کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
1364499 981538 2007 14 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
A synthetic method for diversification of the P1′ substituent in phosphinic dipeptides as a tool for exploration of the specificity of the S1′ binding pockets of leucine aminopeptidases
موضوعات مرتبط
مهندسی و علوم پایه شیمی شیمی آلی
پیش نمایش صفحه اول مقاله
A synthetic method for diversification of the P1′ substituent in phosphinic dipeptides as a tool for exploration of the specificity of the S1′ binding pockets of leucine aminopeptidases
چکیده انگلیسی

A novel, general, and versatile method of diversification of the P1′ position in phosphinic pseudodipeptides, presumable inhibitors of proteolytic enzymes, was elaborated. The procedure was based on parallel derivatization of the amino group in the suitably protected phosphinate building blocks with appropriate alkyl and aryl halides. This synthetic strategy represents an original approach to phosphinic dipeptide chemistry. Its usefulness was confirmed by obtaining a series of P1′ modified phosphinic dipeptides, inhibitors of cytosolic leucine aminopeptidase, through computer-aided design basing on the structure of homophenylalanyl-phenylalanine analogue (hPheP[CH2]Phe) bound in the enzyme active site as a lead structure. In this approach novel interactions between inhibitor P1′ fragment and the S1′ region of the enzyme, particularly hydrogen bonding involving Asn330 and Asp332 enzyme residues, were predicted. The details of the design, synthesis, and activity evaluation toward cytosolic leucine aminopeptidase and aminopeptidase N are discussed. Although the potency of the lead compound has not been improved, marked selectivity of the synthesized inhibitors toward both studied enzymes was observed.

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ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Bioorganic & Medicinal Chemistry - Volume 15, Issue 9, 1 May 2007, Pages 3187–3200
نویسندگان
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