of small-molecule sirtuin-activating compounds (STACs) that increase SIRT1 activity in vitro and in cells have been developed. While the mechanism for how these compounds act on SIRT1 was once controversial, it is becoming increasingly clear that they directly interact with SIRT1 and enhance its activity through an allosteric mechanism. Here, we present detailed chemical syntheses for four STACs, each from a distinct structural class. Also, we provide a general protocol for purifying active SIRT1 enzyme and outline two complementary enzymatic assays for characterizing the effects of STACs and similar compounds on SIRT1 activity.
New pyridobenzodiazepine derivatives as potential antipsychotics: Synthesis and neurochemical study
Liegeois,Bruhwyler,Damas,Thuy Phuong Nguyen,Chleide,Mercier,Rogister,Delarge
, p. 2107 - 2114 (2007/10/02)
The discovery of a new, safe, atypical antipsychotic remains an important challenge. To achieve this goal, a series of N-methylpiperazinopyrido[2,3- b][1,4]- and -[1,5]- and -pyrido[4,3-b][1,4]- and -[1,5]-benzodiazepines were synthesized. The dopaminergic (D1, D2), serotonergic (5-HT2), and cholinergic (M) affinities, frequently remarked in the action mechanisms of antipsychotic drugs, were determined using their respective in vitro receptor binding assays. All affinities were reduced for each compound. Optimal substituents were found to be in the 2- or 8-position for the retention of affinities, while substitution at the 5-position by acyl or alkyl groups dramatically diminished binding affinities. Pyridobenzodiazepine derivatives, such as clozapine, were found to be inactive or only weakly effective against apomorphine-mediated stereotypes in rats. In an original and complex behavioral model developed in dogs and successfully used to differentiate distinct classes of psychotropic drugs and to discriminate between typical and atypical neuroleptic drugs, 8-chloro-6-(4-methyl-1-piperazinyl)-11H- pyrido[2,3-b][1,4]benzodiazepine (9), 8-methyl-6-(4-methyl-1-piperazinyl)- 11H-pyrido[2,3-b][1,4]benzodiazepine (12), and 5-(4-methyl-1-piperazinyl)- 11H-pyrido[2,3-b][1,5]benzodiazepine (16) showed most of the behavioral characteristics previously described for neuroleptics. Their neurochemical profiles, particularly their 5-HT2/D2 pK(i) ratios, were compatible with an atypical antipsychotic effect. These compounds were selected for further investigation. The proposed modulations could lead to new possibilities for the pharmacochemistry of diarylazepines.
