Analogs of iso-azepinomycin as potential transition-state analog inhibitors of guanase: synthesis, biochemical screening, and structure-activity correlations of various selectively substituted imidazo[4,5-e][1,4]diazepines.
Analogs of iso-azepinomycin as potential transition-state analog inhibitors of guanase: synthesis, biochemical screening, and structure-activity correlations of various selectively substituted imidazo[4,5-e][1,4]diazepines.
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异氮卓霉素类似物作为鸟苷酶的潜在过渡态类似物抑制剂：各种选择性取代的咪唑并[4,5-e][1,4]二氮杂卓的合成、生化筛选和结构活性相关性。
DOI：
10.1016/j.bmc.2013.06.069
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发表时间：
2013
影响因子：
3.5
通讯作者：
Hosmane,RamachandraS
中科院分区：
文献类型：
--
作者：
Tantravedi,Saritha;Chakraborty,Saibal;Shah,NitiH;Fishbein,JamesC;Hosmane,RamachandraS
鸟苷酶是核酸代谢嘌呤补救途径的重要酶，其抑制在病毒、细菌和癌症治疗中具有有益的意义。本文所述的工作是基于这样的假设，即氮杂环霉素，一种杂环天然产物和一种据称的鸟苷酶的过渡态类似物抑制剂，并不像其中氮杂环霉素的6-羟基已经移位到5-位的多伊索-氮杂环霉素那样接近地代表酶催化反应的真实过渡态。基于这一假设，并假定异氮卓霉素与鸟苷酶的结合位点与氮卓霉素相同，设计并成功合成了几种异氮卓霉素类似物，以初步了解配体鸟苷酶结合位点周围的疏水和亲水位点。具体而言，设计类似物以探索异氮杂卓霉素的N1、N3和N4氮原子以及O5氧原子附近的疏水口袋（如果有的话）。使用哺乳动物胍酶进行这些类似物的生化抑制研究。结果表明：（1）增加O5附近的疏水性会导致负效应，（2）将疏水性从N3转移到N1也会导致抑制作用减弱，（3）增加N3或N4附近的疏水性会显著增强抑制作用，（四个）增加N3或N4处的疏水性，同时增加O5处的疏水性，增强N3或N4处的疏水性，和（5）最后，增加N3附近的亲水性也对抑制具有有害影响。系列中最强的化合物对兔肝胍酶的aKi值为8.0 ± 1.5 μ M。
Guanase is an important enzyme of the purine salvage pathway of nucleic acid metabolism and its inhibition has beneficial implications in viral, bacterial, and cancer therapy. The work described herein is based on a hypothesis that azepinomycin, a heterocyclic natural product and a purported transition state analog inhibitor of guanase, does not represent the true transition state of the enzyme-catalyzed reaction as closely as doesiso-azepinomycin, wherein the 6-hydroxy group of azepinomycin has been translocated to the 5-position. Based on this hypothesis, and assuming thatiso-azepinomycin would bind to guanase at the same active site as azepinomycin, several analogs ofiso-azepinomycin were designed and successfully synthesized in order to gain a preliminary understanding of the hydrophobic and hydrophilic sites surrounding the guanase binding site of the ligand. Specifically, the analogs were designed to explore the hydrophobic pockets, if any, in the vicinity of N1, N3, and N4 nitrogen atoms as well as O5oxygen atom ofiso-azepinomycin. Biochemical inhibition studies of these analogs were performed using a mammalian guanase. Our results indicate that (1) increasing the hydrophobicity near O5results in a negative effect, (2) translocating the hydrophobicity from N3 to N1 also results in decreased inhibition, (3) increasing the hydrophobicity near N3 or N4 produces significant enhancement of inhibition, (4) increasing the hydrophobicity at either N3 or N4 with a simultaneous increase in hydrophobicity at O5considerably diminishes any gain in inhibition made by solely enhancing hydrophobicity at N3 or N4, and (5) finally, increasing the hydrophilic character near N3 has also a deleterious effect on inhibition. The most potent compound in the series has aKivalue of 8.0 ± 1.5 μM against rabbit liver guanase.
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影响因子：
7.3
作者：
R. B. Meyer;E. B. Skibo
通讯作者：
E. B. Skibo
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影响因子：
2.1
作者：
A. Bhan;R. Hosmane;Hongming Zhang;N. Hosmane
通讯作者：
N. Hosmane
含有咪唑并[4,5-e][1,4]二氮杂环系统的“脂肪”黄嘌呤核苷2′-脱氧类似物的合成、结构和构象
DOI：
10.1080/07328319208018334
发表时间：
1992
期刊：
Nucleosides, Nucleotides & Nucleic Acids
影响因子：
--
作者：
A. Bhan;R. Hosmane
通讯作者：
R. Hosmane
供血鸟苷酶筛查试验预防输血后非甲非乙型肝炎的临床价值
影响因子：
13.5
作者：
S. Ito;Y. Tsuji;Naoyuki Kitagawa;Ishihara Akihiko;J. Syundo;Y. Tamura;S. Kishi;H. Mori
通讯作者：
H. Mori
新型鸟苷酶抑制剂
影响因子：
1.8
作者：
A. Bhan;R. Hosmane
通讯作者：
R. Hosmane