Structure-based drug design combined with homology modeling techniques were used to develop potent inhibitors of HDAC6 that display superior selectivity for the isozyme compared other inhibitors. These can be assembled in a few synthetic steps, and thus are readily scaled up vivo studies. An optimized compound from this series, designated Tubastatin A, was tested primary cortical neuron cultures which it found induce elevated levels acetylated alpha-tubulin, but not histone, consistent its...

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTThe isoxazoline route to the molecules of natureAlan P. KozikowskiCite this: Acc. Chem. Res. 1984, 17, 12, 410–416Publication Date (Print):December 1, 1984Publication History Published online1 May 2002Published inissue 1 December 1984https://pubs.acs.org/doi/10.1021/ar00108a001https://doi.org/10.1021/ar00108a001research-articleACS PublicationsRequest reuse permissionsArticle Views1788Altmetric-Citations473LEARN ABOUT THESE METRICSArticle Views are...

Central nervous system (CNS) trauma can result in tissue disruption, neuronal and axonal degeneration, neurological dysfunction. The limited spontaneous CNS repair adulthood aging is often insufficient to overcome disability. Several investigations have demonstrated that targeting HDAC activity protect neurons glia improve outcomes injury disease models. However, the enthusiasm for pan-HDAC inhibition treating conditions tempered by their toxicity toward a host of cell types -a biological...

Tuberculosis (TB) remains as a global pandemic that is aggravated by lack of health care, the spread HIV, and emergence multidrug-resistant TB (MDR-TB) extensively drug-resistant (XDR-TB) strains. New anti-TB drugs are urgently required to shorten long 6−12 month treatment regimen battle Mtb We have identified several potent quinoline-based compounds, bearing an isoxazole containing side-chain. The most 7g 13, exhibited submicromolar activity against replicating bacteria (R-TB), with minimum...

Prostate specific membrane antigen (PSMA) is a validated molecular marker for prostate cancer. A series of glutamate−urea (Glu-urea-X) heterodimeric inhibitors PSMA were designed and synthesized where X = ε-N-(o-I, m-I, p-I, p-Br, o-Cl, m-Cl, p-Cl, p-F, H)-benzyl-Lys ε-(p-I, H)-phenylureido-Lys. The affinities determined by screening in competitive binding assay. the benzyllysine was significantly affected nature halogen substituent (IC50 values, Cl < I Br ≪ F H) ring position atom p-I o-I...

Prostate-specific membrane antigen (PSMA) is a type II integral protein expressed on the surface of prostate cancer (PCa) cells, particularly in androgen-independent, advanced, and metastatic disease. Previously, we demonstrated that <i>N</i>-[<i>N</i>-[(<i>S</i>)-1,3-dicarboxypropyl]carbamoyl]-4-¹⁸F-fluorobenzyl-l-cysteine (¹⁸F-DCFBC) could image an experimental model PSMA-positive PCa using PET. Here, describe initial clinical experience radiation dosimetry...

AbstractFoxp3+ T-regulatory cells (Tregs) are key to immune homeostasis such that their diminished numbers or function can cause autoimmunity and allograft rejection. Foxp3+ Tregs express multiple histone/protein deacetylases (HDACs) regulate chromatin remodeling, gene expression, protein function. Pan-HDAC inhibitors developed for oncologic applications enhance Treg production suppression but have limited nononcologic utility given broad actions various side effects. We show, using...

Hydroxamate-based histone deacetylase inhibitors (HDACIs) have been approved as therapeutic agents by the US Food and Drug Administration for use in oncology applications. While potential utility of such HDACIs other areas medicinal chemistry is tremendous, there are significant concerns that "pan-HDAC inhibitors" may be too broadly acting and/or toxic clinical beyond oncology. In addition to isozyme selectivity challenge, mutagenicity hydroxamate-containing HDAC represents a major hindrance...

Macroautophagy is an evolutionarily conserved cellular process involved in the clearance of proteins and organelles. Although cytoplasmic machinery that orchestrates autophagy induction during starvation, hypoxia, or receptor stimulation has been widely studied, key epigenetic events initiate maintain remain unknown. Here we show methyltransferase G9a coordinates transcriptional activation regulators autophagosome formation by remodeling chromatin landscape. Pharmacological inhibition RNA...

Alzheimer's disease (AD) characteristically presents with early memory loss. Regulation of K + channels, calcium homeostasis, and protein kinase C (PKC) activation are molecular events that have been implicated during associative which also altered or defective in AD. PKC is involved the processing amyloid precursor (APP), a central element AD pathophysiology. In previous studies, we demonstrated benzolactam (BL), novel activator, reversed channels defects enhanced secretion APPα cells. this...

Abstract Purpose: Prostate-specific membrane antigen (PSMA) is a cell surface protein that overexpressed in prostate cancer, including hormone-refractory and metastatic disease. Our goal this study was to develop series of PSMA-based imaging agents for clinical use. Experimental Design: We have synthesized evaluated the vivo biodistribution two radiolabeled urea derivatives high affinity PSMA severe combined immunodeficient mice harboring MCF-7 (breast, PSMA-negative), PC-3 (prostate, LNCaP...

