Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Synthesis and conformation-activity relationships of the peptide isosteres of FK228 and largazole.

ABSTRACT: The peptide isosteres (10 and 11) of the naturally occurring and potent histone deacetylase (HDAC) inhibitors FK228 and largazole have been synthesized and evaluated side-by-side with FK228, largazole, and SAHA for inhibition of the class I HDACs 1, 2, 3, and 6.

SUBMITTER: Bowers AA

PROVIDER: S-EPMC2880701 | biostudies-literature | 2009 Mar

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Synthesis and conformation-activity relationships of the peptide isosteres of FK228 and largazole.

Bowers Albert A AA Greshock Thomas J TJ West Nathan N Estiu Guillermina G Schreiber Stuart L SL Wiest Olaf O Williams Robert M RM Bradner James E JE

Journal of the American Chemical Society 20090301 8

The peptide isosteres (10 and 11) of the naturally occurring and potent histone deacetylase (HDAC) inhibitors FK228 and largazole have been synthesized and evaluated side-by-side with FK228, largazole, and SAHA for inhibition of the class I HDACs 1, 2, 3, and 6. ...[more]

PMID: 19193120

Similar Datasets

Novel Substituted Purine Isosteres: Synthesis, Structure-Activity Relationships and Cytotoxic Activity Evaluation.

Project description:A number of pyrrolo[2,3-c]pyridines, pyrrolo[3,2-d]pyrimidines and pyrazolo[4,3-d]pyrimidines were designed and synthesized as antiproliferative agents. The target compounds possessed selected substituents in analogous positions on the central scaffold that allowed the extraction of interesting SARs. The cytotoxic activity of the new derivatives was evaluated against prostatic (PC-3) and colon (HCT116) cell lines, and the most potent analogues showed IC50 values in the nM to low µM range, while they were found to be non-toxic against normal human fibroblasts (WI-38). Flow cytometric analysis of DNA content revealed that the most promising derivative 14b caused a statistically significant accumulation of PC-3 cells at G2/M phase and induced apoptosis in PC-3 cells.

| S-EPMC8746528 | biostudies-literature

Comparative pharmacokinetic properties and antitumor activity of the marine HDACi Largazole and Largazole peptide isostere.

Project description:PURPOSE:Largazole is a potent class I-selective HDACi natural product isolated from the marine cyanobacteria Symploca sp. The purpose of this study was to test synthetic analogs of Largazole to identify potential scaffold structural modifications that would improve the drug-like properties of this clinically relevant natural product. METHODS:The impact of Largazole scaffold replacements on in vitro growth inhibition, cell cycle arrest, induction of apoptosis, pharmacokinetic properties, and in vivo activity using a xenograft model was investigated. RESULTS:In vitro studies in colon, lung, and pancreatic cancer cell lines showed that pyridyl-substituted Largazole analogs had low-nanomolar/high-picomolar antiproliferative activity, and induced apoptosis and cell cycle arrest at concentrations equivalent to or lower than the parent compound Largazole. Using IV bolus delivery at 5 mg/kg, two compartmental pharmacokinetic modeling on the peptide isostere analog of Largazole indicated improved pharmacokinetic parameters. In an A549 non-small cell lung carcinoma xenograft model using a dosage of 5 mg/kg administered intraperitoneally every other day, Largazole, Largazole thiol, and Largazole peptide isostere demonstrated tumor growth inhibition (TGI%) of 32, 44, and 66%, respectively. Largazole peptide isostere treatment was statistically superior to control (p = 0.002) and to Largazole (p = 0.006). Surprisingly, tumor growth inhibition was not observed with the potent pyridyl-based analogs. CONCLUSIONS:These results establish that replacing the depsipeptide linkage in Largazole with an amide may impart pharmacokinetic and therapeutic advantage and that alternative prodrug forms of Largazole are feasible.

| S-EPMC4368451 | biostudies-literature

Synthesis and Antimicrobial Activity of δ-Viniferin Analogues and Isosteres.

Project description:The natural stilbenoid dehydro-δ-viniferin, containing a benzofuran core, has been recently identified as a promising antimicrobial agent. To define the structural elements relevant to its activity, we modified the styryl moiety, appended at C5 of the benzofuran ring. In this paper, we report the construction of stilbenoid-derived 2,3-diaryl-5-substituted benzofurans, which allowed us to prepare a focused collection of dehydro-δ-viniferin analogues. The antimicrobial activity of the synthesized compounds was evaluated against S. aureus ATCC29213. The simplified analogue 5,5'-(2-(4-hydroxyphenyl)benzofuran-3,5-diyl)bis(benzene-1,3-diol), obtained in three steps from 4-bromo-2-iodophenol (63% overall yield), emerged as a promising candidate for further investigation (MIC = 4 µg/mL).

| S-EPMC8703454 | biostudies-literature

Synthesis and HDAC inhibitory activity of isosteric thiazoline-oxazole largazole analogs.

Project description:The synthesis of an isosteric analog of the natural product and HDAC inhibitor largazole is described. The sulfur atom in the thizaole ring of the natural product has been replaced with an oxygen atom, constituting an oxazole ring. The biochemical activity and cytotoxicity of this species is described.

| S-EPMC3859309 | biostudies-literature

Structure Property Relationships of Carboxylic Acid Isosteres.

