Publications by authors named "Kiran S Toti"

15 Publications

  • Page 1 of 1

Structure-activity relationships of pyrimidine nucleotides containing a 5'-α,β-methylene diphosphonate at the P2Y receptor.

Bioorg Med Chem Lett 2021 Aug 26;45:128137. Epub 2021 May 26.

Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address:

The G-coupled P2Y receptor (P2YR) is a component of the purinergic signaling system and functions in inflammatory, cardiovascular and metabolic processes. UDP, the native P2YR agonist and P2YR partial agonist, is subject to hydrolysis by ectonucleotidases. Therefore, we have synthesized UDP/CDP analogues containing a stabilizing α,β-methylene bridge as P2YR agonists and identified compatible affinity-enhancing pyrimidine modifications. A distal binding region on the receptor was explored with 4-benzyloxyimino cytidine 5'-diphosphate analogues and their potency determined in a calcium mobilization assay. A 4-trifluoromethyl-benzyloxyimino substituent in 25 provided the highest human P2YR potency (MRS4554, 0.57 µM), and a 5-fluoro substitution of the cytosine ring in 28 similarly enhanced potency, with >175- and 39-fold selectivity over human P2YR, respectively. However, 3-alkyl (31-33, 37, 38), β-d-arabinofuranose (39) and 6-aza (40) substitution prevented P2YR activation. Thus, we have identified new α,β-methylene bridged N-extended CDP analogues as P2YR agonists that are highly selective over the P2YR.
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http://dx.doi.org/10.1016/j.bmcl.2021.128137DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8276771PMC
August 2021

Adenosine Kinase Expression Determines DNA Methylation in Cancer Cell Lines.

ACS Pharmacol Transl Sci 2021 Apr 16;4(2):680-686. Epub 2021 Feb 16.

Department of Neurosurgery, Robert Wood Johnson Medical School, Rutgers University, Piscataway, New Jersey 08854, United States.

DNA methylation has a major role in cancer, and its inhibitors are used therapeutically. DNA methylation depends on methyl group flux through the transmethylation pathway, which forms adenosine. We hypothesized that an adenosine kinase isoform with nuclear expression (ADK-L) determines global DNA methylation in cancer cells. We quantified ADK-L expression (Western Blot) and global DNA methylation as percent 5-methyldeoxycytidine (5mdC, LC-MS/MS) in three cancer lines (HeLa, HepG2, and U373). ADK-L expression and global DNA methylation correlated positively with the highest levels in HeLa cells compared to U373 and HepG2 cells. To determine whether ADK increases global DNA methylation and to validate its potential therapeutics, we treated HeLa cells with potent ADK inhibitors MRS4203 and MRS4380 (IC 88 and 140 nM, respectively). Both nucleosides, but not a structurally related poor ADK inhibitor, significantly reduced global DNA methylation in HeLa cells in a concentration-dependent manner. Thus, ADK-L is a potential target for the therapeutic manipulation of DNA methylation levels in cancer.
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http://dx.doi.org/10.1021/acsptsci.1c00008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8033756PMC
April 2021

Lack of adipocyte purinergic P2Y receptor greatly improves whole body glucose homeostasis.

Proc Natl Acad Sci U S A 2020 12 16;117(48):30763-30774. Epub 2020 Nov 16.

Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD 20892;

Uridine diphosphate (UDP)-activated purinergic receptor P2Y (P2YR) plays a crucial role in controlling energy balance through central mechanisms. However, P2YR's roles in peripheral tissues regulating energy and glucose homeostasis remain unexplored. Here, we report the surprising finding that adipocyte-specific deletion of P2YR protects mice from diet-induced obesity, improving glucose tolerance and insulin sensitivity with reduced systemic inflammation. These changes were associated with reduced JNK signaling and enhanced expression and activity of PPARα affecting downstream PGC1α levels leading to beiging of white fat. In contrast, P2YR deletion in skeletal muscle reduced glucose uptake, resulting in impaired glucose homeostasis. Interestingly, whole body P2YR knockout mice showed metabolic improvements similar to those observed with mice lacking P2YR only in adipocytes. Our findings provide compelling evidence that P2YR antagonists may prove useful for the treatment of obesity and type 2 diabetes.
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http://dx.doi.org/10.1073/pnas.2006578117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7720204PMC
December 2020

Identification of a New Heterocyclic Scaffold for Inhibitors of the Polo-Box Domain of Polo-like Kinase 1.

