两次翻转产生的两种支架结构：dTTP的(α,β)/(β,γ) CH2/NH “甲硫氨酸-异亮氨酸”类似物
Two Scaffolds from Two Flips: (α,β)/(β,γ) CH2/NH "Met-Im" Analogues of dTTP.
作者信息
Kadina Anastasia P, Kashemirov Boris A, Oertell Keriann, Batra Vinod K, Wilson Samuel H, Goodman Myron F, McKenna Charles E
机构信息
†Department of Chemistry, Dana and David Dornsife College of Letters, Arts and Sciences, University of Southern California, University Park Campus, Los Angeles, California 90089, United States.
‡Department of Biological Sciences, Dana and David Dornsife College of Letters, Arts and Sciences, University of Southern California, University Park Campus, Los Angeles, California 90089, United States.
出版信息
Org Lett. 2015 Jun 5;17(11):2586-9. doi: 10.1021/acs.orglett.5b00799. Epub 2015 May 13.
Abstract
Novel α,β-CH2 and β,γ-NH (1a) or α,β-NH and β,γ-CH2 (1b) "Met-Im" dTTPs were synthesized via monodemethylation of triethyl-dimethyl phosphorimido-bisphosphonate synthons (4a, 4b), formed via a base-induced [1,3]-rearrangement of precursors (3a, 3b) in a reaction with dimethyl or diethyl phosphochloridate. Anomerization during final bromotrimethylsilane (BTMS) deprotection after Mitsunobu conjugation with dT was avoided by microwave conditions. 1a was 9-fold more potent in inhibiting DNA polymerase β, attributed to an NH-group interaction with R183 in the active site.
摘要
新型α,β-CH₂和β,γ-NH（1a）或α,β-NH和β,γ-CH₂（1b）“Met-Im”dTTPs通过三乙基-二甲基磷酰亚胺双膦酸酯合成子（4a、4b）的单去甲基化反应合成，该合成子是由前体（3a、3b）在与二甲基或二乙基磷酰氯反应中经碱诱导的[1,3]重排形成的。在与dT进行 Mitsunobu 共轭反应后，通过微波条件避免了最终溴三甲基硅烷（BTMS）脱保护过程中的异头化。1a在抑制DNA聚合酶β方面的效力要强9倍，这归因于其NH基团与活性位点中的R183之间的相互作用。
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