Correspondence analysis of protein kinase C (PKC) inhibition by bis-basic substituted benzamides.

Drug design and discovery Pub Date : 1998-10-01
J Gilbert, M Cheminant, E Bignon, M Pons, T Ojasoo, J C Doré
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Abstract

We describe the synthesis of a novel series of bis-basic substituted benzamides and their relative potency in inhibiting rat brain protein kinase alpha (PKC alpha) activity. None of the compounds inhibited enzyme activity via the catalytic domain but several did via the regulatory domain at 1-5 microM concentrations. Inhibition was comparable to that of several di- and triphenylacrylonitriles and triphenylethylenes. According to a multivariate factor (correspondence) analysis of QSAR descriptors, hydrophobicity (log p) and hydration energy were the most discriminant descriptors, much more so than molecular mass, molar refractivity, polarizability, molecular volume and solvent-accessible surface. Inhibitory activity was correlated with high hydrophobicity and low hydration energy. The higher potency of GL9 (N,N'-oxalyl-bis[(o-amino)[2-(diethylamino)ethyl]-benzamide]) that differed from its congener (GL25) by the presence of an oxamide rather than succinamide moiety was tentatively explained by the greater negative charges associated with the carbonyl groups of its oxamide residue. The higher potency of GL22 (N,N'-tere-phthalyl-bis[(o-amino)[2-(diethylamino)ethyl]-benzamide ] in which an aromatic ring is inserted between two benzamide moieties in para, para' rather than ortho, ortho' positions as in GL23 might be due to a planar conformation facilitating membrane insertion. In conclusion, correspondence analysis is a neat way of highlighting similarities and differences in molecular properties (QSAR descriptors and potency). Therapeutic doses of many classes of drug might interfere with the regulatory domain of PKC alpha if, like our test-compounds, they have basic side-chain(s), high hydrophobicity, low hydration energy, a planar conformation and/or a highly charged reactive (oxamide) moiety.

双碱取代苯酰胺抑制蛋白激酶C (PKC)的对应分析。
我们描述了一系列新的双碱取代苯酰胺的合成及其抑制大鼠脑蛋白激酶α (PKC α)活性的相对效力。没有一种化合物通过催化结构域抑制酶活性,但有几种化合物在1-5微米浓度下通过调节结构域抑制酶活性。抑制作用与几种二苯基和三苯基丙烯腈和三苯基乙烯相当。根据QSAR描述符的多因素(对应)分析,疏水性(log p)和水合能是最具鉴别性的描述符,比分子质量、摩尔折射率、极化率、分子体积和溶剂可及表面更有鉴别性。抑制活性与高疏水性和低水合能有关。GL9 (N,N'-草酰-双[(o-氨基)[2-(二乙胺)乙基]-苯甲酰胺])与同类GL25 (N,N'-草酰-双[(o-氨基)[2-(二乙胺)乙基]-苯甲酰胺])由于存在草酰胺而不是琥珀酰胺部分而具有更高的效力,这一现象初步解释为其草酰胺残基的羰基具有更大的负电荷。GL22 (N,N'-tere-phthalyl-bis[(o-氨基)[2-(二乙胺)乙基]-苯酰胺]的效能更高,其中芳香环插入在对,对'的两个苯酰胺基团之间,而不是GL23的邻位,邻位可能是由于平面构象有利于膜插入。总之,对应分析是突出分子性质(QSAR描述符和效价)相似性和差异性的一种简便方法。许多类药物的治疗剂量可能会干扰PKC α的调节区域,如果它们像我们的测试化合物一样,具有基本侧链,高疏水性,低水合能,平面构象和/或高电荷的反应性(草酰胺)部分。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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