J Med Chem 2020 11 11;63(22):14087-14117. Epub 2020 Nov 11.

Chemistry Section, Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, United States.

As a mitotic-specific target widely deregulated in various human cancers, polo-like kinase 1 (Plk1) has been extensively explored for anticancer activity and drug discovery. Although multiple catalytic domain inhibitors were tested in preclinical and clinical studies, their efficacies are limited by dose-limiting cytotoxicity, mainly from off-target cross reactivity. The C-terminal noncatalytic polo-box domain (PBD) of Plk1 has emerged as an attractive target for generating new protein-protein interaction inhibitors. Here, we identified a 1-thioxo-2,4-dihydro-[1,2,4]triazolo[4,3-]quinazolin-5(1)-one scaffold that efficiently inhibits Plk1 PBD but not its related Plk2 and Plk3 PBDs. Structure-activity relationship studies led to multiple inhibitors having ≥10-fold higher inhibitory activity than the previously characterized Plk1 PBD-specific phosphopeptide, PLHSpT ( ∼ 450 nM). In addition, -methyl prodrugs effectively inhibited mitotic progression and cell proliferation and their metabolic stability was determined. These data describe a novel class of small-molecule inhibitors that offer a promising avenue for future drug discovery against Plk1-addicted cancers.
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http://dx.doi.org/10.1021/acs.jmedchem.0c01669DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7769008PMC
November 2020

Structure activity relationship of novel antiviral nucleosides against Enterovirus A71.

Bioorg Med Chem Lett 2020 12 5;30(23):127599. Epub 2020 Oct 5.

Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Disease, National Institutes of Health, 9000 Rockville Pike, Bethesda, MA 20892, USA. Electronic address:

Various (North)-methanocarba adenosine derivatives, containing rigid bicyclo[3.1.0]hexane ribose substitution, were screened for activity against representative viruses, and inhibition was observed after treatment of Enterovirus A71 with a 2-chloro-N-1-cyclopropyl-2-methylpropan-1-yl derivative (17). µM activity was also seen when testing 17 against other enteroviruses in the Picornaviridae family. Based on this hit, structural congeners of 17, containing other N-alkyl groups and 5' modifications, were synthesized and tested. The structure activity relationship is relatively narrow, with most modifications of the adenine or the methanocarba ring reducing or abolishing the inhibitory potency. 4'-Truncated 31 (MRS5474), 4'-fluoromethyl 48 (MRS7704) and 4'-chloromethyl 49 nucleosides displayed EC ~3-4 µM, and 31 and 48 achieved SI ≥10. However, methanocarba analogues of ribavirin and N-benzyladenosine, shown previously to have anti-EV-A71 activity, were inactive. Thus, we identified methanocarba nucleosides as a new scaffold for enterovirus inhibition with a narrow structure activity relationship and no similarity to previously published anti-enteroviral nucleosides.
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http://dx.doi.org/10.1016/j.bmcl.2020.127599DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7534897PMC
December 2020

Allosteric Antagonism of the A Adenosine Receptor by a Series of Bitopic Ligands.

Cells 2020 05 12;9(5). Epub 2020 May 12.

Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.

Allosteric antagonism by bitopic ligands, as reported for many receptors, is a distinct modulatory mechanism. Although several bitopic A adenosine receptor (AAR) ligand classes were reported as pharmacological tools, their receptor binding and functional antagonism patterns, i.e., allosteric or competitive, were not well characterized. Therefore, here we systematically characterized AAR binding and functional antagonism of two distinct antagonist chemical classes. i.e., fluorescent conjugates of xanthine amine congener (XAC) and SCH442416. Bitopic ligands were potent, weak, competitive or allosteric, based on the combination of pharmacophore, linker and fluorophore. Among antagonists tested, XAC, XAC245, XAC488, SCH442416, MRS7352 showed K binding values consistent with K values from functional antagonism. Interestingly, MRS7396, XAC-X-BY630 (XAC630) and 5-(,-hexamethylene)amiloride (HMA) were 9-100 times weaker in displacing fluorescent MRS7416 binding than radioligand binding. XAC245, XAC630, MRS7396, MRS7416 and MRS7322 behaved as allosteric AAR antagonists, whereas XAC488 and MRS7395 antagonized competitively. Schild analysis showed antagonism slopes of 0.42 and 0.47 for MRS7396 and XAC630, respectively. Allosteric antagonists HMA and MRS7396 were more potent in displacing [H]ZM241385 binding than MRS7416 binding. Sodium site D52N mutation increased and decreased affinity of HMA and MRS7396, respectively, suggesting possible preference for different AAR conformations. The allosteric binding properties of some bitopic ligands were rationalized and analyzed using the Hall two-state allosteric model. Thus, fluorophore tethering to an orthosteric ligand is not neutral pharmacologically and may confer unexpected properties to the conjugate.
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http://dx.doi.org/10.3390/cells9051200DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7290864PMC
May 2020

