Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Two-directional synthesis as a tool for diversity-oriented synthesis: Synthesis of alkaloid scaffolds.

ABSTRACT: Two-directional synthesis represents an ideal strategy for the rapid elaboration of simple starting materials and their subsequent transformation into complex molecular architectures. As such, it is becoming recognised as an enabling technology for diversity-oriented synthesis. Herein, we provide a thorough account of our work combining two-directional synthesis with diversity-oriented synthesis, with particular reference to the synthesis of polycyclic alkaloid scaffolds.

SUBMITTER: O'Connell KM

PROVIDER: S-EPMC3388873 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Two-directional synthesis as a tool for diversity-oriented synthesis: Synthesis of alkaloid scaffolds.

O'Connell Kieron M G KM Díaz-Gavilán Monica M Galloway Warren R J D WR Spring David R DR

Beilstein journal of organic chemistry 20120606

Two-directional synthesis represents an ideal strategy for the rapid elaboration of simple starting materials and their subsequent transformation into complex molecular architectures. As such, it is becoming recognised as an enabling technology for diversity-oriented synthesis. Herein, we provide a thorough account of our work combining two-directional synthesis with diversity-oriented synthesis, with particular reference to the synthesis of polycyclic alkaloid scaffolds. ...[more]

PMID: 23015833

Similar Datasets

Diversity-oriented approach to pyrrole-imidazole alkaloid frameworks.

Project description:An exploration of imidazolylpropargyl amides as linchpin synthons for the construction of a diverse array of heterocyclic frameworks, many of which are related to those found in the oroidin derived alkaloids, is described. One such intermediate has been used in a formal total synthesis of cyclooroidin.

| S-EPMC3099625 | biostudies-literature

A diversity-oriented synthesis strategy enabling the combinatorial-type variation of macrocyclic peptidomimetic scaffolds.

Project description:Macrocyclic peptidomimetics are associated with a broad range of biological activities. However, despite such potentially valuable properties, the macrocyclic peptidomimetic structural class is generally considered as being poorly explored within drug discovery. This has been attributed to the lack of general methods for producing collections of macrocyclic peptidomimetics with high levels of structural, and thus shape, diversity. In particular, there is a lack of scaffold diversity in current macrocyclic peptidomimetic libraries; indeed, the efficient construction of diverse molecular scaffolds presents a formidable general challenge to the synthetic chemist. Herein we describe a new, advanced strategy for the diversity-oriented synthesis (DOS) of macrocyclic peptidomimetics that enables the combinatorial variation of molecular scaffolds (core macrocyclic ring architectures). The generality and robustness of this DOS strategy is demonstrated by the step-efficient synthesis of a structurally diverse library of over 200 macrocyclic peptidomimetic compounds, each based around a distinct molecular scaffold and isolated in milligram quantities, from readily available building-blocks. To the best of our knowledge this represents an unprecedented level of scaffold diversity in a synthetically derived library of macrocyclic peptidomimetics. Cheminformatic analysis indicated that the library compounds access regions of chemical space that are distinct from those addressed by top-selling brand-name drugs and macrocyclic natural products, illustrating the value of our DOS approach to sample regions of chemical space underexploited in current drug discovery efforts. An analysis of three-dimensional molecular shapes illustrated that the DOS library has a relatively high level of shape diversity.

| S-EPMC4441267 | biostudies-literature

Synthesis of unnatural alkaloid scaffolds by exploiting plant polyketide synthase.

Project description:HsPKS1 from Huperzia serrata is a type III polyketide synthase (PKS) with remarkable substrate tolerance and catalytic potential. Here we present the synthesis of unnatural unique polyketide-alkaloid hybrid molecules by exploiting the enzyme reaction using precursor-directed and structure-based approaches. HsPKS1 produced novel pyridoisoindole (or benzopyridoisoindole) with the 6.5.6-fused (or 6.6.5.6-fused) ring system by the condensation of 2-carbamoylbenzoyl-CoA (or 3-carbamoyl-2-naphthoyl-CoA), a synthetic nitrogen-containing nonphysiological starter substrate, with two molecules of malonyl-CoA. The structure-based S348G mutant not only extended the product chain length but also altered the cyclization mechanism to produce a biologically active, ring-expanded 6.7.6-fused dibenzoazepine, by the condensation of 2-carbamoylbenzoyl-CoA with three malonyl-CoAs. Thus, the basic nitrogen atom and the structure-based mutagenesis enabled additional C?C and C?N bond formation to generate the novel polyketide-alkaloid scaffold.

| S-EPMC3158201 | biostudies-literature

Deploying Microbial Synthesis for Halogenating and Diversifying Medicinal Alkaloid Scaffolds.

Project description:Plants produce some of the most potent therapeutics and have been used for thousands of years to treat human diseases. Today, many medicinal natural products are still extracted from source plants at scale as their complexity precludes total synthesis from bulk chemicals. However, extraction from plants can be an unreliable and low-yielding source for human therapeutics, making the supply chain for some of these life-saving medicines expensive and unstable. There has therefore been significant interest in refactoring these plant pathways in genetically tractable microbes, which grow more reliably and where the plant pathways can be more easily engineered to improve the titer, rate and yield of medicinal natural products. In addition, refactoring plant biosynthetic pathways in microbes also offers the possibility to explore new-to-nature chemistry more systematically, and thereby help expand the chemical space that can be probed for drugs as well as enable the study of pharmacological properties of such new-to-nature chemistry. This perspective will review the recent progress toward heterologous production of plant medicinal alkaloids in microbial systems. In particular, we focus on the refactoring of halogenated alkaloids in yeast, which has created an unprecedented opportunity for biosynthesis of previously inaccessible new-to-nature variants of the natural alkaloid scaffolds.

| S-EPMC7644825 | biostudies-literature

Diversity-oriented synthesis of macrocyclic peptidomimetics.

