Natural product-derived building blocks for combinatorial synthesis. Part 1. Fragmentation of natural products from myxobacteria

2002 ◽  
pp. 2490-2503 ◽  
Author(s):  
Jutta Niggemann ◽  
Katrin Michaelis ◽  
Ronald Frank ◽  
Norbert Zander ◽  
Gerhard Höfle
Keyword(s):  
Natural Products ◽  
Natural Product ◽  
Building Blocks ◽  
Combinatorial Synthesis

scholarly journals Catalytic Asymmetric Intramolecular Darzens Reaction of 2-Halomalonate Derivatives

2019 ◽  
Vol 14 (10) ◽  
pp. 1934578X1988440
Author(s):  
Kenichi Kobayashi ◽  
Kosaku Tanaka ◽  
Momoko Suzuki ◽  
Hiroshi Kogen
Keyword(s):  
Natural Products ◽  
Natural Product ◽  
Phase Transfer ◽  
Building Blocks ◽  
Natural Product Synthesis ◽  
Darzens Reaction ◽  
Phase Transfer Catalysts ◽  
Catalytic Asymmetric

A catalytic asymmetric intramolecular Darzens reaction of 2-halomalonate derivatives was developed for the enantioselective preparation of chiral building blocks for epoxide-containing natural products. Among the screened catalysts, some phase-transfer catalysts gave the desired epoxide in moderate enantioselectivity, albeit in low yield. The epoxide product would be useful as versatile chiral building blocks for natural product synthesis.

scholarly journals Expanding the Fluorine Chemistry of Living Systems Using Engineered Polyketide Synthase Pathways

Science ◽  
2013 ◽  
Vol 341 (6150) ◽  
pp. 1089-1094 ◽  
Author(s):  
Mark C. Walker ◽  
Benjamin W. Thuronyi ◽  
Louise K. Charkoudian ◽  
Brian Lowry ◽  
Chaitan Khosla ◽  
...  
Keyword(s):  
Natural Products ◽  
Synthetic Biology ◽  
Natural Product ◽  
Polyketide Synthase ◽  
Building Blocks ◽  
Living Systems ◽  
Synthetic Compounds ◽  
Fluorinated Building Blocks

Organofluorines represent a rapidly expanding proportion of molecules that are used in pharmaceuticals, diagnostics, agrochemicals, and materials. Despite the prevalence of fluorine in synthetic compounds, the known biological scope is limited to a single pathway that produces fluoroacetate. Here, we demonstrate that this pathway can be exploited as a source of fluorinated building blocks for introduction of fluorine into natural-product scaffolds. Specifically, we have constructed pathways involving two polyketide synthase systems, and we show that fluoroacetate can be used to incorporate fluorine into the polyketide backbone in vitro. We further show that fluorine can be inserted site-selectively and introduced into polyketide products in vivo. These results highlight the prospects for the production of complex fluorinated natural products using synthetic biology.

scholarly journals Towards the de Novo Design of HIV-1 Protease Inhibitors Based on Natural Products

2021 ◽  
Author(s):  
Ana L. Chávez-Hernández ◽  
K. Eurídice Juárez-Mercado ◽  
Fernanda I. Saldívar-González ◽  
José L. Medina-Franco
Keyword(s):  
Natural Products ◽  
Natural Product ◽  
Protease Inhibitors ◽  
De Novo ◽  
Chemical Space ◽  
Public Health Problem ◽  
Building Blocks ◽  
De Novo Design ◽  
Viral Protease ◽  
Hiv 1