Prevention and rescue of cardiac dysfunction by methanocarba adenosine monophosphonate derivatives.

Purinergic Signal 2020 03 27;16(1):61-72. Epub 2020 Jan 27.

NIDDK, National Institutes of Health, Bethesda, MD, 20892, USA.

Accumulating evidence supports a therapeutic role of purinergic signaling in cardiac diseases. Previously, efficacy of systemically infused MRS2339, a charged methanocarba derivative of 2-Cl-adenosine monophosphate, was demonstrated in animal models of heart failure. We now test the hypothesis that an uncharged adenine nucleoside phosphonate, suitable as an oral agent with a hydrolysis-resistant phospho moiety, can prevent the development of cardiac dysfunction in a post-infarction ischemic or pressure overload-induced heart failure model in mice. The diester-masked uncharged phosphonate MRS2978 was efficacious in preventing cardiac dysfunction with improved left ventricular (LV) fractional shortening when administered orally at the onset of ischemic or pressure overload-induced heart failure. MRS2925, the charged, unmasked MRS2978 analog, prevented heart dysfunction when infused subcutaneously but not by oral gavage. When administered orally or systemically, MRS2978 but not MRS2925 could also rescue established cardiac dysfunction in both ischemic and pressure overload heart failure models. The diester-masked phosphate MRS4074 was highly efficacious at preventing the development of dysfunction as well as in rescuing pressure overload-induced and ischemic heart failure. MRS2978 was orally bioavailable (57-75%) giving rise to MRS2925 as a minor metabolite in vivo, tested in rats. The data are consistent with a novel therapeutic role of adenine nucleoside phosphonates in systolic heart failure.
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http://dx.doi.org/10.1007/s11302-020-09688-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7166228PMC
March 2020

Pyrimidine Nucleotides Containing a (S)-Methanocarba Ring as P2Y Receptor Agonists.

Medchemcomm 2017 Oct 6;8(10):1897-1908. Epub 2017 Sep 6.

Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892 USA.

Both agonists and antagonists of the UDP-activated P2Y receptor (P2YR) have been proposed for therapeutic use, in conditions such as cancer, inflammation, neurodegeneration and diabetes. Uracil nucleotides containing a South-bicyclo[3.1.0]hexane ((S)-methanocarba) ring system in place of the ribose ring were synthesized and shown to be potent P2YR agonists in a calcium mobilization assay. The (S)-methanocarba modification was compatible with either a 5-iodo or 4-methoxyimino group on the pyrimidine, but not with a α,β-methylene 5´-diphosphate. (S)-Methanocarba dinucleotide potency was compatible with a N-methoxy modification on the proximal nucleoside that is assumed to bind at the P2YR similarly to UDP; (N)-methanocarba was preferred on the distal nucleoside moiety. This suggests that the distal dinucleotide P2YR binding site prefers a ribose-like group that can attain a (N) conformation, rather than (S). Dinucleotide binding was modeled by homology modeling, docking and molecular dynamics simulations, which suggested the same ribose conformational preferences found empirically.
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http://dx.doi.org/10.1039/C7MD00397HDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5798474PMC
October 2017

Polypharmacology of conformationally locked methanocarba nucleosides.

Drug Discov Today 2017 12 3;22(12):1782-1791. Epub 2017 Aug 3.

Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes & Digestive & Kidney Diseases, National Institutes of Health, Bldg 8A, Rm B1A-19, Bethesda, MD 20892-0810, USA.

