13652 Cantara St
Panorama City CA 91402
Medical School: New York University School Of Medicine - 2000
Accepts Medicare: Yes
Participates In eRX: No
Participates In PQRS: No
Participates In EHR: No
License #: A89729
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Design, Synthesis and Antitumor Evaluation of Novel Histone Deacetylase (HDAC) Inhibitors Equipped with Phenylsulfonylfuroxan Module as Nitric Oxide (NO) Donor. - Journal of medicinal chemistry
Based on the strategy of "multifunctional drugs," a novel series of phenylsulfonylfuroxan-based hydroxamates with histone deacetylase (HDAC) inhibitory and nitric oxide (NO) donating activities were designed, synthesized, and evaluated. The most potent NO donor-HDAC inhibitor (HDACI) hybrid 5c exhibited much more potent in vitro antiproliferative activity against human erythroleukemia (HEL) cell line than the approved drug SAHA (Vorinostat), and its antiproliferative activity was diminished by the NO scavenger hemoglobin in a dose-dependent manner. Further mechanism studies revealed that 5c strongly induced cellular apoptosis and G1 phase arrest in HEL cells. Animal experiment identified 5c as an orally active agent with potent antitumor activity in a HEL cell xenograft model. Interestingly, although compound 5c was remarkably HDAC6 selective in the molecular level, it exhibited pan-HDAC inhibition in the western blot assay likely due to NO release causing class I HDACs inhibition in the cellular level.
Silver-Catalyzed Direct Thiolation of Quinones by Activation of Aryl Disulfides to Synthesize Quinonyl Aryl Thioethers. - The Journal of organic chemistry
A silver-catalyzed coupling reaction of quinones with aryl disulfides for the synthesis of quinonyl aryl thioethers is described. In the presence of AgOAc (0.2 equiv)/dppp (0.24 equiv) as the catalyst, (NH4)2S2O8 (3.0 equiv) as the oxidant, and Bu4NBF4 (1.0 equiv) as the additive, the reaction is simple, provides high yield (up to 88% yield), and possesses a broad substrate scope. The reaction is believed to proceed via direct activation of disulfides evidenced by observation of a metathesis reaction between two different disulfides placed together under the reaction conditions and (13)C NMR spectroscopy analysis.
Mechanism of Action of 2-Aminobenzamide HDAC Inhibitors in Reversing Gene Silencing in Friedreich's Ataxia. - Frontiers in neurology
The genetic defect in Friedreich's ataxia (FRDA) is the hyperexpansion of a GAAâ€¢TTC triplet in the first intron of the FXN gene, encoding the essential mitochondrial protein frataxin. Histone post-translational modifications near the expanded repeats are consistent with heterochromatin formation and consequent FXN gene silencing. Using a newly developed human neuronal cell model, derived from patient-induced pluripotent stem cells, we find that 2-aminobenzamide histone deacetylase (HDAC) inhibitors increase FXN mRNA levels and frataxin protein in FRDA neuronal cells. However, only compounds targeting the class I HDACs 1 and 3 are active in increasing FXN mRNA in these cells. Structural analogs of the active HDAC inhibitors that selectively target either HDAC1 or HDAC3 do not show similar increases in FXN mRNA levels. To understand the mechanism of action of these compounds, we probed the kinetic properties of the active and inactive inhibitors, and found that only compounds that target HDACs 1 and 3 exhibited a slow-on/slow-off mechanism of action for the HDAC enzymes. HDAC1- and HDAC3-selective compounds did not show this activity. Using siRNA methods in the FRDA neuronal cells, we show increases in FXN mRNA upon silencing of either HDACs 1 or 3, suggesting the possibility that inhibition of each of these class I HDACs is necessary for activation of FXN mRNA synthesis, as there appears to be redundancy in the silencing mechanism caused by the GAAâ€¢TTC repeats. Moreover, inhibitors must have a long residence time on their target enzymes for this activity. By interrogating microarray data from neuronal cells treated with inhibitors of different specificity, we selected two genes encoding histone macroH2A (H2AFY2) and Polycomb group ring finger 2 (PCGF2) that were specifically down-regulated by the inhibitors targeting HDACs1 and 3 versus the more selective inhibitors for further investigation. Both genes are involved in transcriptional repression and we speculate their involvement in FXN gene silencing. Our results shed light on the mechanism whereby HDAC inhibitors increase FXN mRNA levels in FRDA neuronal cells.
