Synthesis of Flavonoid Analogues as Scaffolds for Natural Product-Based Combinatorial Libraries

Yao, Nianhuan; Song, Aiming; Wang, Xiaobing; Dixon, Seth; Lam, Kit S.

doi:10.1021/cc070009y

Cited by 56 publications

(44 citation statements)

References 28 publications

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“…In addition to natural products, combinatorial libraries are attractive sources to expand the medicinal-relevant chemical space (13). Some combinatorial libraries, though small-sized, are inspired by natural product scaffolds (1,14,15).Drug discovery programs that use natural products and compounds from other sources involve a large amount of structural and bioactivity data. The information is stored in commercial, in-house or public databases and has been reviewed elsewhere (16-18).…”

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Molecular Scaffold Analysis of Natural Products Databases in the Public Domain

2012

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Natural products represent important sources of bioactive compounds in drug discovery efforts. In this work, we compiled five natural products databases available in the public domain and performed a comprehensive chemoinformatic analysis focused on the content and diversity of the scaffolds with an overview of the diversity based on molecular fingerprints. The natural products databases were compared with each other and with a set of molecules obtained from in-house combinatorial libraries, and with a general screening commercial library. It was found that publicly available natural products databases have different scaffold diversity. In contrast to the common concept that larger libraries have the largest scaffold diversity, the largest natural products collection analyzed in this work was not the most diverse. The general screening library showed, overall, the highest scaffold diversity. However, considering the most frequent scaffolds, the general reference library was the least diverse. In general, natural products databases in the public domain showed low molecule overlap. In addition to benzene and acyclic compounds, flavones, coumarins, and flavanones were identified as the most frequent molecular scaffolds across the different natural products collections. The results of this work have direct implications in the computational and experimental screening of natural product databases for drug discovery.Key words: chemoinformatics, cyclic system, molecular diversity, natural product, Shannon entropy, Traditional Chinese Medicine.Abbreviations: CSR, cumulative scaffold recovery; MACCS, Molecular ACCess System; MEQI, Molecular Equivalence Index; MOE, molecular operating environment; SE, Shannon entropy; TCM, Traditional Chinese Medicine.Received 22 June 2012, revised 18 July 2012 and accepted for publication 19 July 2012Traditionally, natural products have played a major role in drug discovery and development by providing novel chemical scaffolds, and serving as leads or drugs (1,2). For many years, 80% of drugs were either natural products or natural product-derived compounds. Even in the modern era, after the advent of techniques such as high-throughput screening of synthetic libraries, half of the drugs approved since 1994 are based on natural products research (3,4). Recent comprehensive reviews of natural products, or compounds inspired by natural products, indicate that more than 100 natural product compounds are currently in clinical trials. Natural products offer the advantage of discovering novel structural classes (5,6) because of their well-documented better coverage of chemical space relative to large synthetic compounds (7). Hence, the structural or chemical diversity of natural products can be utilized to access bioactive compounds with novel scaffolds (7-9). The inclusion of sources of natural products in drug discovery would open up more avenues for new classes of drugs (10) as well as new chemical entities, evidenced by studies that show structural or chemical complementarity between natural...

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Molecular Scaffold Analysis of Natural Products Databases in the Public Domain

2012

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“…Small amounts of cyclized flavonoid-like compounds derived from intramolecular additions of the free phenolic hydroxyl groups to the adjacent unsaturated ketones were unexpectedly obtained as products. [31][32][33] …”

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confidence: 99%

Use of a Hexasubstituted Benzene Scaffold in the Development of Multivalent HIV-1 Integrase Inhibitors

Tupchiangmai

Choksakulporn

Tewtrakul

et al. 2014

CHEMICAL & PHARMACEUTICAL BULLETIN

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The highly directional hexasubstituted benzene moiety was used as the central scaffold to create new human immunodeficiency virus (HIV)-1 integrase inhibitors through the attachment of multiple active groups. A series of potential inhibitors having substituted polyhydroxylated mono, bis and tris-cinnamoyl derivatives connected on the scaffold were prepared through Claisen-Schmidt condensations with substituted benzaldehydes, followed by partial demethylation to uncover the active phenolic groups required for the interactions with the integrase enzyme active sites. Using a multiplate integration assay method, four compounds carrying at least two sets of interacting moieties were found to be relatively potent integrase inhibitors with IC 50 values in the low micromolar range. The results confirmed that multiple polyhydroxylated groups were required on the platform in order to effectively interact with the enzyme. The results from molecular docking studies consistently complemented the experimental results and revealed the nature of the potential key binding interactions responsible for the apparent activity of the active compounds.

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“…A different strategy was employed by Yao et al 66 for the preparation of a flavone library. The functionalized flavone 297 was prepared in solution phase by classical Claisen condensation, mixed acid nitration and oxidative cyclization reaction with iodine-DMSO.…”

Section: Flavonoidsmentioning

confidence: 99%

Highlights in the solid-phase organic synthesis of natural products and analogues

Eifler‐Lima¹,

Graebin²,

Uchôa³

et al. 2010

J. Braz. Chem. Soc.

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Neste trabalho nós apresentamos uma revisão sobre a síntese em fase sólida de metabólitos secundários, tais como alcalóides, poliaminas, esteróides, terpenos e flavonóides, descritos na literatura a partir de 2000. Um número considerável de rotas sintéticas elegantes e desafiadoras, usando suportes sólidos, será discutido.In this manuscript, we disclose solid-phase organic syntheses (SPOS) of small-molecules of some secondary metabolites, such as alkaloids, polyamines, steroids, terpenes, and flavonoids, described in the literature since 2000. A number of elegant, efficient and challenging syntheses on solid support will be presented.

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Synthesis of Flavonoid Analogues as Scaffolds for Natural Product-Based Combinatorial Libraries

Cited by 56 publications

References 28 publications

Molecular Scaffold Analysis of Natural Products Databases in the Public Domain

Molecular Scaffold Analysis of Natural Products Databases in the Public Domain

Use of a Hexasubstituted Benzene Scaffold in the Development of Multivalent HIV-1 Integrase Inhibitors

Highlights in the solid-phase organic synthesis of natural products and analogues

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