A single molecular scaffold can be adapted to interact with diverse targets, either separately or simultaneously. Nucleosides and nucleotides in which ribose is substituted with bicyclo[3.1.0]hexane are an example of a versatile drug-like scaffold for increasing selectivity at their classical targets: kinases, polymerases, adenosine and P2 receptors. Also, by applying structure-based functional group manipulations, rigidified adenosine derivatives can be repurposed to satisfy pharmacophoric requirements of various GPCRs, ion channels, enzymes and transporters, initially detected as off-target activities. Recent examples include 5HT serotonin receptor antagonists and novel dopamine transporter allosteric modulators. This directable target diversity establishes rigid nucleosides as privileged scaffolds.
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http://dx.doi.org/10.1016/j.drudis.2017.07.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5705437PMC
December 2017

South (S)- and North (N)-Methanocarba-7-Deazaadenosine Analogues as Inhibitors of Human Adenosine Kinase.

J Med Chem 2016 07 13;59(14):6860-77. Epub 2016 Jul 13.

Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health , Bldg. 8A, Rm. B1A-19, Bethesda, Maryland 20892-0810, United States.

Adenosine kinase (AdK) inhibitors raise endogenous adenosine levels, particularly in disease states, and have potential for treatment of seizures, neurodegeneration, and inflammation. On the basis of the South (S) ribose conformation and molecular dynamics (MD) analysis of nucleoside inhibitors bound in AdK X-ray crystallographic structures, (S)- and North (N)-methanocarba (bicyclo[3.1.0]hexane) derivatives of known inhibitors were prepared and compared as human (h) AdK inhibitors. 5'-Hydroxy (34, MRS4202 (S); 55, MRS4380 (N)) and 5'-deoxy 38a (MRS4203 (S)) analogues, containing 7- and N(6)-NH phenyl groups in 7-deazaadenine, robustly inhibited AdK activity (IC50 ∼ 100 nM), while the 5'-hydroxy derivative 30 lacking the phenyl substituents was weak. Docking in the hAdK X-ray structure and MD simulation suggested a mode of binding similar to 5'-deoxy-5-iodotubercidin and other known inhibitors. Thus, a structure-based design approach for further potency enhancement is possible. The potent AdK inhibitors in this study are ready to be further tested in animal models of epilepsy.
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http://dx.doi.org/10.1021/acs.jmedchem.6b00689DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5032833PMC
July 2016

Synthesis and evaluation of N⁶-substituted apioadenosines as potential adenosine A₃ receptor modulators.

Bioorg Med Chem 2014 Aug 23;22(15):4257-68. Epub 2014 May 23.

Laboratory for Medicinal Chemistry, Faculty of Pharmaceutical Sciences, Ghent University, Harelbekestraat 72, B-9000 Gent, Belgium. Electronic address:

Adenosine receptors (ARs) trigger signal transduction pathways inside the cell when activated by extracellular adenosine. Selective modulation of the A₃AR subtype may be beneficial in controlling diseases such as colorectal cancer and rheumatoid arthritis. Here, we report the synthesis and evaluation of β-D-apio-D-furano- and α-D-apio-L-furanoadenosines and derivatives thereof. Introduction of a 2-methoxy-5-chlorobenzyl group at N(6) of β-D-apio-D-furanoadenosine afforded an A₃AR antagonist (10c, Ki=0.98 μM), while a similar modification of an α-D-apio-L-furanoadenosine gave rise to a partial agonist (11c, Ki=3.07 μM). The structural basis for this difference was examined by docking to an A₃AR model; the antagonist lacked a crucial interaction with Thr94.
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http://dx.doi.org/10.1016/j.bmc.2014.05.036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4128473PMC
August 2014

Synthesis of an apionucleoside family and discovery of a prodrug with anti-HIV activity.

J Org Chem 2014 Jun 20;79(11):5097-112. Epub 2014 May 20.

Laboratory for Medicinal Chemistry, Faculty of Pharmaceutical Sciences, Ghent University , Harelbekestraat 72, B-9000 Ghent, Belgium.

