• Home
  • Goutam Chowdhury
Goutam Chowdhury

Goutam Chowdhury

PhD

About

53
Publications
6,512
Reads
How we measure 'reads'
A 'read' is counted each time someone views a publication summary (such as the title, abstract, and list of authors), clicks on a figure, or views or downloads the full-text. Learn more
1,534
Citations
Citations since 2016
12 Research Items
680 Citations
2016201720182019202020212022020406080100120
2016201720182019202020212022020406080100120
2016201720182019202020212022020406080100120
2016201720182019202020212022020406080100120
Introduction
I am currently working on the short and long term effect of acute inflammation in the context of GSH. We have recently shown that GSH protects the DNA from the toxic effect of peroxynitrite formed during acute inflammation by forming stable DNA adducts in guanine bases. We have also demonstrated that the adducts are mutagenic. At present we are studying the consequences of these adducts formed during acute inflammation. https://goutamgc.wixsite.com/goutam
Education
August 1998 - April 2005
University of Missouri-Columbia
Field of study
  • Bioorganic Chemistry

Publications

Publications (53)
Article
Full-text available
The current COVID-19 pandemic caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) created a global health crisis. The ability of vaccines to protect immunocompromised individuals and from emerging new strains are major concerns. Hence antiviral drugs against SARS-CoV-2 are essential. The SARS-CoV-2 main protease M pro is vita...
Article
Full-text available
Triple negative breast cancer (TNBC) is classically treated with combination chemotherapies. Although, initially responsive to chemotherapies, TNBC patients frequently develop drug-resistant, metastatic disease. Chemotherapy resistance can develop through many mechanisms, including induction of a transient growth-arrested state, known as the therap...
Article
Full-text available
Withania somnifera, commonly known as Ashwagandha, is a medicinal plant used for thousands of years for various remedies. Extracts of Ashwagandha contain more than 200 metabolites, with withanone (win) being one of the major ones responsible for many of its medicinal properties. Recently, several cases of liver toxicity resulting from commercially...
Article
Full-text available
Survivin is a lucrative broad-spectrum drug target for different cancer types, including triple negative breast cancer (TNBC). Sepantronium bromide (YM155) is the first of its class of survivin suppressants and was found to be quite effective in pre-clinical models of TNBC. However, in clinical trials when given in combination with docetaxel, YM55...
Article
Inflammation is an immune response to protect against various types of infections. When unchecked, acute inflammation can be life-threatening, as seen with the current corona virus pandemic. Strong oxidants, such as peroxynitrite produced by immune cells, are major mediators of the inflammation-associated pathogenesis. Cellular thiols play importan...
Article
Full-text available
Gastrointestinal (GI) cancers are malignancies of the gastrointestinal tract and accessory organs of the digestive system including the esophagus, pancreas, stomach, colon, rectum, anus, liver, gallbladder, biliary system, and small intestine. These account for 28% of global cancer incidence and 35% of cancer-related mortalities. The most common ty...
Article
Full-text available
In pre-clinical models, co-existence of Human Epidermal Growth Factor Receptor-2 (HER2)-amplification and PI3K catalytic subunit (PIK3CA) mutations results in aggressive, anti-HER2 therapy-resistant breast tumors. This is not always reflected in clinical setting. We speculated that the complex interaction between the HER2 and PIK3CA oncogenes is re...
Article
Full-text available
Sepantronium bromide (YM155), originally developed against the anti-apoptotic protein survivin, performed exceptionally well in pre-clinical and phase I clinical trials. However, in phase II trials of several cancer types including breast cancer it performed poorly. Additionally, no definitive correlation between survivin level and response to ther...
Article
Sepantronium bromide (YM155) is a small molecule antitumor agent currently in phase II clinical trials. Although developed as survivin suppressor, YM155’s primary mode of action has recently been found to be DNA damage. However, the mechanism of DNA damage by YM155 is still unknown. Knowing the mechanism of action of an anticancer drug is necessary...
