A series of analogues of isopentenyl diphosphate (IPP) having a dicarboxylate moiety in place of the diphosphate were synthesized and investigated as inhibitors of undecaprenyl diphosphate (UPP) synthase and protein farnesyltransferase (PFTase). PFTase is involved in control of cell proliferation and is known to be inhibited by certain maleic acid derivatives bearing long alkyl substituents (> or =12 carbons, e.g., chaetomellic acid). UPP synthase is a potential target for antimicrobial agents and utilizes isopentenyl diphosphate (IPP) as a substrate. A number of dicarboxylate-containing IPP analogues were prepared in 2-5 steps from commercially available starting materials with good overall yield (20-78%). These syntheses involved the conjugate addition of an organocuprate to dimethyl acetylenedicarboxylate (DMAD) followed by basic ester hydrolysis. The E-pentenylbutanedioic acid 32 showed inhibition of UPP synthase with an IC(50) of 135 microM. Compound 30 displays competitive inhibition of PFTase with a K(i) of 287 microM.

中文翻译：

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异戊烯基二磷酸酯类似物的合成和生物活性。

合成了具有二羧酸酯部分代替二磷酸酯的一系列异戊烯基二磷酸酯（IPP）的类似物，并研究了它们作为十一碳烯基二磷酸酯（UPP）合酶和蛋白法呢基转移酶（PFTase）的抑制剂。PFTase参与细胞增殖的控制，并且已知会被某些带有长烷基取代基（>或= 12个碳，例如Chaetomellic酸）的马来酸衍生物抑制。UPP合酶是抗菌剂的潜在靶标，并利用异戊烯基二磷酸酯（IPP）作为底物。从市售的起始原料中，以2-5个步骤制备了许多含二羧酸盐的IPP类似物，具有良好的总收率（20-78％）。这些合成涉及将有机铜酸酯共轭添加至乙炔二羧酸二甲酯（DMAD），然后进行碱性酯水解。E-戊烯基丁二酸32显示UPP合酶的抑制作用，其IC（50）为135 microM。化合物30表现出竞争性抑制PFTase的K（i）为287 microM。