We report the synthesis of a family of D- and L-furano-D-apionucleosides, their 3'-deoxy, as well as their 2',3'-dideoxy analogues with thymine and adenine nucleobases. Single carbon homologation of 1,2-O-isopropylidene-D-glycero-tetrafuranos-3-ulose (15) and optimized glycosylation conditions involving microwave irradiation were key to the successful synthesis of the target compounds. While all target nucleosides failed to show significant antiviral activity, we demonstrated that the triphosphate of 2',3'-deoxy-D-apio-D-furanoadenosine (1), in contrast to that of its D-apio-L-furanose epimer 2, was readily incorporated into a DNA template by HIV reverse transcriptase to act as a DNA chain terminator. This led us to convert adenine derivative 1 into two phosphoramidate prodrugs. ProTide 9b was found active against HIV-1 and HIV-2 (EC50 = 0.5-1.5 μM), indicating that the lack of activity of the parent nucleoside, and possibly also other members of the D-apio-D-furanose nucleoside family must be sought in the inefficient cellular conversion to the monophosphate.
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http://dx.doi.org/10.1021/jo500659eDOI Listing
June 2014

Synthesis and evaluation of 5'-modified thymidines and 5-hydroxymethyl-2'-deoxyuridines as Mycobacterium tuberculosis thymidylate kinase inhibitors.

Bioorg Med Chem 2013 Jan 5;21(1):257-68. Epub 2012 Nov 5.

Laboratory for Medicinal Chemistry, Faculty of Pharmaceutical Sciences (FFW), Ghent University, Harelbekestraat 72, 9000 Ghent, Belgium.

We report the synthesis of 5'-modified thymidines (16, 18, 21, 23) and 5,5'-bis-substituted 2'-deoxyuridine analogues (30, 47) as inhibitors of thymidine monophosphate kinase of Mycobacterium tuberculosis (TMPKmt). These analogues were evaluated for their capacity to inhibit TMPKmt and solely two 5'-modified thymidines were found to possess moderate inhibitory activity. In addition, a feasibility study of protecting groups for the 5-CH(2)OH moiety of 2'-deoxyuridines is described that enables to introduce the desired 5'-modification.
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http://dx.doi.org/10.1016/j.bmc.2012.10.018DOI Listing
January 2013

Synthesis and antiviral evaluation of α-L-2'-deoxythreofuranosyl nucleosides.

Eur J Med Chem 2011 Sep 20;46(9):3704-13. Epub 2011 May 20.

Laboratory for Medicinal Chemistry, FFW, UGent, Harelbekestraat 72, 9000 Gent, Belgium.

The synthesis of a series of α-L-2'-deoxythreofuranosyl nucleosides featuring the nucleobases A, T, C and U is described in seven steps from 1,2-O-isopropyledene-α-L-threose, involving a Vorbrüggen coupling and a Barton-McCombie deoxygenation protocol as the key steps. All analogues, including a phosphoramidate nucleoside phosphate prodrug of the T analogue, were evaluated against a broad panel of different viruses but found inactive, while also lacking notable cellular toxicity. The thymidine analogue showed inhibition to mitochondrial thymidine kinase-2 (TK-2), herpes simplex virus type 1 (HSV-1) TK, varicella-zoster virus (VZV) TK and Mycobacterium tuberculosis thymidylate kinase.
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http://dx.doi.org/10.1016/j.ejmech.2011.05.036DOI Listing
September 2011

Synthesis and evaluation of antifungal properties of a series of the novel 2-amino-5-oxo-4-phenyl-5,6,7,8-tetrahydroquinoline-3-carbonitrile and its analogues.

Bioorg Med Chem 2007 Nov 15;15(21):6705-15. Epub 2007 Aug 15.

Division of Organic Chemistry; Technology, National Chemical Laboratory, Pune, India.

A series of 2-amino-5-oxo-4-phenyl-5,6,7,8-tetrahydroquinoline-3-carbonitrile and various analogues have been synthesized in excellent isolated yields starting from various arylidenemalononitrile and 3-amino-2-cyclohexen-1-one in 1-propanol as solvent at reflux temperature in the absence of any added catalyst. All the synthesized compounds were evaluated for their antifungal activity. The relationship between functional group variation and biological activity of the evaluated compounds is discussed in the article.
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http://dx.doi.org/10.1016/j.bmc.2007.08.009DOI Listing
November 2007
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