Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Improved total synthesis of the potent HDAC inhibitor FK228 (FR-901228).

ABSTRACT: A scaleable synthesis of the potent histone deacetylase (HDAC) inhibitor FK228 is described. A reliable strategy for preparing the key beta-hydroxy mercapto heptenoic acid partner was accomplished in nine steps and 13% overall yield. A Noyori asymmetric hydrogen-transfer reaction established the hydroxyl stereochemistry in >99:1 er via the reduction of a propargylic ketone.

SUBMITTER: Greshock TJ

PROVIDER: S-EPMC3097137 | biostudies-literature | 2008 Feb

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Improved total synthesis of the potent HDAC inhibitor FK228 (FR-901228).

Greshock Thomas J TJ Johns Deidre M DM Noguchi Yasuo Y Williams Robert M RM

Organic letters 20080119 4

A scaleable synthesis of the potent histone deacetylase (HDAC) inhibitor FK228 is described. A reliable strategy for preparing the key beta-hydroxy mercapto heptenoic acid partner was accomplished in nine steps and 13% overall yield. A Noyori asymmetric hydrogen-transfer reaction established the hydroxyl stereochemistry in >99:1 er via the reduction of a propargylic ketone. ...[more]

PMID: 18205373

Similar Datasets

Enantioselective total synthesis of pladienolide B: a potent spliceosome inhibitor.

Project description:An enantioselective and convergent total synthesis of pladienolide B (1) is described. Pladienolide B binds to the SF3b complex of a spliceosome and inhibits mRNA splicing activity. The synthesis features an epoxide opening reaction, an asymmetric reduction of a ?-keto ester, and a cross metathesis strategy for the side chain synthesis.

| S-EPMC3482479 | biostudies-literature

Enantioselective total synthesis of (+)-largazole, a potent inhibitor of histone deacetylase.

Project description:An enantioselective total synthesis of the cytotoxic natural product (+)-largazole (1) is described. It is a potent histone deacetylase inhibitor. Our synthesis is convergent and involves the assembly of thiazole 3-derived carboxylic acid with amino ester 4 followed by cycloamidation of the corresponding amino acid. The synthesis features an efficient cross-metathesis, an enzymatic kinetic resolution of a beta-hydroxy ester, a selective removal of a Boc-protecting group, a HATU/HOAt-promoted cycloamidation reaction, and synthetic manipulations to a sensitive thioester functional group.

| S-EPMC2945909 | biostudies-literature

The HDAC inhibitor FK228 enhances adenoviral transgene expression by a transduction-independent mechanism but does not increase adenovirus replication.

Project description:The histone deacetylase inhibitor FK228 has previously been shown to enhance adenoviral transgene expression when cells are pre-incubated with the drug. Upregulation of the coxsackie adenovirus receptor (CAR), leading to increased viral transduction, has been proposed as the main mechanism. In the present study, we found that the highest increase in transgene expression was achieved when non-toxic concentrations of FK228 were added immediately after transduction, demonstrating that the main effect by which FK228 enhances transgene expression is transduction-independent. FK228 had positive effects both on Ad5 and Ad5/f35 vectors with a variety of transgenes and promoters, indicating that FK228 works mainly by increasing transgene expression at the transcriptional level. In some cases, the effects were dramatic, as demonstrated by an increase in CD40L expression by FK228 from 0.3% to 62% when the murine prostate cancer cell line TRAMP-C2 was transduced with Ad[CD40L]. One unexpected finding was that FK228 decreased the transgene expression of an adenoviral vector with the prostate cell-specific PPT promoter in the human prostate adenocarcinoma cell lines LNCaP and PC-346C. This is probably a consequence of alteration of the adenocarcinoma cell lines towards a neuroendocrine differentiation after FK228 treatment. The observations in this study indicate that FK228 enhances adenoviral therapy by a transduction-independent mechanism. Furthermore, since histone deacetylase inhibitors may affect the differentiation of cells, it is important to keep in mind that the activity and specificity of tissue- and tumor-specific promoters may also be affected.

| S-EPMC3040751 | biostudies-literature

Improved Synthesis of MDL 73811 - a Potent AdoMetDC Inhibitor and Anti-Trypanosomal Compound.

Project description:An improved synthesis of MDL 73811 - a potent AdoMetDC (S-adenosylmethionine decarboxylease) inhibitor and anti-trypanosomal compound with in vivo activity has been completed in four steps from commercially available 2',3'-O-isopropylideneadenosine. Utilization of Mitsunobu chemistry was crucial for the reliable and scalable introduction of the 5'-methylamine moiety, which was problematic using traditional activation/displacement chemistry as previously reported. All reactions in this synthesis were run on gram-scale resulting in a five-fold increase in yield over the original synthesis.

| S-EPMC4966539 | biostudies-other

Total synthesis of (+/-)-agelastatin A, a potent inhibitor of osteopontin-mediated neoplastic transformations.

Project description:A stereoselective synthesis of agelastatin A, a potent cytotoxin and inhibitor of osteopontin (OPN)-mediated neoplastic transformations, has been accomplished in 14 steps (12 operations) with an approximate overall yield of 8%. Notable features of this route include the direct manner in which the pyrroloketopiperazine A-ring of the target is generated and the efficient employment of a trichloroacetamide, introduced through Overman rearrangement, as a protecting group, pendant nucleophile, and latent urea.

| S-EPMC2671850 | biostudies-other

An improved high yield total synthesis and cytotoxicity study of the marine alkaloid neoamphimedine: an ATP-competitive inhibitor of topoisomerase IIα and potent anticancer agent.

