具有膦酸酯基团的化合物,即,通过P-C键直接连接至分子的-P(O)(OH)2基团在各种生物医学应用中用作合适的不可水解的磷酸酯模拟物。原则上,它们通常利用各种磷酸盐作为底物来抑制酶。在这篇综述中,我们主要关注源自我们研究所(布拉格有机化学与生物化学研究所)的生物活性膦酸盐;即无环核苷膦酸酯(ANPs,例如,阿德福韦,替诺福韦,和西多福韦)和非核苷膦酸酯的衍生物,例如2-(膦酰基甲基)戊二酸(2-PMPA)。报告了其合成和前药修饰的主要策略。除了临床使用的ANP抗病毒药物,对于新出现的感染和许多病原体对标准治疗产生的抗性,特别注意新的生物活性分子。这些新结构包括2,4-二氨基-6-[2-(膦酰基甲氧基)乙氧基]嘧啶或所谓的“开环”衍生物,以5-氮杂胞嘧啶为碱基部分的无环核苷膦酸酯,侧链氟化ANPs,氮杂/脱氮嘌呤ANPs。当通过衍生它们的带电官能团转化为适当的前药时,所有这些化合物都显示出有望成为治疗病毒感染的候选药物的潜力.具有合适药代动力学的ANP前药包括氨基酸磷酸酯,新戊酰氧基甲基(POM)和异丙氧基羰基氧基甲基(POC)酯,烷基和烷氧基烷基酯,水杨酸酯,(甲基-2-氧代-1,3-二氧代-4-基)甲基(ODOL)酯和拟肽前药。我们还专注于与9-[2-(膦酰基甲氧基)乙基]鸟嘌呤及其前药相关的细胞抑制剂的故事,这些前药最终导致了兽药rabacfosadine的开发。目前还研究了各种新的ANP结构作为抗寄生虫剂,尤其是抗疟药,例如,鸟嘌呤和次黄嘌呤衍生物与2-(膦酰基乙氧基)乙基部分,它们的thia类似物和N-支链衍生物。除了ANPs及其类似物,我们还描述了2-(膦酰基甲基)戊二酸(2-PMPA)的前药,谷氨酸羧肽酶II(GCPII)的有效抑制剂,也称为前列腺特异性膜抗原(PSMA)。谷氨酸羧肽酶II抑制剂,已经发现,包括2-PMPA在由谷氨酸能兴奋性毒性引起的神经障碍的各种临床前模型中是有效的。不幸的是,其高极性特性和因此低生物利用度严重限制了其临床应用的潜力。为了克服这个问题,各种前药策略已被用于掩蔽羧酸酯和/或膦酸酯官能团与新戊酰氧基甲基,POC,ODOL和烷基酯。化学和生物学表征导致鉴定具有44-80倍的口服生物利用度(tetra-ODOL-2-PMPA)的前药。
Compounds with a phosphonate group, i.e., -P(O)(OH)2 group attached directly to the molecule via a P-C bond serve as suitable non-hydrolyzable phosphate mimics in various biomedical applications. In principle, they often inhibit enzymes utilizing various phosphates as substrates. In this review we focus mainly on biologically active phosphonates that originated from our institute (Institute of Organic Chemistry and Biochemistry in Prague); i.e., acyclic nucleoside phosphonates (ANPs, e.g., adefovir, tenofovir, and cidofovir) and derivatives of non-nucleoside phosphonates such as 2-(phosphonomethyl) pentanedioic acid (2-PMPA). Principal strategies of their syntheses and modifications to prodrugs is reported. Besides clinically used ANP antivirals, a special attention is paid to new biologically active molecules with respect to emerging infections and arising resistance of many pathogens against standard treatments. These new structures include 2,4-diamino-6-[2-(phosphonomethoxy)ethoxy]pyrimidines or so-called \"open-ring\" derivatives, acyclic nucleoside phosphonates with 5-azacytosine as a base moiety, side-chain fluorinated ANPs, aza/deazapurine ANPs. When transformed into an appropriate prodrug by derivatizing their charged functionalities, all these compounds show promising potential to become drug candidates for the treatment of viral infections. ANP prodrugs with suitable pharmacokinetics include amino acid phosphoramidates, pivaloyloxymethyl (POM) and isopropoxycarbonyloxymethyl (POC) esters, alkyl and alkoxyalkyl esters, salicylic esters, (methyl-2-oxo-1,3-dioxol-4-yl) methyl (ODOL) esters and peptidomimetic prodrugs. We also focus on the story of cytostatics related to 9-[2-(phosphonomethoxy)ethyl]guanine and its prodrugs which eventually led to development of the veterinary drug rabacfosadine. Various new ANP structures are also currently investigated as antiparasitics, especially antimalarial agents e.g., guanine and hypoxanthine derivatives with 2-(phosphonoethoxy)ethyl moiety, their thia-analogues and N-branched derivatives. In addition to ANPs and their analogs, we also describe prodrugs of 2-(phosphonomethyl)pentanedioic acid (2-PMPA), a potent inhibitor of the enzyme glutamate carboxypeptidase II (
GCPII), also known as prostate-specific membrane antigen (PSMA). Glutamate carboxypeptidase II inhibitors, including 2-PMPA have been found efficacious in various preclinical models of neurological disorders which are caused by glutamatergic excitotoxicity. Unfortunately its highly polar character and hence low bioavailability severely limits its potential for clinical use. To overcome this problem, various prodrug strategies have been used to mask carboxylates and/or phosphonate functionalities with pivaloyloxymethyl, POC, ODOL and alkyl esters. Chemistry and biological characterization led to identification of prodrugs with 44-80 fold greater oral bioavailability (tetra-ODOL-2-PMPA).