Article
Full-text available
Thalidomide [α-(N-phthalimido)glutarimide] (1) is a sedative and antiemetic drug originally introduced into the clinic in the 1950s for the treatment of morning sickness. Although marketed as entirely safe, more than 10,000 babies were born with severe birth defects. Thalidomide was banned and subsequently approved for the treatment of multiple mye...
Chapter
Nucleic acids are prone to fragmentation in the ionization process of mass spectrometry (MS). The cause can be found in the polar nature of this analyte class. Following the introduction of the so-called soft-ionization techniques of electrospray ionization (ESI) and matrix-assisted laser desorption ionization (MALDI) at the end of the 1980s, mass...
Article
Full-text available
This unit contains a complete procedure for the detection and structural characterization of DNA protein crosslinks (DPCs). The procedure also describes an approach for the quantitation of the various structurally distinct DPCs. Although various methods have been described in the literature for labile DPCs, characterization of nonlabile adducts rem...
Article
The sedative and antiemetic drug thalidomide [α-(N-phthalimido)glutarimide] was withdrawn in the early 1960s due to its potent teratogenic effects but was approved for the treatment of lesions associated with leprosy in 1998 and multiple myeloma in 2006. The mechanism of teratogenicity of thalidomide still remains unclear, but it is well establishe...
Article
A combination of chemical modifications and LC-tandem MS was used for the structure elucidation of various ethylene crosslinks of DNA with O(6) -alkylguanine-DNA alkyltransferase (AGT, see picture). The elucidation of the chemical structures of such DNA-protein crosslinks is necessary to understand mechanisms of mutagenesis.
Article
Eine Kombination aus chemischen Modifikationen und LC‐Tandem‐MS wurde für die Strukturaufklärung verschiedener Ethylen‐Verknüpfungen von DNA mit O 6‐Alkylguanin‐DNA‐Alkyltransferase (AGT, siehe Bild) verwendet. Die Aufklärung der chemischen Struktur solcher DNA‐Protein‐Verknüpfungen ist für das Verständnis von Mutagenesemechanismen notwendig.
Article
Full-text available
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a neurotoxic side product formed in the chemical synthesis of desmethylprodine opioid analgesic, which induces Parkinson disease. Monoamine oxidase B, present in the mitochondrial outer membrane of glial cells, catalyzes the oxidation of MPTP to the toxic 1-methyl-4-phenylpyridinium ion (MPP⁺),...
Article
Full-text available
Cytochrome P450 (P450) 2E1 is the major enzyme that oxidizes N-nitrosodimethylamine (N,N-dimethylnitrosamine, DMN), a carcinogen and also a representative of some nitrosamines formed endogenously. Oxidation of DMN by rat or human P450 2E1 to HCHO showed a high apparent intrinsic kinetic deuterium isotope effect (KIE), ≥ 8. The KIE was not attenuate...
Article
Full-text available
The formation of dihydroxythalidomide and glutathione (GSH) conjugate(s) of 5-hydroxythalidomide was investigated in chimeric mice modified with "humanized" liver: novel humanized TK-NOG mice were prepared by the introduction of thymidine kinase, followed by induction with ganciclovir, and human liver cells were transplanted. Following oral adminis...
Article
Full-text available
This unit describes experimental and analytical procedures for characterizing the efficiency and fidelity of translesion DNA synthesis across various DNA damages by DNA polymerases in vitro. This procedure utilizes primer extension assays followed by LC-MS and LC-MS/MS analysis of the extension products. Detailed explanations for the analysis of th...
Article
Heterocyclic N-oxides are an interesting class of antitumor agents that selectively kill the hypoxic cells found in solid tumors. The hypoxia-selective activity of the lead compound in this class, tirapazamine, stems from its ability to undergo intracellular one-electron reduction to an oxygen-sensitive drug radical intermediate. In the presence of...
Article
Full-text available
Catalysis of sequential oxidation reactions is not unusual in cytochrome P450 (P450) reactions, not only in steroid metabolism but also with many xenobiotics. One issue is how processive/distributive these reactions are, i.e., how much do the "intermediate" products dissociate. Our work with human P450s 2E1, 2A6, and 19A1 on this subject has reveal...
