基于S-乙烯-异硫乙烯的二和1,2,4-氧化伪二:作为NO合成抑制剂的固体相合成和评估

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Elodie Mauchauffée¹, Jérémy Leroy², Jihanne Chamcham¹

¹Institut des Biomolécules Max Mousseron, CNRS, Univ. Montpellier, ENSCM, Pôle Chimie Balard, 34293 Montpellier, France.

Molecules (Basel, Switzerland)

|July 14, 2023

概括

新的二二胺化合物有效抑制神经元氧化合成酶 (nNOS) 和可诱导氧化合成酶 (iNOS),其选择性高于内皮氧化合成酶 (eNOS). 这些强大的抑制剂对针对NOS途径的治疗应用有前途.

科学领域:

药用化学医学化学
生物化学生物化学
药理学药理学是指药理学的学科.

背景情况:

氧化合成酶 (NOS) 在生理和病理过程中起着关键作用.
选择性抑制神经元NOS (nNOS) 和诱导性NOS (iNOS) 而不是内皮NOS (eNOS) 在治疗上是可取的.
以前的二二胺化合物显示出有希望的结果,但需要进一步优化.

研究的目的:

开发具有增强强效和对nNOS/iNOS的选择性的新型二二胺抑制剂.
通过增加抑制剂的延伸大小来研究结构-活性关系.
通过计算和光谱研究阐明选择性的分子基础.

主要方法:

固体相合成涉及氨基-皮佩里丁或氨基乙基部分与甲的还原性化.
在体外酶抑制试验中测定对nNOS,iNOS和eNOS的IC50值.
分子建模和光谱研究 (例如,血红素活性位点相互作用) 以了解选择性.
基于细胞的测试,以评估RAW264.7 (iNOS) 和INS-1 (nNOS) 细胞中的细胞内抑制.

主要成果:

合成了两种新的二二胺化合物系列,其中包括扩展部分.
确定了在微分子到亚微分子范围内的IC50值的强抑制剂.
化合物对nNOS比eNOS表现出显著的选择性.
分子建模和光谱数据证实了在血红素活性部位的相互作用,并解释了选择性.
选择的抑制剂在相关细胞系中成功抑制了细胞内nNOS和iNOS.

结论:

开发的二二胺化合物在nNOS/iNOS抑制方面取得了重大进展.
扩展尺寸的增加有利于在NOS基底接入通道内调节相互作用,增强功效和选择性.
这些发现为进一步开发用于治疗应用的选择性NOS抑制剂提供了坚实的基础.

关键词:

一,二,四-氧化二醇没有NO合成酶.酶抑制剂是一种酶抑制剂.异基氨酸是异基氨酸.伪二化物是一种伪二化物.固相合成的固相合成方法

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