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Synthesis and PTP Inhibitory Activity of Illudalic Acid and Its Methyl Ether, with Insights into Selectivity for LAR PTP over Other Tyrosine Phosphatases under Physiologically Relevant Conditions.
Journal of Natural Products ( IF 3.3 ) Pub Date : 2019-12-06 , DOI: 10.1021/acs.jnatprod.9b00663 Brandon S McCullough 1 , Paratchata Batsomboon 2 , Kacey B Hutchinson 1 , Gregory B Dudley 2 , Amy M Barrios 1
Journal of Natural Products ( IF 3.3 ) Pub Date : 2019-12-06 , DOI: 10.1021/acs.jnatprod.9b00663 Brandon S McCullough 1 , Paratchata Batsomboon 2 , Kacey B Hutchinson 1 , Gregory B Dudley 2 , Amy M Barrios 1
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The protein tyrosine phosphatase (PTP) family of enzymes includes many attractive therapeutic targets, such as those in the leukocyte common antigen-related (LAR) subfamily of receptor PTPs. Synthesis and PTP inhibitory activity of illudalic acid and its methyl ether are described, with a focus on selective inhibition of LAR PTP relative to a small collection of other representative PTPs. The synthesis comprises 16 steps and provides illudalic acid in up to 12% overall yield from neopentylene-fused benzoate 1 (20 steps from commercial materials). Illudalic acid dose-dependently (measured IC50 = 2.1 ± 0.2 μM) and time-dependently inhibits LAR consistent with previous reports of covalent binding. The kinetics of LAR inhibition by illudalic acid are consistent with a two-step mechanism in which the inhibitor and enzyme first interact noncovalently (KI = 130 ± 50 μM), followed by covalent ligation at a rate kinact = 1.3 ± 0.4 min-1. The kinact/KI ratio of 104 corresponds to a t∞1/2 of 0.5 min, as discussed herein. The phenol methyl ether of illudalic acid was found to be less potent in our dose-response assays (measured IC50 = 55 ± 6 μM) but more selective for LAR, with a weaker initial noncovalent interaction and faster covalent ligation of LAR as compared to illudalic acid itself. A truncated analogue of illudalic acid that lacks the neopentylene ring fusion was found to be devoid of significant activity under our assay conditions, in contrast to previous reports. These observations collectively help inform further development of illudalic acid analogues as potent and selective inhibitors of the LAR subfamily of tyrosine phosphatases.
中文翻译：
二十二碳六烯酸及其甲基醚的合成和PTP抑制活性，以及在生理相关条件下对LAR PTP对其他酪氨酸磷酸酶的选择性的见解。
蛋白质酪氨酸磷酸酶（PTP）酶家族包括许多有吸引力的治疗靶标，例如受体PTP的白细胞常见抗原相关（LAR）亚家族中的靶标。描述了乙二酸及其甲基醚的合成和PTP抑制活性，重点是相对于少量其他代表性PTP选择性抑制LAR PTP。合成过程包括16个步骤，并从新戊烯基稠合的苯甲酸酯1（购自商业原料的20个步骤）中提供了高达12％的总产率的杜鹃酸。与以前的共价结合报道相一致，异丁酸的剂量依赖性（测得的IC50 = 2.1±0.2μM）和时间依赖性抑制LAR。杜鹃酸对LAR的抑制动力学与两步机制一致，其中抑制剂和酶首先非共价相互作用（KI = 130±50μM），然后以kinact = 1.3±0.4 min-1的速率共价连接。如本文所讨论的，运动/ KI之比104对应于0.5分钟的∞1/2。在我们的剂量反应分析中，发现伊达酸的酚甲基醚效力较低（测得的IC50 = 55±6μM），但对LAR的选择性更高，与伊库酸相比，LAR的初始非共价相互作用弱，共价连接速度更快酸本身。与先前的报道相反，在我们的测定条件下，发现缺少新戊烯基环融合的截短的伊斯洛达酸类似物没有显着活性。
更新日期：2019-12-07
中文翻译：
二十二碳六烯酸及其甲基醚的合成和PTP抑制活性，以及在生理相关条件下对LAR PTP对其他酪氨酸磷酸酶的选择性的见解。
蛋白质酪氨酸磷酸酶（PTP）酶家族包括许多有吸引力的治疗靶标，例如受体PTP的白细胞常见抗原相关（LAR）亚家族中的靶标。描述了乙二酸及其甲基醚的合成和PTP抑制活性，重点是相对于少量其他代表性PTP选择性抑制LAR PTP。合成过程包括16个步骤，并从新戊烯基稠合的苯甲酸酯1（购自商业原料的20个步骤）中提供了高达12％的总产率的杜鹃酸。与以前的共价结合报道相一致，异丁酸的剂量依赖性（测得的IC50 = 2.1±0.2μM）和时间依赖性抑制LAR。杜鹃酸对LAR的抑制动力学与两步机制一致，其中抑制剂和酶首先非共价相互作用（KI = 130±50μM），然后以kinact = 1.3±0.4 min-1的速率共价连接。如本文所讨论的，运动/ KI之比104对应于0.5分钟的∞1/2。在我们的剂量反应分析中，发现伊达酸的酚甲基醚效力较低（测得的IC50 = 55±6μM），但对LAR的选择性更高，与伊库酸相比，LAR的初始非共价相互作用弱，共价连接速度更快酸本身。与先前的报道相反，在我们的测定条件下，发现缺少新戊烯基环融合的截短的伊斯洛达酸类似物没有显着活性。
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