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首页> 外文期刊>Journal of Medicinal Chemistry >Protein kinase C ligands based on tetrahydrofuran templates containing a new set of phorbol ester pharmacophores.
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Protein kinase C ligands based on tetrahydrofuran templates containing a new set of phorbol ester pharmacophores.

机译：基于四氢呋喃模板的蛋白激酶C配体，其中包含一组新的佛波酯酯药效基团。

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A series of substituted tetrahydrofurans with an embedded glycerol backbone carrying additional tetrahydrofuranylideneacetate or tetrahydrofuranylacetate motifs were grouped into four distinct templates (I-IV) according to stereochemistry. The compounds were designed to mimic three essential pharmacophores (C(3)-C=O, C(20)-OH and C(13)-C=O) of the phorbol esters according to a new, revised model. The tetrahydrofuran ring was constructed from glycidyl 4-methoxyphenyl ether, and the structures of the isomeric templates were assigned by NMR spectroscopy, including NOE. The binding affinity for protein kinase C (PKC) was assessed in terms of the ability of the ligands to displace bound [(3)H-20]phorbol 12, 13-dibutyrate (PDBU) from a recombinant alpha isozyme of PKC. Geometric Z- and E-isomers (1 and 3, respectively) containing a tetrahydrofuranylideneacetate motif were the most potent ligands with identical K(i) values of 0.35 microM. Molecular modeling studies of the four templates showed that the rms values when fitted to a prototypical phorbol 12,13-diacetate ester correlated inversely with affinities in the following order: I approximately II > III > IV. These compounds represent the first generation of rigid glycerol templates seeking to mimic the binding of the C(13)-C=O of the phorbol esters. The binding affinities of the most potent compounds are in the same range of the diacylglycerols (DAGs) despite the lack of a phorbol ester C(9)-OH pharmacophore surrogate. This finding confirms that mimicking the binding of the C(13)-C=O pharmacophore of phorbol is a useful strategy. However, since the C(9)-OH and C(13)-C=O in the phorbol esters appear to form an intramolecular hydrogen bond that functions as a combined pharmacophore, it is possible the lack of this combined motif in the target templates restricts the compounds from reaching higher binding affinities.
机译：根据立体化学，一系列带有嵌入的甘油主链的取代的四氢呋喃带有附加的四氢呋喃亚基乙酸盐或四氢呋喃基乙酸盐基序，分为四个不同的模板（I-IV）。根据新的修订模型，将这些化合物设计为模仿佛波酯的三个基本药效基团（C（3）-C = O，C（20）-OH和C（13）-C = O）。由缩水甘油基4-甲氧基苯基醚构成四氢呋喃环，并通过NMR光谱法（包括NOE）确定异构体模板的结构。对蛋白激酶C（PKC）的结合亲和力是根据配体从PKC的重组α同工酶置换结合的[（3）H-20] phorbol 12、13-二丁酸酯（PDBU）的能力来评估的。含有四氢呋喃亚基乙酸酯基序的几何Z-异构体和E-异构体（分别为1和3）是最有效的配体，其K（i）值相同，为0.35 microM。对这四个模板的分子建模研究表明，当拟合到典型的佛波醇12,13-二乙酸酯时，均方根值与亲和力成反比，其相关性依次为：I约II> III> IV。这些化合物代表了第一代刚性甘油模板，试图模仿佛波酯的C（13）-C = O的结合。尽管没有佛波酯C（9）-OH药效基团的替代物，但最有效的化合物的结合亲和力在二酰基甘油（DAGs）的相同范围内。这一发现证实，模仿佛波的C（13）-C = O药效团的结合是一种有用的策略。但是，由于佛波酯中的C（9）-OH和C（13）-C = O似乎形成了分子内氢键，起着结合药效基团的作用，因此目标模板中可能缺少结合的基序限制了化合物达到更高的结合亲和力。

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