Publications by authors named "Amruta R Poreddy"

7 Publications

  • Page 1 of 1

Roles of free radicals in type 1 phototherapeutic agents: aromatic amines, sulfenamides, and sulfenates.

J Phys Chem A 2013 Jul 24;117(26):5454-62. Epub 2013 Jun 24.

Department of Chemistry, Washington University , St. Louis, Missouri 63130, United States.

Detailed analyses of the electron spin resonance (ESR) spectra, cell viability, and DNA degradation studies are presented for the photolyzed Type I phototherapeutic agents: aromatic amines, sulfenamides, and sulfenates. The ESR studies provided evidence that copious free radicals can be generated from these N-H, N-S, and S-O containing compounds upon photoirradiation with UV/visible light. The analyses of spectral data allowed us to identify the free radical species. The cell viability studies showed that these agents after exposure to light exert cytotoxicity to kill cancer cells (U937 leukemia cell lines HTC11, KB, and HT29 cell lines) in a dosage- and time-dependent manner. We examined a possible pathway of cell death via DNA degradation by a plasmid cleavage assay for several compounds. The effects of photosensitization with benzophenone in the presence of oxygen were examined. The studies indicate that planar tricyclic amines and sulfenamides tend to form π-electron delocalized aminyl radicals, whereas nonplanar ones tend to yield nitroxide radicals resulting from the recombination of aminyl radicals with oxygen. The ESR studies coupled with the results of cell viability measurements and DNA degradation reveal that planar N-centered radicals can provide higher potency in cell death and allow us to provide some insights on the reaction mechanisms. We also found the formation of azatropylium cations possessing high aromaticity derived from azepines can facilitate secondary electron transfer to form toxic O2(•-) radicals, which can further exert oxidative stress and cause cell death.
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http://dx.doi.org/10.1021/jp402745mDOI Listing
July 2013

Type 1 Phototherapeutic Agents. 2. Cancer Cell Viability and ESR Studies of Tricyclic Diarylamines.

ACS Med Chem Lett 2012 Apr 16;3(4):284-8. Epub 2012 Feb 16.

Covidien Pharmaceuticals , 675 McDonnell Boulevard, Hazelwood, Missouri 63042, United States.

Type 1 phototherapeutic agents based on diarylamines were assessed for free radical generation and evaluated in vitro for cell death efficacy in the U937 leukemia cancer cell line. All of the compounds were found to produce copious free radicals upon photoexcitation with UV-A and/or UV-B light, as determined by electron spin resonance (ESR) spectroscopy. Among the diarylamines, the most potent compounds were acridan (4) and 9-phenylacridan (5), with IC50 values of 0.68 μM and 0.17 μM, respectively.
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http://dx.doi.org/10.1021/ml200266vDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4025672PMC
April 2012

Exogenous fluorescent tracer agents based on pegylated pyrazine dyes for real-time point-of-care measurement of glomerular filtration rate.

Bioorg Med Chem 2012 Apr 10;20(8):2490-7. Epub 2012 Mar 10.

Covidien Pharmaceuticals, 675 McDonnell Boulevard, Hazelwood, MO 63042, USA.

Novel pyrazine carboxamides bearing hydrophilic poly(ethylene glycol) (PEG) moieties were designed, synthesized, and evaluated for use as fluorescent glomerular filtration rate (GFR) tracer agents. Among these, compounds 4d and 5c that contain about 48 ethylene oxide units in the PEG chain exhibited the most favorable physicochemical and renal clearance properties. In vitro studies show that these two compounds have low plasma protein binding, a necessary condition for renal excretion. In vivo animal model results show that 4d and 5c have a higher urine recovery of the injected dose than iothalamate (a commonly considered gold standard GFR agent). Pharmacokinetic studies show that these two compounds exhibit a plasma clearance equivalent to iothalamate, but with a faster (i.e. lower) terminal half-life than iothalamate (possibly from restricted distribution into the extracellular space due to large molecular size and hydrodynamic volume). Furthermore, the plasma clearance of 4d and 5c remained unchanged upon blockage of the tubular secretion pathway with probenecid, a necessary condition for establishment of clearance via glomerular filtration exclusively. Finally, noninvasive real-time monitoring of this class of compounds was demonstrated by pharmacokinetic clearance of 5c by optical measurements in rat model, which correlates strongly with plasma concentration of the tracer. Hence, 4d and 5c are promising candidates for translation to the clinic as exogenous fluorescent tracer agents in real-time point-of-care monitoring of GFR.
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http://dx.doi.org/10.1016/j.bmc.2012.03.015DOI Listing
April 2012

Type 1 phototherapeutic agents, part I: preparation and cancer cell viability studies of novel photolabile sulfenamides.

