10.1021/jm070864w
The research focuses on the development of dual inhibitors targeting Inosine Monophosphate Dehydrogenase (IMPDH) and Histone Deacetylases (HDACs) for cancer treatment, specifically for Chronic Myelogenous Leukemia (CML). The study involves the synthesis and evaluation of mycophenolic hydroxamic acid (MAHA) and a SAHA analogue, which are found to inhibit both IMPDH and HDACs, with potential as antiproliferation and differentiation-inducing agents. Experiments include enzyme assays to determine IMPDH and HDAC inhibition, proliferation assays using human myelogenous leukemia K562 cells, and differentiation assays to evaluate the compounds' effects on cellular differentiation. Reactants used in the chemical synthesis of these inhibitors include mycophenolic acid, various protected hydroxylamines, and other organic compounds, while analyses involve high-performance liquid chromatography (HPLC), nuclear magnetic resonance (NMR), and high-resolution mass spectrometry (HRMS) to characterize the synthesized compounds.
10.1016/j.bmcl.2011.11.078
The research aims to develop new compounds that could inhibit T-cell proliferation and IMPDH type II activity, with the aim of creating safer and more effective immunosuppressive drugs. The researchers synthesized a series of isobenzofuran-based compounds, including a,b-unsaturated amides, ureas, and diamides, and assessed their structure-activity relationships. The conclusions drawn from the study indicated that the a,b-unsaturated amide series generally demonstrated higher potency than the urea and diamide series, with compounds 2d, 2e, 2h, and 2j showing superior immunosuppressive properties compared to mycophenolic acid (MPA), a known immunosuppressive agent. Other compounds like 2k, 2m, 2n, 4c, and 5d exhibited inhibitory activity comparable to MPA. The study provided insights into the development of new immunosuppressive agents and further evaluation of these compounds is underway to determine their therapeutic potential and toxicity profiles.
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