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Multicomponent approach to natural product-like compounds

Screening of small-molecule libraries has been the most commonly used tool in drug discovery over the past two decades. [1] However, most libraries typically represent collections of a large number of structurally similar compounds, i.e., the “chemical space” covered is infinitely small. [2] This limitation significantly hampers development of novel lead compounds needed to tackle new generations of biological targets. Contrary to that, natural products with complex molecular architectures and numerous stereogenic centers represent valuable pool of drug candidates. The concept of expanding the chemical space by developing large collections of structurally diverse natural product-like compounds is one of the main challenges nowadays. In order to achieve high degree of structural diversity, it is important to have various building blocks equipped with functional groups than can generate diverse molecular scaffolds with different stereochemistry. Our group is currently aiming to expand the chemical space by using multicomponent reactions to generate structural variations and complexity. Multicomponent reactions (MCRs, Fig. 1a) are powerful tool for introducing chemical diversity and the rapid generation of small-molecule libraries. Among numerous types of MCRs, of special interest are those that include isocyanide functional group, particularly the Passerini and Ugi reaction. We focused on building blocks derived from natural and non-natural amino acids, carbohydrates and enediynes (Fig. 1b), and their utilization in MCRs. [3]

Multicomponent reactions ; natural product-like compounds ; Passerini reaction ; mimetics

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