A5006548835- Histone Deacetylase Inhibitors Research
- Protein Degradation and Inhibitors
- Protein Kinase Regulation and GTPase Signaling
- Synthetic Organic Chemistry Methods
- Enzyme Structure and Function
- Peptidase Inhibition and Analysis
- Cancer-related Molecular Pathways
- Carbohydrate Chemistry and Synthesis
- Synthesis and Biological Evaluation
- Chemical synthesis and alkaloids
- Cell death mechanisms and regulation
- Insect Resistance and Genetics
- Synthesis and Catalytic Reactions
- Cytomegalovirus and herpesvirus research
- Herpesvirus Infections and Treatments
- Organic Chemistry Cycloaddition Reactions
- Epigenetics and DNA Methylation
- PI3K/AKT/mTOR signaling in cancer
- Ubiquitin and proteasome pathways
- Biotin and Related Studies
- Click Chemistry and Applications
- Asymmetric Synthesis and Catalysis
- Cancer-related gene regulation
- Retinoids in leukemia and cellular processes
- Acute Myeloid Leukemia Research
La Roche College
2013
Novartis (United States)
2003-2004
Dana-Farber Cancer Institute
2003
Harvard University
2003
University of Oklahoma
2003
University of California, Santa Cruz
2003
University of Münster
2002
Duke University
1998
Philadelphia University
1992
Pennsylvania State University
1984-1986
Four novel bisulfide bromotyrosine derivatives, psammaplins E (9), F (10), G (11), and H (12), two new I (13) J (14), were isolated from the sponge Pseudoceratina purpurea, along with known A (4), B (6), C (7), D (8) bisaprasin (5). The structures of (9) which each contain an oxalyl group rarely found in marine organisms, determined by spectroscopic analysis. Compounds 4, 5, 10 are potent histone deacetylase inhibitors also show mild cytotoxicity. Furthermore, compounds 11 DNA...
We have synthesized a histone deacetylase inhibitor, NVP-LAQ824, cinnamic hydroxamic acid, that inhibited in vitro enzymatic activities and transcriptionally activated the p21 promoter reporter gene assays. NVP-LAQ824 selectively growth of cancer cell lines at submicromolar levels after 48-72 h exposure, whereas higher concentrations longer exposure times were required to retard normal dermal human fibroblasts. Flow cytometry studies revealed both tumor cells arrested G(2)-M phase cycle...
A series of N-hydroxy-3-phenyl-2-propenamides were prepared as novel inhibitors human histone deacetylase (HDAC). These compounds potent enzyme inhibitors, having IC(50)s < 400 nM in a partially purified assay. However, potency cell growth inhibition assays ranged over 2 orders magnitude two carcinoma lines. Selected cellular IC(50) 750 tested for maximum tolerated dose (MTD) and efficacy the HCT116 colon tumor xenograft Four an MTD > or = 100 mg/kg selected dose-response studies model. One...
Inhibitors of histone deacetylase (HDAC) have been shown to induce terminal differentiation human tumor cell lines and antitumor effects in vivo. We prepared analogues suberoylanilide hydroxamic acid (SAHA) trichostatin A evaluated them a HDAC enzyme inhibition assay, p21waf1 (p21) promoter monolayer growth assays. One compound, 4-(dimethylamino)-N-[7-(hydroxyamino)-7-oxoheptyl]-benzamide, was found affect the panel eight differentially.
Histone deacetylase (HDAC) inhibitors have shown promise in treating various forms of cancer. However, many HDAC from diverse structural classes been associated with QT prolongation humans. Inhibition the human ether a-go-go related gene (hERG) channel has and fatal arrhythmias. To determine if observed cardiac effects humans is due to hERG blockade, a highly potent inhibitor devoid activity was required. Starting dacinostat (LAQ824), inhibitor, we explored SAR pharmacophores required for...
We have previously shown that appropriate modification of the benzocycloheptapyridine tricyclic ring system can provide potent farnesyl protein transferase (FPT) inhibitors with good cellular activity. Our laboratories also established incorporation either pyridinylacetyl N-oxide or 4-N-carboxamidopiperidinylacetyl moieties results in pharmacokinetically stable are orally efficacious nude mice. now demonstrate further elaboration by introducing a bromine atom at 7- 10-position...
