Synthesis of 2,3-dihydrobenzo[b][1,4]dioxine-5-carboxamide and 3-oxo-3,4-dihydrobenzo[b][1,4]oxazine-8-carboxamide derivatives as PARP1 inhibitors.
Synthesis of 2,3-dihydrobenzo[b][1,4]dioxine-5-carboxamide and 3-oxo-3,4-dihydrobenzo[b][1,4]oxazine-8-carboxamide derivatives as PARP1 inhibitors.
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DOI：
10.1016/j.bioorg.2020.104075
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发表时间：
2020-09
影响因子：
5.1
通讯作者：
Talele TT
中科院分区：
文献类型：
--
作者：
Shao X;Pak S;Velagapudi UK;Gobbooru S;Kommaraju SS;Low WK;Subramaniam G;Pathak SK;Talele TT
聚腺苷二磷酸核糖聚合酶1（Poly（ADP-ribose）polymerase 1，PARP 1）是一种广泛研究的抗癌药物靶点，在单链DNA断裂修复过程中起重要作用。使用PARP 1-苯并咪唑-4-甲酰胺晶体结构和药效团模型对Maybridge小分子文库进行高通量虚拟筛选（HTVS），鉴定出11种化合物。使用重组PARP 1酶试验评价这些化合物，获得3种PARP 1抑制剂：3（IC 50 = 12 μM）、4（IC 50 = 5.8 μM）和10（IC 50 = 0.88 μM）。选择化合物4（2，3-二氢-1，4-苯并二氧杂环己烯-5-甲酰胺）作为先导化合物，并对其进行进一步的化学修饰，包括类似物合成和支架跳跃。通过这些努力，鉴定出（Z）-2-（4-羟基亚苄基）-3-氧代-3，4-二氢-2H-苯并[B][1，4]恶嗪-8-甲酰胺（49，IC 50 = 0.082 μM）是该系列中最有效的PARP 1抑制剂。
Poly(ADP-ribose)polymerase 1 (PARP1), a widely explored anticancer drug target, plays an important role in single-strand DNA break repair processes. High-throughput virtual screening (HTVS) of the Maybridge small molecule library using the PARP1-benzimidazole-4-carboxamide crystal structure and pharmacophore model led to the identification of eleven compounds. These compounds were evaluated using recombinant PARP1 enzyme assay that resulted in the acquisition of three PARP1 inhibitors: 3 (IC50 = 12 μM), 4 (IC50 = 5.8 μM), and 10 (IC50 = 0.88 μM). Compound 4 (2,3-dihydro-1,4-benzodioxine-5-carboxamide) was selected as a lead and it was subjected to further chemical modifications, involving analogue synthesis and scaffold hopping. These efforts led to the identification of (Z)-2-(4-hydroxybenzylidene)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-8-carboxamide (49, IC50 = 0.082 μM) as the most potent inhibitor of PARP1 from the series.
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影响因子：
28.2
作者：
Fojo T;Bates S
通讯作者：
Bates S
影响因子：
3.4
作者：
Heinrich, Timo;Boettcher, Henning;van Amsterdam, Christoph
通讯作者：
van Amsterdam, Christoph
影响因子：
3.5
作者：
Dixon, Steven L.;Smondyrev, Alexander M.;Friesner, Richard A.
通讯作者：
Friesner, Richard A.
影响因子：
7.3
作者：
Ferraris, Dana V.
通讯作者：
Ferraris, Dana V.
影响因子：
3.6
作者：
ADAM, W;PETERS, EM;TAKAYAMA, K
通讯作者：
TAKAYAMA, K