Project description:Structurally diverse libraries of novel small molecules represent important sources of biologically active agents. In this paper we report the development of a diversity-oriented synthesis strategy for the generation of diverse small molecules based around a common macrocyclic peptidomimetic framework, containing structural motifs present in many naturally occurring bioactive compounds. Macrocyclic peptidomimetics are largely underrepresented in current small-molecule screening collections owing primarily to synthetic intractability; thus novel molecules based around these structures represent targets of significant interest, both from a biological and a synthetic perspective. In a proof-of-concept study, the synthesis of a library of 14 such compounds was achieved. Analysis of chemical space coverage confirmed that the compound structures indeed occupy underrepresented areas of chemistry in screening collections. Crucial to the success of this approach was the development of novel methodologies for the macrocyclic ring closure of chiral ?-azido acids and for the synthesis of diketopiperazines using solid-supported N methylmorpholine. Owing to their robust and flexible natures, it is envisaged that both new methodologies will prove to be valuable in a wider synthetic context.

| S-EPMC3084124 | biostudies-literature

Diversity-oriented synthesis of 17-spirosteroids.

Project description:A diversity-oriented synthesis (DOS) approach has been used to functionalize 17-ethynyl-17-hydroxysteroids through a one-pot procedure involving a ring-closing enyne metathesis (RCEYM) and a Diels-Alder reaction on the resulting diene, under microwave irradiations. Taking advantage of the propargyl alcohol moiety present on commercially available steroids, this classical strategy was applied to mestranol and lynestrenol, giving a collection of new complex 17-spirosteroids.

| S-EPMC7214869 | biostudies-literature

Modular Synthesis of Polycyclic Alkaloid Scaffolds via an Enantioselective Dearomative Cascade.

Project description:The polycyclic core of the akuammiline alkaloids can be synthesized from simple tryptamine and tryptophol derivatives via a Ag(I)-catalyzed enantioselective dearomative cyclization cascade sequence. The complex tetracyclic scaffolds are prepared via a rapid, versatile, three-step modular synthesis from simple commercially available indole derivatives in high yields and enantiomeric excess (up to 99% yield and >99% ee).

| S-EPMC7145359 | biostudies-literature

Aminoazole-Based Diversity-Oriented Synthesis of Heterocycles.

Project description:The comprehensive review contains the analysis of literature data concerning reactions of heterocyclization of aminoazoles and demonstrates the application of these types of transformations in diversity-oriented synthesis. The review is oriented to wide range of chemists working in the field of organic synthesis and both experimental and theoretical studies of nitrogen-containing heterocycles.

| S-EPMC6282055 | biostudies-literature

Oriented matrix promotes directional tubulogenesis.

Project description:Detailed control over the structural organization of scaffolds and engineered tissue constructs is a critical need in the quest to engineer functional tissues using biomaterials. This work presents a new approach to spatially direct endothelial tubulogenesis. Micropatterned fibronectin substrates were used to control lung fibroblast adhesion and growth and the subsequent deposition of fibroblast-derived matrix during culture. The fibroblast-derived matrix produced on the micropatterned substrates was tightly oriented by these patterns, with an average variation of only 8.5°. Further, regions of this oriented extracellular matrix provided directional control of developing endothelial tubes to within 10° of the original micropatterned substrate design. Endothelial cells seeded directly onto the micropatterned substrate did not form tubes. A metric for matrix anisotropy showed a relationship between the fibroblast-derived matrix and the endothelial tubes that were subsequently developed on the same micropatterns with a resulting aspect ratio over 1.5 for endothelial tubulogenesis. Micropatterns in "L" and "Y" shapes were used to direct endothelial tubes to turn and branch with the same level of precision. These data demonstrate that anisotropic fibroblast-derived matrices instruct the alignment and shape of endothelial tube networks, thereby introducing an approach that could be adapted for future design of microvascular implants featuring organ-specific natural matrix that patterns microvascular growth.

| S-EPMC4256113 | biostudies-literature

Diversity-oriented synthesis yields novel multistage antimalarial inhibitors.

Project description:Antimalarial drugs have thus far been chiefly derived from two sources-natural products and synthetic drug-like compounds. Here we investigate whether antimalarial agents with novel mechanisms of action could be discovered using a diverse collection of synthetic compounds that have three-dimensional features reminiscent of natural products and are underrepresented in typical screening collections. We report the identification of such compounds with both previously reported and undescribed mechanisms of action, including a series of bicyclic azetidines that inhibit a new antimalarial target, phenylalanyl-tRNA synthetase. These molecules are curative in mice at a single, low dose and show activity against all parasite life stages in multiple in vivo efficacy models. Our findings identify bicyclic azetidines with the potential to both cure and prevent transmission of the disease as well as protect at-risk populations with a single oral dose, highlighting the strength of diversity-oriented synthesis in revealing promising therapeutic targets.

| S-EPMC5515376 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data