Department of Molecular Biotechnology and Health Sciences , University of Turin , Turin 10126 , Italy.
Molecular Biotechnology Center , Turin 10126 , Italy.
J Med Chem. 2018 Jul 26;61(14):6034-6055. doi: 10.1021/acs.jmedchem.8b00373. Epub 2018 Jul 9.
Human dihydroorotate dehydrogenase ( hDHODH) catalyzes the rate-limiting step in de novo pyrimidine biosynthesis, the conversion of dihydroorotate to orotate. hDHODH has recently been found to be associated with acute myelogenous leukemia, a disease for which the standard of intensive care has not changed over decades. This work presents a novel class of hDHODH inhibitors, which are based on an unusual carboxylic group bioisostere 2-hydroxypyrazolo[1,5- a]pyridine, that has been designed starting from brequinar, one of the most potent hDHODH inhibitors. A combination of structure-based and ligand-based strategies produced compound 4, which shows brequinar-like hDHODH potency in vitro and is superior in terms of cytotoxicity and immunosuppression. Compound 4 also restores myeloid differentiation in leukemia cell lines at concentrations that are one log digit lower than those achieved in experiments with brequinar. This Article reports the design, synthesis, SAR, X-ray crystallography, biological assays, and physicochemical characterization of the new class of hDHODH inhibitors.
人二氢乳清酸脱氢酶（hDHODH）催化从头嘧啶生物合成的限速步骤，即二氢乳清酸转化为乳清酸。hDHODH 最近被发现与急性髓细胞白血病有关，几十年来，这种疾病的强化治疗标准没有改变。这项工作提出了一类新型的 hDHODH 抑制剂，它们基于一种不寻常的羧酸基团生物等排体 2-羟基吡唑并[1,5-a]吡啶，该抑制剂是从布雷奎纳开始设计的，布雷奎纳是最有效的 hDHODH 抑制剂之一。基于结构和基于配体的策略的结合产生了化合物 4，它在体外显示出类似于布雷奎纳的 hDHODH 效力，并且在细胞毒性和免疫抑制方面具有优势。化合物 4 还能在比布雷奎纳实验中达到的浓度低一个对数的浓度下恢复白血病细胞系中的髓样分化。本文报道了新型 hDHODH 抑制剂的设计、合成、SAR、X 射线晶体学、生物测定和物理化学特性。
