Michne W F, Schroeder J D, Bailey T R, Neumann H C, Cooke D, Young D C, Hughes J V, Kingsley S D, Ryan K A, Putz H S
Department of Medicinal Chemistry, Sterling Winthrop Pharmaecuticals Research Division, Collegeville, Pennsylvania 19426-0900, USA.
J Med Chem. 1995 Aug 18;38(17):3197-206. doi: 10.1021/jm00017a003.
Inhibition of the HIV-1 nuclear regulatory protein tat could potentially yield particularly useful drugs because it functions as an activator of transcription. It has no known cellular counterpart, and deletions in the tat gene destroy the ability of HIV-1 to replicate. We recently reported that a structurally unique class of tat inhibitors, 3-keto/enol 4,5-alpha-epoxy steroids bearing electron-withdrawing substituents at position 2, specifically inhibit tat-induced gene expression in virus free transfected SW480 cells. In this paper, we report on additional SAR (structure-activity relationships) for the steroid series and the localization of the pharmacophore to the A-ring functionality. There is a weak enantioselective preference for the natural steroid stereochemistry and hints of additional SAR in the electron-withdrawing group. Compound 34a is of particular interest in that it inhibits HIV replication in H9 cells at a concentration equivalent to its inhibitory level in the primary tat assay.
抑制HIV-1核调节蛋白tat可能会产生特别有用的药物，因为它作为转录激活剂发挥作用。它没有已知的细胞对应物，tat基因的缺失会破坏HIV-1的复制能力。我们最近报道了一类结构独特的tat抑制剂，即在2位带有吸电子取代基的3-酮/烯醇4,5-α-环氧类固醇，能特异性抑制无病毒转染的SW480细胞中tat诱导的基因表达。在本文中，我们报告了类固醇系列的更多构效关系（SAR）以及药效团在A环功能上的定位。对天然类固醇立体化学存在较弱的对映选择性偏好，并且在吸电子基团中存在更多构效关系的线索。化合物34a特别令人感兴趣，因为它在H9细胞中抑制HIV复制的浓度与其在初级tat检测中的抑制水平相当。