Crystallographic and thermodynamic studies of farnesyl protein transferase (FPT) complexed with novel tricyclic inhibitors provide insights into the observed SAR for this unique class nonpeptidic FPT inhibitors. The crystallographic structures reveal a binding pattern conserved across mono-, di-, trihalogen series. In complexes, tricycle spans active site cavity interacts both atoms isoprenoid portion bound diphosphate. An amide carbonyl, common to compounds described here, participates in...
ADVERTISEMENT RETURN TO ISSUEPREVArticleSynthesis of 5-epi-desosamine via a stereoselective intramolecular N-sulfinyl Diels-Alder cycloadditionStacy W. Remiszewski, Robert R. Whittle, and Steven M. WeinrebCite this: J. Org. Chem. 1984, 49, 17, 3243–3244Publication Date (Print):August 1, 1984Publication History Published online1 May 2002Published inissue 1 August 1984https://pubs.acs.org/doi/10.1021/jo00191a049https://doi.org/10.1021/jo00191a049research-articleACS PublicationsRequest reuse...
Most drugs used to treat viral disease target a virus-coded product. They inhibit single virus or family, and the pathogen can readily evolve resistance. Host-targeted antivirals overcome these limitations. The broad-spectrum activity achieved by host targeting be especially useful in combating emerging viruses for treatment of diseases caused multiple pathogens, such as opportunistic agents immunosuppressed patients. We have developed family compounds that modulate sirtuin 2, an...
ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTTotal synthesis of the latrunculinsAmos B. Smith III, James W. Leahy, Ichio Noda, Stacy Remiszewski, Nigel J. Liverton, and Regina ZibuckCite this: Am. Chem. Soc. 1992, 114, 8, 2995–3007Publication Date (Print):April 1, 1992Publication History Published online1 May 2002Published inissue 1 April 1992https://pubs.acs.org/doi/10.1021/ja00034a036https://doi.org/10.1021/ja00034a036research-articleACS PublicationsRequest reuse permissionsArticle...
The IAPs are key regulators of the apoptotic pathways and commonly overexpressed in many cancer cells. contain one to three BIR domains that crucial for their inhibitory function. pro-survival properties XIAP come from binding pro-apoptotic caspases. BIR3 domain binds inhibits caspase 9, while BIR2 terminal caspases 3 7. While inhibitors have previously been reported, they also inhibit cIAP1/2 promote release TNFα, potentially limiting therapeutic utility. This paper will focus on...
XIAP, a member of the inhibitor apoptosis family proteins, is critical regulator apoptosis. Inhibition BIR domain–caspase interaction promising approach towards treating cancer. Previous work has been directed inhibiting BIR3–caspase-9 interaction, which blocks intrinsic apoptotic pathway; selectively BIR2–caspase-3 would also block extrinsic pathway. The BIR2 domain XIAP successfully crystallized; peptides and small-molecule inhibitors can be soaked into these crystals, diffract to high...
XIAP is a key regulator of apoptosis, and its overexpression in cancer cells may contribute to their survival. The antiapoptotic function derives from BIR domains, which bind inhibit pro-apoptotic caspases. Most known IAP inhibitors are selective for the BIR3 domain cIAP1 cIAP2 as well XIAP. Pathways activated upon cIAP binding these compounds. Inhibitors should exert effects through competition with terminal This paper details our synthetic explorations novel BIR2-selective benzazepinone...
Mutated, tumorigenic Ras is present in a variety of human tumors. Compounds that inhibit function may be useful the treatment Ras-related The interaction novel GDP exchange inhibitor (SCH-54292) with Ras-GDP protein was studied by NMR spectroscopy. binding to enhanced at low Mg2+ concentrations, which enabled preparation stable complex for study. To understand and increased dissociation rates protein, conformational changes concentrations investigated using two-dimensional 1H-15N HSQC...
We have developed a cinnamic hydroxamic class of histone deacetylase inhibitors which prototype was designated as NVP-LAQ824. NVP-LAQ824, inhibits enzymatic activities in vitro and transcriptionally activated the p21 promoter reporter gene assays. When tested on variety solid tumour cell lines, NVP-LAQ824 exhibited selective anti-proliferative effects, inducing growth inhibition some, while death others. To induce death, minimum 16 h exposure to is required. Flow cytometry studies revealed...