Tetrahydroisoquinolines as novel histone deacetylase inhibitors for treatment of cancer.

Histone acetylation is a critical process in the regulation of chromatin structure and gene expression. Histone deacetylases (HDACs) remove the acetyl group, leading to chromatin condensation and transcriptional repression. HDAC inhibitors are considered a new class of anticancer agents and have been shown to alter gene transcription and exert antitumor effects. This paper describes our work on the structural determination and structure-activity relationship (SAR) optimization of tetrahydroisoquinoline compounds as HDAC inhibitors. These compounds were tested for their ability to inhibit HDAC 1, 3, 6 and for their ability to inhibit the proliferation of a panel of cancer cell lines. Among these, compound 82 showed the greatest inhibitory activity toward HDAC 1, 3, 6 and strongly inhibited growth of the cancer cell lines, with results clearly superior to those of the reference compound, vorinostat (SAHA). Compound 82 increased the acetylation of histones H3, H4 and tubulin in a concentration-dependent manner, suggesting that it is a broad inhibitor of HDACs.

CCLab--a multi-objective genetic algorithm based combinatorial library design software and an application for histone deacetylase inhibitor design.

The introduction of the multi-objective optimization has dramatically changed the virtual combinatorial library design, which can consider many objectives simultaneously, such as synthesis cost and drug-likeness, thus may increase positive rates of biological active compounds. Here we described a software called CCLab (Combinatorial Chemistry Laboratory) for combinatorial library design based on the multi-objective genetic algorithm. Tests of the convergence ability and the ratio to re-take the building blocks in the reference library were conducted to assess the software in silico, and then it was applied to a real case of designing a 5×6 HDAC inhibitor library. Sixteen compounds in the resulted library were synthesized, and the histone deactetylase (HDAC) enzymatic assays proved that 14 compounds showed inhibitory ratios more than 50% against tested 3 HDAC enzymes at concentration of 20 µg/mL, with IC(50) values of 3 compounds comparable to SAHA. These results demonstrated that the CCLab software could enhance the hit rates of the designed library and would be beneficial for medicinal chemists to design focused library in drug development (the software can be downloaded at: http://202.127.30.184:8080/drugdesign.html).

Discovery of benzhydrylpiperazine derivatives as CB1 receptor inverse agonists via privileged structure-based approach.

The present study describes the identification via privileged structure-based approach of the benzhydrylpiperazine moiety as a potential scaffold to develop novel CB(1) receptor modulators. Efficient structural optimization of the initial four hit compounds led to a high quality lead series, represented by compound 6c. Compound 6c is a highly potent and selective CB(1) receptor inverse agonist that is able to reduce body weight in diet-induced obese Sprague-Dawley rats. The preparation of privileged structure-based library, the progression from hit to lead, the structure-activity relationships in the lead series and in vitro and in vivo activity of compound 6c are discussed.