ACS Med Chem Lett 2011 Nov 13;2(11):828-33. Epub 2011 Sep 13.

Covidien Pharmaceuticals , 675 McDonnell Boulevard, Hazelwood, Missouri 63042, United States.

Novel type 1 phototherapeutic agents based on compounds containing S-N bonds (sulfenamides) were synthesized, assessed for free radical generation, and evaluated in vitro for cell death efficacy in four cancer cell lines (U937, HTC11, KB, and HT29). All of the compounds were found to produce copious free radicals upon photoexcitation with UV-A and/or UV-B light, as determined by electron spin resonance spectroscopy. Among the sulfenamides, the most potent compounds were derived from dibenzazepine 7b and dihydroacridine 8b as determined in all of the four cancer cell lines.
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http://dx.doi.org/10.1021/ml2001483DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4018100PMC
November 2011

Hydrophilic pyrazine dyes as exogenous fluorescent tracer agents for real-time point-of-care measurement of glomerular filtration rate.

J Med Chem 2011 Jul 27;54(14):5048-58. Epub 2011 Jun 27.

Covidien Pharmaceuticals, 675 McDonnell Boulevard, Hazelwood, Missouri 63042, USA.

Various hydrophilic pyrazine-bis(carboxamides) derived from 3,5-diamino-pyrazine-2,5-dicarboxylic acid bearing neutral and anionic groups were prepared and evaluated for use as fluorescent glomerular filtration rate (GFR) tracer agents. Among these, the dianionic d-serine pyrazine derivatives 2d and 2j, and the neutral dihydroxypropyl 2h, exhibited favorable physicochemical and clearance properties. In vitro studies show that 2d, 2h, and 2j have low plasma protein binding, a necessary condition for renal excretion. In vivo animal model results show that these three compounds exhibit a plasma clearance equivalent to iothalamate (a commonly considered gold standard GFR agent). In addition, these compounds have a higher urine recovery compared to iothalamate. Finally, the plasma clearance of 2d, 2h, and 2j remained unchanged upon blockage of the tubular secretion pathway with probenecid, a necessary condition for establishment of clearance via glomerular filtration only. Hence, 2d, 2h, and 2j are promising candidates for translation to the clinic as exogenous fluorescent tracer agents in real-time point-of-care monitoring of GFR.
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http://dx.doi.org/10.1021/jm200257kDOI Listing
July 2011

Hydroxamate-based iron chelators: combinatorial syntheses of desferrioxamine B analogues and evaluation of binding affinities.

J Comb Chem 2004 Mar-Apr;6(2):239-54

MetaPhore Pharmaceuticals, Inc., 1910 Innerbelt Business Center Drive, Saint Louis, MO 63114, USA.

This article describes the solid-phase combinatorial methods developed for the synthesis of polyhydroxamate-based siderophores. This strategy was applied to generate several libraries of structural DFO (1a) analogues that include DFO variants, non-amide analogues, C-terminal modified analogues, reverse-amide analogues, and hybrid analogues. To assess the relative iron-binding affinities of these compounds, a high-throughput spectrophotometric screening method based on competition with 8-hydroxyquinoline-5-sulfonic acid was developed. Some of the promising candidates containing various terminal functional groups were identified and prepared on large scale to enable future studies in animal models for iron-overload diseases.
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http://dx.doi.org/10.1021/cc030039aDOI Listing
May 2004

Solid-phase synthesis of methyl carboxymycobactin T 7 and analogues as potential antimycobacterial agents.

Bioorg Med Chem Lett 2003 Aug;13(15):2553-6

MetaPhore Pharmaceuticals, Inc., 1910 Innerbelt Business Center Drive, Saint Louis, MO 63114, USA.

A solid-phase approach for the total synthesis of methyl carboxymycobactins 1a-d, with an on-resin cyclization leading to azopine 5 as the key step, was developed. The iron-affinity of these compounds was assessed by a competitive sulfoxine-binding assay, and antimycobacterial activity was tested against the growth of Mycobacterium avium.
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http://dx.doi.org/10.1016/s0960-894x(03)00473-6DOI Listing
August 2003