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Conformation-activity relationships of polyketide natural products.

ABSTRACT: Polyketides represent an important class of secondary metabolites that interact with biological targets connected to a variety of disease-associated pathways. Remarkably, nature's assembly lines, polyketide synthases, manufacture these privileged structures through a combinatorial mixture of just a few structural units. This review highlights the role of these structural elements in shaping a polyketide's conformational preferences, the use of computer-based molecular modeling and solution NMR studies in the identification of low-energy conformers, and the importance of conformational analogues in probing the bound conformation. In particular, this review covers several examples wherein conformational analysis complements classic structure-activity relationships in the design of biologically active natural product analogues.

SUBMITTER: Larsen EM

PROVIDER: S-EPMC4443481 | biostudies-literature | 2015 Aug

REPOSITORIES: biostudies-literature

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Conformation-activity relationships of polyketide natural products.

Larsen Erik M EM Wilson Matthew R MR Taylor Richard E RE

Natural product reports 20150801 8

Polyketides represent an important class of secondary metabolites that interact with biological targets connected to a variety of disease-associated pathways. Remarkably, nature's assembly lines, polyketide synthases, manufacture these privileged structures through a combinatorial mixture of just a few structural units. This review highlights the role of these structural elements in shaping a polyketide's conformational preferences, the use of computer-based molecular modeling and solution NMR s ...[more]

PMID: 25974024

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Project description:Marine natural products (MNPs) have been an important and rich source for antimicrobial drug discovery and an effective alternative to control drug resistant infections. Herein, we report bioassay guided fractionation of marine extracts from sponges Lendenfeldia, Ircinia and Dysidea that led us to identify novel compounds with antimicrobial properties. Tertiary amines or quaternary amine salts: aniline 1, benzylamine 2, tertiary amine 3 and 4, and quaternary amine salt 5, along with three known compounds (6-8) were isolated from a crude extract and MeOH eluent marine extracts. The antibiotic activities of the compounds, and their isolation as natural products have not been reported before. Using tandem mass spectrometry (MS) analysis, potential structures of the bioactive fractions were assigned, leading to the hit validation of potential compounds through synthesis, and commercially available compounds. This method is a novel strategy to overcome insufficient quantities of pure material (NPs) for drug discovery and development which is a big challenge for pharmaceutical companies. The antibacterial screening of the marine extracts has shown several of the compounds exhibited potent in-vitro antibacterial activity, especially against methicillin-resistant Staphylococcus aureus (MRSA) with minimum inhibitory concentration (MIC) values between 15.6 to 62.5 microg mL-1. Herein, we also report structure activity relationships of a diverse range of commercial structurally similar compounds. The structure-activity relationships (SAR) results demonstrate that modification of the amines through linear chain length, and inclusion of aromatic rings, modifies the observed antimicrobial activity. Several commercially available compounds, which are structurally related to the discovered molecules, showed broad-spectrum antimicrobial activity against different test pathogens with a MIC range of 50 to 0.01 µM. The results of cross-referencing antimicrobial activity and cytotoxicity establish that these compounds are promising potential molecules, with a favourable therapeutic index for antimicrobial drug development. Additionally, the SAR studies show that simplified analogues of the isolated compounds have increased bioactivity.

Dataset Information

Conformation-activity relationships of polyketide natural products.

Publications

Conformation-activity relationships of polyketide natural products.

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