The acquired immunodeficiency syndrome (AIDS) caused by the human immunodeficiency virus (HIV) continues to be a public health problem. In 2020, 680,000 people died from HIV-related causes, and 1.5 million people were infected. Antiretrovirals are only a way to control HIV infection but not to cure AIDS. As such, effective treatment must be developed to control AIDS. Developing a drug is not an easy task, and there is an enormous amount of work and economic resources invested. For this reason, it is highly convenient to employ computer-aided drug design methods, which can help generate and identify novel molecules. Using the de novo design, new novel molecules can be developed using fragments as building blocks. In this work, we develop a virtual-focused compound library of HIV-1 viral protease inhibitors from natural product fragments. Natural products are characterized by a large diversity of functional groups, many sp3 atoms, and chiral centers. Pseudo-natural products are a combination of natural products fragments that keep the desired structural characteristics from different natural products. An interactive version of chemical space visualization of virtual compounds focused on HIV-1 viral protease inhibitors from natural product fragments is freely available at https://figshare.com/s/ceb58d58e8f5585ce67e.

Latest Applications of the Diels-Alder Reaction in the Synthesis of Natural Products (2017-2020)

Synthesis ◽  
2021 ◽  
Author(s):  
Markus Kalesse ◽  
Aamer Saeed ◽  
Alexandru Sara ◽  
Um-e Farwa
Keyword(s):  
Natural Products ◽  
Natural Product ◽  
Building Blocks ◽  
Alder Reaction ◽  
Diels Alder ◽  
High Rank ◽  
Total Syntheses ◽  
Diels Alder Reaction ◽  
Natural Product Chemist

The Diels-Alder reaction has long established its high rank in the toolbox of any natural product chemist. The tremendous toleration of building blocks of various complexity and derivatization degree, as well as the enablement of furnishing six-membered rings with well-defined stereochemistry represents its main features and advantages. In recent years, many total syntheses of natural products relied at some point on the use of a [4+2]-cycloaddition step. Among classic approaches, several modifications of the Diels-Alder reaction, such as hetero-Diels-Alder reactions, dehydro-Diels-Alder reactions or domino-Diels-Alder reactions have been employed to extend the scope in the synthesis of natural products. Our review covers the application of the Diels-Alder reaction in natural product syntheses from 2017 to 2020, as well as selected methodologies which were inspired by, or could be used to access natural products.

scholarly journals Discovery of the leinamycin family of natural products by mining actinobacterial genomes

2017 ◽  
Vol 114 (52) ◽  
pp. E11131-E11140 ◽  
Author(s):  
Guohui Pan ◽  
Zhengren Xu ◽  
Zhikai Guo ◽  
Hindra ◽  
Ming Ma ◽  
...  
Keyword(s):  
Natural Products ◽  
Natural Product ◽  
Structural Diversity ◽  
Building Blocks ◽  
Combinatorial Biosynthesis ◽  
Pathway Engineering ◽  
Natural Product Discovery ◽  
Knowledge Based ◽  
Metabolic Pathway Engineering ◽  
Strain Collection

Nature’s ability to generate diverse natural products from simple building blocks has inspired combinatorial biosynthesis. The knowledge-based approach to combinatorial biosynthesis has allowed the production of designer analogs by rational metabolic pathway engineering. While successful, structural alterations are limited, with designer analogs often produced in compromised titers. The discovery-based approach to combinatorial biosynthesis complements the knowledge-based approach by exploring the vast combinatorial biosynthesis repertoire found in Nature. Here we showcase the discovery-based approach to combinatorial biosynthesis by targeting the domain of unknown function and cysteine lyase domain (DUF–SH) didomain, specific for sulfur incorporation from the leinamycin (LNM) biosynthetic machinery, to discover the LNM family of natural products. By mining bacterial genomes from public databases and the actinomycetes strain collection at The Scripps Research Institute, we discovered 49 potential producers that could be grouped into 18 distinct clades based on phylogenetic analysis of the DUF–SH didomains. Further analysis of the representative genomes from each of the clades identified 28 lnm-type gene clusters. Structural diversities encoded by the LNM-type biosynthetic machineries were predicted based on bioinformatics and confirmed by in vitro characterization of selected adenylation proteins and isolation and structural elucidation of the guangnanmycins and weishanmycins. These findings demonstrate the power of the discovery-based approach to combinatorial biosynthesis for natural product discovery and structural diversity and highlight Nature’s rich biosynthetic repertoire. Comparative analysis of the LNM-type biosynthetic machineries provides outstanding opportunities to dissect Nature’s biosynthetic strategies and apply these findings to combinatorial biosynthesis for natural product discovery and structural diversity.

