Two Scaffolds from Two Flips: (α,β)/(β,γ) CH2/NH "Met-Im" Analogues of dTTP.
Two Scaffolds from Two Flips: (α,β)/(β,γ) CH2/NH "Met-Im" Analogues of dTTP.
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DOI：
10.1021/acs.orglett.5b00799
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发表时间：
2015-06-05
期刊：
影响因子：
5.2
通讯作者：
McKenna CE
中科院分区：
文献类型：
--
作者：
Kadina AP;Kashemirov BA;Oertell K;Batra VK;Wilson SH;Goodman MF;McKenna CE
通过三乙基二甲基亚磷酰亚胺双膦酸酯（4a，4 b）的单脱甲基反应合成了新型α，β-CH 2和β，γ-NH（1a）或α，β-NH和β，γ-CH 2（1b）“Met-Im”dTTP。微波条件避免了Mitsunobu与dT缀合后最终溴三甲基硅烷（BTMS）脱保护期间的端基异构化。1a对DNA聚合酶β的抑制作用强9倍，这归因于活性位点上的NH基团与R183的相互作用。
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.