Inhibition of Class I Histone Deacetylase Activity Represses Matrix Metalloproteinase-2 and -9 Expression and Preserves LV Function Post Myocardial Infarction. - American journal of physiology. Heart and circulatory physiology
Left ventricular (LV) remodeling, following myocardial infarction (MI), can result in LV dilation and LV pump dysfunction. Post-MI induction of matrix metalloproteinases (MMPs), particularly MMP-2 and MMP-9, have been implicated as causing deleterious effects on LV and extracellular matrix (ECM) remodeling in the MI region and within the initially unaffected remote zone. Histone deacetylases (HDACs) are a class of enzymes that affect the transcriptional regulation of genes during pathological conditions. We assessed the efficacy of both class I/IIb and class I selective HDAC inhibitors on MMP-2 and MMP-9 abundance, determined if treatment results in the attenuation of adverse LV and ECM remodeling, and improved LV pump function post-MI. MI was surgically induced in MMP-9 promoter reporter mice and randomized for treatment with a class I/IIb-HDAC inhibitor for 7 days post-MI. After MI, LV dilation, LV pump dysfunction, and activation of the MMP-9 gene promoter were significantly attenuated in mice treated with either the class I/IIb-HDAC inhibitor, Trichostatin A (TSA), or Voronistat (suberanilohydroxamic acid; SAHA) compared to MI only mice. Immunohistological staining and zymographic levels of MMP-2 and MMP-9 were reduced with either TSA or SAHA treatment. Class I HDAC activity is dramatically increased post-MI. Treatment with the selective class I HDAC inhibitor, PD-106 reduced post-MI levels of both MMP-2 and MMP-9 and attenuated LV dilation and LV pump dysfunction post-MI similar to class I/IIb-HDAC inhibition. Taken together, these unique findings demonstrate that selective inhibition of class I HDACs may provide a novel therapeutic means to attenuate adverse LV remodeling post-MI.Copyright Â© 2014, American Journal of Physiology - Heart and Circulatory Physiology.
Genotype-specific differences in structural features of hepatitis C virus (HCV) p7 membrane protein. - Biochimica et biophysica acta
The 63 amino acid polytopic membrane protein, p7, encoded by hepatitis C virus (HCV) is involved in the modulation of electrochemical gradients across membranes within infected cells. Structural information relating to p7 from multiple genotypes has been generated in silico (e.g. genotype (GT) 1a), as well as obtained from experiments in form of monomeric and hexameric structures (GTs 1b and 5a, respectively). However, sequence diversity and structural differences mean that comparison of their channel gating behaviour has not thus far been simulated. Here, a molecular model of the monomeric GT 1a protein is optimized and assembled into a hexameric bundle for comparison with both the 5a hexamer structure and another hexameric bundle generated using the GT 1b monomer structure. All bundles tend to turn into a compact structure during molecular dynamics (MD) simulations (Gromos96 (ffG45a3)) in hydrated lipid bilayers, as well as when simulated at 'low pH', which may trigger channel opening according to some functional studies. Both GT 1a and 1b channel models are gated via movement of the parallel aligned helices, yet the scenario for the GT 5a protein is more complex, with a short N-terminal helix being involved. However, all bundles display pulsatile dynamics identified by monitoring water dynamics within the pore.Copyright Â© 2015 Elsevier B.V. All rights reserved.
Transverse relaxation dispersion of the p7 membrane channel from hepatitis C virus reveals conformational breathing. - Journal of biomolecular NMR
The p7 membrane protein encoded by hepatitis C virus (HCV) assembles into a homo-hexamer that selectively conducts cations. An earlier solution NMR structure of the hexameric complex revealed a funnel-like architecture and suggests that a ring of conserved asparagines near the narrow end of the funnel are important for cation interaction. NMR based drug-binding experiments also suggest that rimantadine can allosterically inhibit ion conduction via a molecular wedge mechanism. These results suggest the presence of dilation and contraction of the funnel tip that are important for channel activity and that the action of the drug is attenuating this motion. Here, we determined the conformational dynamics and solvent accessibility of the p7 channel. The proton exchange measurements show that the cavity-lining residues are largely water accessible, consistent with the overall funnel shape of the channel. Our relaxation dispersion data show that residues Val7 and Leu8 near the asparagine ring are subject to large chemical exchange, suggesting significant intrinsic channel breathing at the tip of the funnel. Moreover, the hinge regions connecting the narrow and wide regions of the funnel show strong relaxation dispersion and these regions are the binding sites for rimantadine. Presence of rimantadine decreases the conformational dynamics near the asparagine ring and the hinge area. Our data provide direct observation of Î¼s-ms dynamics of the p7 channel and support the molecular wedge mechanism of rimantadine inhibition of the HCV p7 channel.