Article
Full-text available
Metabolism of the teratogen thalidomide is proposed to be relevant to its toxicological action. We demonstrated the formation of the glutathione (GSH) conjugate of (R)-5-hydroxythalidomide in vivo in chimeric NOD-scid IL2Rg(null) mice with humanized livers (uPA-NOG mice). After an oral administration of racemic thalidomide (270 mg/kg), plasma conce...
Conference Paper
Numerous cytochrome P450 (P450) enzymes catalyze multi-step reactions. At least five occur in physiological steroid oxidations, including androgen oxidation to estrogens by P450 19A1, the steroid aromatase. Such reactions are also known with xenobiotic substrates. Oxidation of N,N-dimethyl- or diethylnitrosamine by P450 2A6 yields formaldehyde or a...
Article
Full-text available
(R)-Thalidomide was oxidized to 5-hydroxythalidomide and 5'-hydroxythalidomide by NADPH-fortified liver microsomes from humans and monkeys. (R)-Thalidomide was hydroxylated more efficiently than (S)-thalidomide. Recombinant human P450s 3A4, 3A5, and 3A7 and monkey P450s 3A8 and 3A5 (coexpressed with NADPH-P450 reductase in bacterial membranes) also...
Article
2-Amino-3-methylimidazo[1,2-d]naphthalene (cIQ) is a carbocyclic analogue of the dietary carcinogen 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) in which a naphthalene ring system replaces the quinoline unit of IQ. The activity of cIQ in Ames Salmonella typhimurium tester strain TA98 is known to be 4-5 orders of magnitude lower than IQ. cIQ undergo...
Article
Full-text available
Cytochrome P450 (P450) 2A6 activates nitrosamines, including N,N-dimethylnitrosamine (DMN) and N,N-diethylnitrosamine (DEN), to alkyl diazohydroxides (which are DNA-alkylating agents) and also aldehydes (HCHO from DMN and CH3CHO from DEN). The N-dealkylation of DMN had a high intrinsic kinetic deuterium isotope effect (Dkapp ∼ 10), which was highly...
Article
Full-text available
Aerobic incubation of the tryptophan transamination/oxidation product indole-3-pyruvic acid (I3P) at pH 7.4 and 37 degrees C yielded products with activity as Ah receptor (AHR) agonists. The extracts were fractionated using HPLC and screened for AHR agonist activity. Two compounds were identified as agonists: 1,3-di(1H-indol-3-yl)propan-2-one (1) a...
Article
The aryl hydrocarbon receptor (AHR) is well-known for its role in mediating the toxic and adaptive responses to xenobiotic compounds. Recent studies also indicate that AHR ligands are endogenously produced and may be essential for normal development. Previously, we showed that the endogenous enzyme, aspartate aminotransferase (AST), generates the A...
Article
Full-text available
Oxidative damage to DNA has been linked to aging, cancer, and other biological processes. Reactive oxygen species and various antitumor agents including bleomycin and ionizing radiation have been shown to cause oxidative DNA sugar damage. Detection of DNA lesions is important for understanding the toxicological or therapeutic consequences associate...
Article
O (6)-Alkylguanine-DNA alkyltransferase (AGT) plays an important role by protecting cells from alkylating agents. This reduces the frequency of carcinogenesis and mutagenesis initiated by such agents, but AGT also provides a major resistance mechanism to some chemotherapeutic drugs. To improve our understanding of the AGT-mediated repair reaction a...
Article
(Graph Presented) Map reading: Alkylation of a 15-base-pair double-stranded oligonucleotide modified with the carcinogen (±)-anti-benzo[a]pyrene diol epoxide (see picture) or N-hydroxy-4-aminobiphenyl is mapped by liquid chromatograhy-tandem mass spectrometry and collision-induced dissociation (CID). The method does not require prior DNA cleavage o...
Article
The compound 3-amino-1,2,4-benzotriazine 1,4-dioxide (tirapazamine, TPZ) is a clinically promising anticancer agent that selectively kills the oxygen-poor (hypoxic) cells found in solid tumors. It has long been known that, under hypoxic conditions, TPZ causes DNA strand damage that is initiated by the abstraction of hydrogen atoms from the deoxyrib...
Article
Full-text available
Reversible phosphorylation of tyrosine residues serves as a biochemical "switch" that alters the functional properties of many proteins involved in cellular signal transduction processes. Protein tyrosine phosphatases (PTPs) catalyze the removal of phosphoryl groups from tyrosine residues in target proteins, thereby playing a central role in the re...
