Mills Stephen J, Rossi Ana M, Konieczny Vera, Bakowski Daniel, Taylor Colin W, Potter Barry V L
Drug Discovery & Medicinal Chemistry, Department of Pharmacology, University of Oxford, Mansfield Road, Oxford OX1 3QT, United Kingdom.
Department of Pharmacology, University of Cambridge, Tennis Court Road, Cambridge CB2 1PD, United Kingdom.
J Med Chem. 2020 Mar 26;63(6):3238-3251. doi: 10.1021/acs.jmedchem.9b01986. Epub 2020 Mar 10.
Analogues of the Ca-releasing intracellular messenger d--inositol 1,4,5-trisphosphate [, Ins(1,4,5)P] are important synthetic targets. Replacement of the α-glucopyranosyl motif in the natural product mimic adenophostin by d--inositol in d--inositol adenophostin increased the potency. Similar modification of the non-nucleotide Ins(1,4,5)P mimic ribophostin may increase the activity. d--Inositol ribophostin was synthesized by coupling as building blocks suitably protected ribose with l-(+)-3--trifluoromethylsulfonyl-6---methoxybenzyl-1,2:4,5-di--isopropylidene--inositol . Separable diastereoisomeric 3--camphanate esters of (±)-6---methoxy-benzyl-1,2:4,5-di--isopropylidene--inositol allowed the preparation of . Selective -isopropylidene deprotection in coupled , then monobenzylation gave separable regioisomers and . -Methoxybenzyl group deprotection of , phosphitylation/oxidation, then deprotection afforded , which was a full agonist in Ca-release assays; its potency and binding affinity for Ins(1,4,5)PR were similar to those of adenophostin. Both and elicited a store-operated Ca current I in patch-clamped cells, unlike Ins(1,4,5)P consistent with resistance to metabolism. d--Inositol ribophostin is the most potent small-molecule Ins(1,4,5)P receptor agonist without a nucleobase yet synthesized.
可释放钙离子的细胞内信使1,4,5-三磷酸肌醇（Ins(1,4,5)P）的类似物是重要的合成靶点。在天然产物模拟物腺嘌呤磷酯素中，用D-肌醇取代α-吡喃葡萄糖基序得到D-肌醇腺嘌呤磷酯素，其活性增强。对非核苷酸Ins(1,4,5)P模拟物核糖磷酯素进行类似修饰可能会提高其活性。D-肌醇核糖磷酯素是通过将适当保护的核糖与L-(+)-3-三氟甲基磺酰基-6-甲氧基苄基-1,2:4,5-二异亚丙基-D-肌醇偶联作为构建块合成的。(±)-6-甲氧基苄基-1,2:4,5-二异亚丙基-D-肌醇的可分离非对映异构体3-樟脑酸酯可用于制备[相关产物]。在偶联产物中进行选择性异亚丙基脱保护，然后进行单苄基化，得到可分离的区域异构体[具体产物]和[具体产物]。对[具体产物]进行甲氧基苄基脱保护、亚磷酸化/氧化，然后脱保护得到[具体产物]，其在钙离子释放测定中是完全激动剂；其对Ins(1,4,5)P受体（Ins(1,4,5)PR）的活性和结合亲和力与腺嘌呤磷酯素相似。与Ins(1,4,5)P不同，[具体产物]和[具体产物]在膜片钳细胞中均能引发储存操纵性钙电流I，这与它们对代谢的抗性一致。D-肌醇核糖磷酯素是目前已合成的没有核碱基的最有效的小分子Ins(1,4,5)P受体激动剂。