scholarly journals Towards the De Novo Design of HIV-1 Protease Inhibitors Based on Natural Products

Biomolecules ◽  
2021 ◽  
Vol 11 (12) ◽  
pp. 1805
Author(s):  
Ana L. Chávez-Hernández ◽  
K. Eurídice Juárez-Mercado ◽  
Fernanda I. Saldívar-González ◽  
José L. Medina-Franco
Keyword(s):  
Natural Products ◽  
Natural Product ◽  
Protease Inhibitors ◽  
De Novo ◽  
Chemical Space ◽  
Public Health Problem ◽  
Building Blocks ◽  
De Novo Design ◽  
Viral Protease ◽  
Hiv 1

Acquired immunodeficiency syndrome (AIDS) caused by the human immunodeficiency virus (HIV) continues to be a public health problem. In 2020, 680,000 people died from HIV-related causes, and 1.5 million people were infected. Antiretrovirals are a way to control HIV infection but not to cure AIDS. As such, effective treatment must be developed to control AIDS. Developing a drug is not an easy task, and there is an enormous amount of work and economic resources invested. For this reason, it is highly convenient to employ computer-aided drug design methods, which can help generate and identify novel molecules. Using the de novo design, novel molecules can be developed using fragments as building blocks. In this work, we develop a virtual focused compound library of HIV-1 viral protease inhibitors from natural product fragments. Natural products are characterized by a large diversity of functional groups, many sp3 atoms, and chiral centers. Pseudo-natural products are a combination of natural products fragments that keep the desired structural characteristics from different natural products. An interactive version of chemical space visualization of virtual compounds focused on HIV-1 viral protease inhibitors from natural product fragments is freely available in the supplementary material.

Synthesis and Biological Evaluation of the Antimicrobial Natural Product Lipoxazolidinone A

2018 ◽  
Author(s):  
Jonathan J. Mills ◽  
Kaylib R. Robinson ◽  
Troy E. Zehnder ◽  
Joshua G. Pierce
Keyword(s):  
Natural Products ◽  
Natural Product ◽  
Mechanism Of Action ◽  
Marine Natural Products ◽  
Biological Evaluation ◽  
Lead Compounds ◽  
Follow Up Studies ◽  
Initial Resistance ◽  
Synthesis And Biological Evaluation

The lipoxazolidinone family of marine natural products, with an unusual 4-oxazolidinone heterocycle at their core, represents a new scaffold for antimicrobial discovery; however, questions regarding their mechanism of action and high lipophilicity have likely slowed follow-up studies. Herein, we report the first synthesis of lipoxazolidinone A, 15 structural analogs to explore its active pharmacophore, and initial resistance and mechanism of action studies. These results suggest that 4-oxazolidinones are valuable scaffolds for antimicrobial development and reveal simplified lead compounds for further optimization.

Unzipping Natural Products: Improved Natural Product Structure Predictions by Ensemble Modeling and Fingerprint Matching

2018 ◽  
Author(s):  
William A. Shirley ◽  
Brian P. Kelley ◽  
Yohann Potier ◽  
John H. Koschwanez ◽  
Robert Bruccoleri ◽  
...  
Keyword(s):  
Natural Products ◽  
Open Source ◽  
Natural Product ◽  
Gene Cluster ◽  
Public Domain ◽  
Product Structure ◽  
Fingerprint Matching ◽  
Ensemble Modeling ◽  
Chemical Structures ◽  
Source Gene

This pre-print explores ensemble modeling of natural product targets to match chemical structures to precursors found in large open-source gene cluster repository antiSMASH. Commentary on method, effectiveness, and limitations are enclosed. All structures are public domain molecules and have been reviewed for release.

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