Project description:The replacement of a carboxylic acid with a surrogate structure, or (bio)-isostere, is a classical strategy in medicinal chemistry. The general underlying principle is that by maintaining the features of the carboxylic acid critical for biological activity, but appropriately modifying the physicochemical properties, improved analogs may result. In this context, a systematic assessment of the physicochemical properties of carboxylic acid isosteres would be desirable to enable more informed decisions of potential replacements to be used for analog design. Herein we report the structure-property relationships (SPR) of 35 phenylpropionic acid derivatives, in which the carboxylic acid moiety is replaced with a series of known isosteres. The data set generated provides an assessment of the relative impact on the physicochemical properties that these replacements may have compared to the carboxylic acid analog. As such, this study presents a framework for how to rationally apply isosteric replacements of the carboxylic acid functional group.

| S-EPMC4833640 | biostudies-literature

Conformation-activity relationships of polyketide natural products.

Project description: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.

| S-EPMC4443481 | biostudies-literature

Identification, Synthesis, Conformation and Activity of an Insulin-like Peptide from a Sea Anemone.

Project description:The role of insulin and insulin-like peptides (ILPs) in vertebrate animals is well studied. Numerous ILPs are also found in invertebrates, although there is uncertainty as to the function and role of many of these peptides. We have identified transcripts with similarity to the insulin family in the tentacle transcriptomes of the sea anemone Oulactis sp. (Actiniaria: Actiniidae). The translated transcripts showed that these insulin-like peptides have highly conserved A- and B-chains among individuals of this species, as well as other Anthozoa. An Oulactis sp. ILP sequence (IlO1_i1) was synthesized using Fmoc solid-phase peptide synthesis of the individual chains, followed by regioselective disulfide bond formation of the intra-A and two interchain disulfide bonds. Bioactivity studies of IlO1_i1 were conducted on human insulin and insulin-like growth factor receptors, and on voltage-gated potassium, sodium, and calcium channels. IlO1_i1 did not bind to the insulin or insulin-like growth factor receptors, but showed weak activity against KV1.2, 1.3, 3.1, and 11.1 (hERG) channels, as well as NaV1.4 channels. Further functional studies are required to determine the role of this peptide in the sea anemone.

| S-EPMC8698791 | biostudies-literature

Potent CXCR4 antagonists containing amidine type Peptide bond isosteres.

Project description:A series of FC131 [cyclo(-d-Tyr-Arg-Arg-Nal-Gly-)] analogues containing amidine type peptide bond isosteres were synthesized as selective CXC chemokine receptor type 4 (CXCR4) antagonists. An isosteric amidine substructure was constructed by a macrocyclization process using nitrile oxide-mediated C-N bond formation. All of the amidine-containing FC131 analogues exhibited potent SDF-1 binding inhibition to CXCR4. The Nal-Gly-substituted analogue was characterized as one of the most potent cyclic pentapeptide-based CXCR4 antagonists reported to date. The improved activity against human immunodeficiency virus (HIV) type-1 X4 strains suggested that addition of another basic amidine group to the peptide backbone effectively increases the selective binding of the peptides to CXCR4 receptor.

| S-EPMC4018133 | biostudies-literature

1,2,4-Oxadiazole-Based Bio-Isosteres of Benzamides: Synthesis, Biological Activity and Toxicity to Zebrafish Embryo.

Project description:To discover new compounds with broad spectrum and high activity, we designed a series of novel benzamides containing 1,2,4-oxadiazole moiety by bioisosterism, and 28 benzamides derivatives with antifungal activity were synthesized. These compounds were evaluated against four fungi: Botrytis cinereal, FusaHum graminearum, Marssonina mali, and Thanatephorus cucumeris. The results indicated that most of the compounds displayed good fungicidal activities, especially against Botrytis cinereal. For example, 10a (84.4%), 10d (83.6%), 10e (83.3%), 10f (83.1%), 10i (83.3%), and 10l (83.6%) were better than pyraclostrobin (81.4%) at 100 mg/L. In addition, the acute toxicity of 10f to zebrafish embryo was 20.58 mg/L, which was classified as a low-toxicity compound.

| S-EPMC7956408 | biostudies-literature

Structure-activity relationships for ?-calcitonin gene-related peptide.

Project description:Calcitonin gene-related peptide (CGRP) is a member of the calcitonin (CT) family of peptides. It is a widely distributed neuropeptide implicated in conditions such as neurogenic inflammation. With other members of the CT family, it shares an N-terminal disulphide-bonded ring which is essential for biological activity, an area of potential ?-helix, and a C-terminal amide. CGRP binds to the calcitonin receptor-like receptor (CLR) in complex with receptor activity-modifying protein 1 (RAMP1), a member of the family B (or secretin-like) GPCRs. It can also activate other CLR or calcitonin-receptor/RAMP complexes. This 37 amino acid peptide comprises the N-terminal ring that is required for receptor activation (residues 1-7); an ?-helix (residues 8-18), a region incorporating a ?-bend (residues 19-26) and the C-terminal portion (residues 27-37), that is characterized by bends between residues 28-30 and 33-34. A few residues have been identified that seem to make major contributions to receptor binding and activation, with a larger number contributing either to minor interactions (which collectively may be significant), or to maintaining the conformation of the bound peptide. It is not clear if CGRP follows the pattern of other family B GPCRs in binding largely as an ?-helix.This article is part of a themed section on Neuropeptides. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2013.170.issue-7.

| S-EPMC3838678 | 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