ADVERTISEMENT RETURN TO ISSUEPREVLetterNEXTDesign of Remarkably Simple, Yet Potent Urea-Based Inhibitors Glutamate Carboxypeptidase II (NAALADase)Alan P. Kozikowski, Fajun Nan, Paola Conti, Jiazhong Zhang, Epolia Ramadan, Tomasz Bzdega, Barbara Wroblewska, Joseph H. Neale, Sergey Pshenichkin, and Jarda T. WroblewskiView Author Information Drug Discovery Program, Department Neurology, Pharmacology, Georgetown University Medical Center, 3900 Reservoir Road, N.W., Washington, D.C. 20007,...

Abstract The neuropathology of Alzheimer's disease (AD) and other tauopathies is characterized by filamentous deposits the microtubule‐associated protein tau, but relationship between tau polymerization neurotoxicity unknown. Here, we examined effects on fast axonal transport (FAT) using isolated squid axoplasm. Monomeric forms recombinant human were perfused in axoplasm, their kinesin‐ dynein‐dependent FAT rates evaluated video microscopy. Although perfusion monomeric at physiological...

The prostate-specific membrane antigen (PSMA) is increasingly recognized as a viable target for imaging and therapy of cancer. We prepared seven 99mTc/Re-labeled compounds by attaching known Tc/Re chelating agents to an amino-functionalized PSMA inhibitor (lys-NHCONH-glu) with or without variable length linker moiety. Ki values ranged from 0.17 199 nM. Ex vivo biodistribution in demonstrated the degree specific binding engineered PSMA+ PC3 PIP tumors. PC3-PIP cells are derived that have been...

Abstract Purpose: Previously, we showed successful imaging of xenografts that express the prostate-specific membrane antigen (PSMA) using small-animal positron emission tomography (PET) and radiolabeled PSMA inhibitor N-[N-[(S)-1,3-dicarboxypropyl]carbamoyl]-S-[11C]methyl-l-cysteine. Herein, extend work by preparing testing a same class labeled with fluorine-18. Experimental Design: N-[N-[(S)-1,3-Dicarboxypropyl]carbamoyl]-4-[18F]fluorobenzyl-l-cysteine ([18F]DCFBC) was prepared reacting...

The neuropeptidase glutamate carboxypeptidase II (GCPII) hydrolyzes N-acetyl-l-aspartyl-l-glutamate (NAAG) to liberate N-acetylaspartate and glutamate. GCPII was originally cloned as PSMA, an Mr 100 000 type transmembrane glycoprotein highly expressed in prostate tissues. PSMA/GCPII is located on the short arm of chromosome 11 functions both a folate hydrolase neuropeptidase. Inhibition brain may have therapeutic potential treatment certain disease states arising from pathologically...

The synthesis from l-quebrachitol of a series 3-deoxygenated ether lipid-type phosphatidylinositol (PI) analogues is reported, that selectively block activation Akt and downstream substrates without affecting the upstream kinase, PDK-1, or other kinases ras such as MAPK in H157 H1703 lung cancer cells have high levels constitutively active Akt. 2-hydroxyl these compounds was deleted alkylated with intent to preclude metabolic degradation by PI-specific phospholipase C (PI-PLC). PI phosphate...

Phosphatidylinositol 3-kinase (PI3-K) phosphorylates the 3-position of phosphatidylinositol to give rise three signaling phospholipids. Binding pleckstrin homolgy (PH) domain Akt membrane PI(3)P's causes translocation plasma bringing it into contact with membrane-bound kinase (PDK1 and 2), which activates Akt. inhibits apoptosis by phosphorylating Bad, thus promoting its binding blockade activity cell survival factor Bcl-x. Herein we present synthesis biological several novel analogues...

The incidence of malignant melanoma has dramatically increased in recent years thus requiring the need for improved therapeutic strategies. In our efforts to design selective histone deactylase inhibitors (HDACI), we discovered that aryl urea 1 is a modestly potent yet nonselective inhibitor. Structure-activity relationship studies revealed adding substituents nitrogen atom so as generate compounds bearing branched linker group results potency and selectivity HDAC6. Compound 5 g shows low...

A series of hydroxamate based HDAC inhibitors containing a phenylisoxazole as the CAP group has been synthesized using nitrile oxide cycloaddition chemistry. An HDAC6 selective inhibitor having potency ∼2 picomolar was identified. Some compounds were examined for their ability to block pancreatic cancer cell growth and found be about 10-fold more potent than SAHA. This research provides valuable, new molecular probes use in exploring biology.

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTMethods for the stereoselective cis-cyanohydroxylation and -carboxyhydroxylation of olefinsAlan P. Kozikowski Maciej AdamczCite this: J. Org. Chem. 1983, 48, 3, 366–372Publication Date (Print):February 1, 1983Publication History Published online1 May 2002Published inissue 1 February 1983https://pubs.acs.org/doi/10.1021/jo00151a017https://doi.org/10.1021/jo00151a017research-articleACS PublicationsRequest reuse permissionsArticle...

Urea-based, low molecular weight ligands of glutamate carboxypeptidase II (GCPII) have demonstrated efficacy in various models neurological disorders and can serve as imaging agents for prostate cancer. To enhance further development such compounds, we determined X-ray structures four complexes between human GCPII urea-based inhibitors at high resolution. All demonstrate an invariant glutarate moiety within the S1′ pocket enzyme. The ureido linkage P1 P1′ inhibitor sites interacts with...