Mapping conformational heterogeneity of mitochondrial nucleotide transporter in uninhibited states. - Angewandte Chemie (International ed. in English)
One of the less well understood aspects of membrane transporters is the dynamic coupling between conformational change and substrate transport. NMR approaches are used herein to investigate conformational heterogeneity of the GTP/GDP carrier (GGC) from yeast mitochondria. NMR residual dipolar coupling (RDC) analysis of GGC in a DNA-origami nanotube liquid crystal shows that several structured segments have different generalized degrees of order (GDO), thus indicating the presence of conformational heterogeneity. Complete GDO mapping reveals asymmetry between domains of the transporter and even within certain transmembrane helices. Nucleotide binding partially reduces local structural heterogeneity, and the substrate binds to multiple sites along the transport cavity. These observations suggest that mitochondrial carriers in the uninhibited states are intrinsically plastic and structural plasticity is asymmetrically distributed among the three homologous domains.Â© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
Acetylation preserves retinal ganglion cell structure and function in a chronic model of ocular hypertension. - Investigative ophthalmology & visual science
The current studies investigate if the histone deacetylase (HDAC) inhibitor, valproic acid (VPA), can limit retinal ganglion cell (RGC) degeneration in an ocular-hypertensive rat model.Intraocular pressure (IOP) was elevated unilaterally in Brown Norway rats by hypertonic saline injection. Rats received either vehicle or VPA (100 mg/kg) treatment for 28 days. Retinal ganglion cell function and number were assessed by pattern electroretinogram (pERG) and retrograde FluoroGold labeling. Western blotting and a fluorescence assay were used for determination of histone H3 acetylation and HDAC activity, respectively, at 3-day, 1-week, and 2-week time points.Hypertonic saline injections increased IOPs by 7 to 14 mm Hg. In vehicle-treated animals, ocular hypertension resulted in a 29.1% and 39.4% decrease in pERG amplitudes at 2 and 4 weeks, respectively, and a 42.9% decrease in mean RGC density at 4 weeks. In comparison, VPA treatment yielded significant amplitude preservation at 2 and 4 weeks and showed significant RGC density preservation at 4 weeks. No significant difference in RGC densities or IOPs was measured between control eyes of vehicle- and VPA-treated rats. In ocular-hypertensive eyes, class I HDAC activity was significantly elevated within 1 week (13.3 Â± 2.2%) and histone H3 acetylation was significantly reduced within 2 weeks following the induction of ocular hypertension.Increase in HDAC activity is a relatively early retinal event induced by elevated IOP, and suppressing HDAC activity can protect RGCs from ocular-hypertensive stress. Together these data provide a basis for developing HDAC inhibitors for the treatment of optic neuropathies.Copyright 2014 The Association for Research in Vision and Ophthalmology, Inc.
Proton association constants of His 37 in the Influenza-A M218-60 dimer-of-dimers. - Biochemistry
The membrane protein M2 from influenza-A forms a single-pass transmembrane helix that assembles in lipid membrane as homotetramers whose primary function is to act as a proton transporter for viral acidification. A single residue, histidine 37 (His 37), is known to be responsible for selectivity and plays an integral role in the protein's function. We report pH-dependent (15)N MAS NMR spectra of His 37 within the influenza-A proton conduction domain of M2, M218-60, which has been previously shown to be a fully functional construct and was recently determined to adopt a dimer-of-dimers structure in lipids. By extracting the ratio of [His]/[HisH(+)] as a function of pH, we obtained two doubly degenerate proton disassociation constants, 7.63 Â± 0.15 and 4.52 Â± 0.15, despite a possible maximum of four. We also report the (1)HNÎµ chemical shifts at pH 6.5 recorded at 60 kHz MAS in a CP-based (1)H-(15)N spectrum. We were unable to detect resonances indicative of direct proton sharing among His 37 side chains when the tetramer is in the +2 state. In the neutral state, His 37 is exclusively in the Ï„ tautomer, indicating that the Î´ nitrogen is protonated solely as a function of pH. We also found that the plot of [HisH(+)]/[His] as a function of pH is qualitatively similar to previously reported proton conduction rates, indicating that proton conduction rate is proportional to the level of histidine protonation within the channel. Two-dimensional (13)C-(13)C and (13)C-(15)N correlations suggest that at low pH multiple conformations are populated as the spectra broaden and eventually disappear as the acidity is increased. A second highly resolved state at low pH was not observed.
Fatty acid flippase activity of UCP2 is essential for its proton transport in mitochondria. - Cell metabolism
Modulation of cellular energy expenditure is fundamental to normal and pathological cell growth and differentiation. Mitochondria stores energy as a proton gradient across their inner membrane. Uncoupling proteins (UCPs) can dissipate the gradient to produce heat or regulate metabolite fluxes. UCP-mediated proton currents require fatty acids (FAs) and are blocked by nucleotides, but the molecular basis of these processes is unknown. We find, by nuclear magnetic resonance and functional mutagenesis, that UCP2 can bind FAs laterally through its peripheral site, and this intramembrane molecular recognition is essential for UCP2-catalyzed FA flipping across the membrane, which in turn is essential for proton translocation. The antagonist GDP binds inside the UCP2 cavity and perturbs its conformation, which can displace FA from the peripheral site as a mean of inhibiting proton currents. Our data provide a biophysical perspective of the intricate interplay ofÂ UCPs, FA, and nucleotides in determining proton fluxes in mitochondria.Copyright Â© 2014 Elsevier Inc. All rights reserved.
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