Project description:Recently, we characterized neoamphimedine (neo) as an ATP-competitive inhibitor of the ATPase domain of human Topoisomerase IIα. Thus far, neo is the only pyridoacridine with this mechanism of action. One limiting factor in the development of neo as a therapeutic agent has been access to sufficient amounts of material for biological testing. Although there are two reported syntheses of neo, both require 12 steps with low overall yields (≤6%). In this article, we report an improved total synthesis of neo achieved in 10 steps with a 25% overall yield. In addition, we report an expanded cytotoxicity study using a panel of human cancer cell lines, including: breast, colorectal, lung, and leukemia. Neo displays potent cytotoxicity (nM IC50 values) in all, with significant potency against colorectal cancer (lowest IC50 = 6 nM). We show that neo is cytotoxic not cytostatic, and that neo exerts cytotoxicity by inducing G2-M cell cycle arrest and apoptosis.

| S-EPMC4178486 | biostudies-literature

Design and Synthesis of LM146, a Potent Inhibitor of PB1 with an Improved Selectivity Profile over SMARCA2.

Project description:PB1 is a bromodomain-containing protein hypothesized to act as the nucleosome-recognition subunit of the PBAF complex. Although PB1 is a key component of the PBAF chromatin remodeling complex, its exact role has not been elucidated due to the lack of potent and selective inhibitors. Chemical probes that target specific bromodomains within the complex would constitute highly valuable tools to characterize the function and therapeutic pertinence of PB1 and of each of its bromodomains. Here, we report the design and synthesis of lead compound LM146, which displays strong stabilization of the second and fifth bromodomains of PB1 as shown by DSF. LM146 does not interact with bromodomains outside of sub-family VIII and binds to PB1(2), PB1(5), and SMARCA2B with K D values of 110, 61, and 2100 nM, respectively, providing a ∼34-fold selectivity profile for PB1(5) over SMARCA2.

| S-EPMC8387997 | biostudies-literature

First total synthesis of (+)-Vedelianin, a potent antiproliferative agent.

Project description:The total synthesis of (+)-vedelianin has been accomplished in 18 steps from vanillin. Preparation of a key intermediate in nonracemic form through a Shi epoxidation has allowed determination of the absolute stereochemistry of the natural product as the (2S, 3R, 4aR, 9aR)-isomer.

| S-EPMC3204860 | biostudies-literature

Improved total synthesis and biological evaluation of potent apratoxin S4 based anticancer agents with differential stability and further enhanced activity.

Project description:Apratoxins are cytotoxic natural products originally isolated from marine cyanobacteria that act by preventing cotranslational translocation early in the secretory pathway to downregulate receptor levels and inhibit growth factor secretion, leading to potent antiproliferative activity. Through rational design and total synthesis of an apratoxin A/E hybrid, apratoxin S4 (1a), we have previously improved the antitumor activity and tolerability in vivo. Compound 1a and newly designed analogues apratoxins S7-S9 (1b-d), with various degrees of methylation at C34 (1b,c) or epimeric configuration at C30 (1d), were efficiently synthesized utilizing improved procedures. Optimizations have been applied to the synthesis of key intermediate aldehyde 7 and further include the application of Leighton's silanes and modifications of Kelly's methods to induce thiazoline ring formation in other crucial steps of the apratoxin synthesis. Apratoxin S9 (1d) exhibited increased activity with subnanomolar potency. Apratoxin S8 (1c) lacks the propensity to be deactivated by dehydration and showed efficacy in a human HCT116 xenograft mouse model.

| S-EPMC3993931 | biostudies-literature

Biochemical, biological and structural properties of romidepsin (FK228) and its analogs as novel HDAC/PI3K dual inhibitors.

Project description:Romidepsin (FK228, depsipeptide) is a potent histone deacetylase (HDAC) inhibitor that has FDA approval for the treatment of cutaneous and peripheral T-cell lymphomas. We have previously reported that FK228 and its analogs have an additional activity as phosphatidylinositol 3-kinase (PI3K) inhibitors, and are defined as HDAC/PI3K dual inhibitors. Because a combination of an HDAC inhibitor and a PI3K inhibitor induces apoptosis in human cancer cells in a synergistic manner, development of an HDAC/PI3K dual inhibitor will provide an attractive novel drug for cancer therapy. Using structure-based optimization of the analogs, FK-A11 was identified as the most potent analog. FK-A11 inhibited phosphorylation of AKT and accelerated histone acetylation at lower concentrations, resulting in stronger cytotoxic effects than FK228 and the other analogs in human cancer cells. In this study, we have characterized the biochemical, biological and structural properties of FK228 analogs as PI3K inhibitors. First, FK-A11 is an ATP competitive PI3K inhibitor. Second, FK-A11 is a pan-p110 isoform inhibitor. Third, FK-A11 selectively inhibits PI3K among 22 common cellular kinases. Fourth, conformational changes of FK228 analogs by reduction of an internal disulfide bond have no effect on PI3K inhibitory activity, unlike HDAC inhibitory activity. Finally, molecular modeling of PI3K-FK228 analogs and analyses of the binding affinities identified the structure that defines potency for PI3K inhibitory activity. These results prove our concept that a series of FK228 analogs are HDAC/PI3K dual inhibitors. These findings should help in the development of FK228 analogs as novel HDAC/PI3K dual inhibitors.

| S-EPMC4399029 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

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