Article
Full-text available
Abasic sites which are generated by hydrolysis of the glycosidic bonds connecting the heterocyclic nucleobases to the deoxyribose backbone represent the most common form of damage suffered by genomic DNA. Interestingly, an early report suggested that abasic sites can generate interstrand cross-links in duplex DNA, but the structure of these lesions...
Article
Full-text available
Previous studies have shown that replicative bacterial and viral DNA polymerases are able to bypass the mutagenic lesions O(6)-methyl and -benzyl (Bz) G. Recombinant human polymerase (pol) delta also copied past these two lesions but was totally blocked by O(6)-[4-oxo-4-(3-pyridyl)butyl] (Pob)G, an important mutagenic lesion formed following metabo...
Article
Full-text available
2-Amino-3-methylimidazo[4,5-f]quinoline (IQ) is found in cooked meats and forms DNA adducts at the C8- and N2-positions of dGuo after appropriate activation. IQ is a potent inducer of frameshift mutations in bacteria and is carcinogenic in laboratory animals. We have incorporated both IQ-adducts into the G1- and G3-positions of the NarI recognition...
Article
Full-text available
Heterocyclic arylamines are highly mutagenic and cause tumors in animal models. The mutagenicity is attributed to the C8- and N2-G adducts, the latter of which accumulates due to slower repair. The C8- and N 2-G adducts derived from 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) were placed at the G1 and G3 sites of the NarI sequence, in which the G3...
Article
Heterocyclic arylamines are highly mutagenic and cause tumors in animal models. The mutagenicity is attributed to the C8- and N2-G adducts, the latter of which accumulates due to slower repair. The C8- and N 2-G adducts derived from 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) were placed at the G1 and G3 sites of the NarI sequence, in which the G3...
Article
The mechanisms by which derivatives of polycyclic aromatic hydrocarbons (PAHs) cause mutations have been of considerable interest. Three different N(6)-adenyl PAH-diol epoxide oligonucleotide derivatives were studied with the archebacterial translesion DNA polymerase Sulfolobus solfataricus Dpo4. Steady-state kinetic analysis indicated insertion of...
Article
Full-text available
The compound 3-amino-2-quinoxalinecarbonitrile 1,4-dioxide (4) displays potent hypoxia-selective cytotoxicity in cell culture. This compound is structurally similar to the known hypoxia-selective DNA-damaging agent tirapazamine (1, TPZ), but the ability of 4 to cause DNA damage under low-oxygen conditions has not previously been characterized. The...
Article
Tirapazamine is a bioreductively activated DNA-damaging agent that selectively kills the hypoxic cells found in solid tumors. This compound shows clinical promise and is currently being examined in a variety of clinical trials, including several phase III studies. It is well established that DNA is an important cellular target for tirapazamine; how...
Article
Reaction of the antitumor agent leinamycin with cellular thiols results in conversion of the natural product to a DNA-alkylating episulfonium alkylating agent via an intriguing sequence of chemical reactions. To establish whether the chemistry first seen in leinamycin represents a general motif that can function in various molecular frameworks, con...
Article
The absorption and fluorescence spectra of 3-aminobenzo-1,2,4-triazine di-N-oxide (tirapazamine) have been recorded and exhibit a dependence on solvent that correlates with the Dimroth ET30 parameter. Time-dependent density functional theory calculations reveal that the transition of tirapazamine in the visible region is pi-->pi* in nature. The flu...
Article
Quinoxaline 1,4-dioxide (4) is the historical prototype for modern heterocyclic N-oxide antitumor agents such as 3-amino-1,2,4-benzotriazine 1,4-dioxide (tirapazamine, 1) and 3-amino-2-quinoxalinecarbonitrile 1,4-dioxide (11). Early experiments in bacterial cell lines suggested that enzymatic, single-electron reduction of quinoxaline 1,4-dioxides u...
Article
Tirapazamine (1) is a promising antitumor agent that selectively causes DNA damage in hypoxic tumor cells, following one-electron bioreductive activation. Surprisingly, after more than 10 years of study, the products arising from bioreductive metabolism of tirapazamine have not been completely characterized. The two previously characterized metabol...

Network

Cited By

Projects