Crucial enzymes involved in nucleic acid metabolism and cellular proliferation are targeted for inhibition by synthetic carbohydrate and nucleoside analogues. Living organisms, from bacteria to humans, use S-adenosylmethionine (SAM) as the methyl donor. The byproduct of these reactions is S-adenosylhomocysteine (AdoHcy). Both prokaryotes and eukaryotes have developed detoxification mechanisms to eliminate AdoHcy. Eukaryotes contain an AdoHcy hydrolase, which directly hydrolyzes AdoHcy into homocysteine (Hcy) and adenosine. However, the majority of bacterial species employ a different, two-step mechanism to remove AdoHcy. First, the adenine base of AdoHcy is removed by a 5'- methylthioadenosine/ AdoHcy nucleosidase (MTAN) to produce S-ribosylhomocysteine (SRH). Next, the thioether bond in SRH is cleaved by an S-ribosylhomocysteinase (LuxS enzyme) to produce Hcy and 4,5-dihydroxy-2,3-pentanedione (DPD), important precursors to quorum-sensing-regulated auto-inducers. We are interested in probing substrate similarities and mechanistic differences between AdoHcy hydrolase and LuxS enzymes. The major objective is to prepare modified SRH analogues lacking an enolizable hydroxyl group at carbon-2 or 3. These competitive substrates should act as mechanism-based inhibitors of LuxS and impede the production of autoinducer of type 2, and disrupt quorum sensing and cell-cell communication in bacteria. Ribonucleotide reductases (RNRs) are enzymes that execute 2'-deoxygenation of ribonucleotides and present attractive chemotherapeutic targets for intervention with replication of cancer cells. Our objective is to synthesize a series of 3'-azido-3'-deoxynucleosides bearing a thiol or vicinal dithiol substituent attached to C2'or C5'and perform biomimetic simulation of the reactions postulated to occur during inhibition of RNR by 2'-azido-2'-deoxynucleotides. To expand our findings from the current award, we plan to explore application of organogermanes toward Pd-catalyzed cross-coupling reactions. Relevance to Public Health: Understanding the mechanism of action of the targeted enzymes is essential to pursue the rational design of new mechanism-based inhibitor drugs. Inhibitors of LuxS enzyme should affect quorum sensing regulated processes in bacterial cell-cell communication, which will allow interventions based on virulence, antibiotic production, and biofilm formation.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Enhancement Award (SC1)
Project #
5SC1CA138176-02
Application #
7664314
Study Section
Special Emphasis Panel (ZGM1-MBRS-X (CH))
Program Officer
Wali, Anil
Project Start
2008-08-01
Project End
2012-07-31
Budget Start
2009-08-01
Budget End
2010-07-31
Support Year
2
Fiscal Year
2009
Total Cost
$216,125
Indirect Cost
Name
Florida International University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
071298814
City
Miami
State
FL
Country
United States
Zip Code
33199
Pulido, Jesse; de Cabrera, Maria; Sobczak, Adam J et al. (2018) 4-N-Alkanoyl and 4-N-alkyl gemcitabine analogues with NOTA chelators for 68-gallium labelling. Bioorg Med Chem 26:5624-5630
Mudgal, Mukesh; Rishi, Sunny; Lumpuy, Daniel A et al. (2017) Prehydrated One-Electron Attachment to Azido-Modified Pentofuranoses: Aminyl Radical Formation, Rapid H-Atom Transfer, and Subsequent Ring Opening. J Phys Chem B 121:4968-4980
Rayala, Ramanjaneyulu; Giuglio-Tonolo, Alain; Broggi, Julie et al. (2016) Studies toward the oxidative and reductive activation of C-S bonds in 2'-S-aryl-2'-thiouridine derivatives. Tetrahedron 72:1969-1977
Liang, Yong; Suzol, Sazzad H; Wen, Zhiwei et al. (2016) Uracil Nucleosides with Reactive Group at C5 Position: 5-(1-Halo-2-sulfonylvinyl)uridine Analogues. Org Lett 18:1418-21
Chbib, Christiane; Sobczak, Adam J; Mudgal, Mukesh et al. (2016) S-Ribosylhomocysteine Analogues Modified at the Ribosyl C-4 Position. J Sulphur Chem 37:307-327
Gonzalez, Cesar; Kavoosi, Sam; Sanchez, Andersson et al. (2016) Reduction of sugar lactones to hemiacetals with lithium triethylborohydride. Carbohydr Res 432:17-22
Sobczak, Adam J; Chbib, Christiane; Wnuk, Stanislaw F (2015) S-Ribosylhomocysteine analogs containing a [4-thio]ribose ring. Carbohydr Res 415:39-47
Zayas, Jessica; Annoual, Marie; Das, Jayanta Kumar et al. (2015) Strain Promoted Click Chemistry of 2- or 8-Azidopurine and 5-Azidopyrimidine Nucleosides and 8-Azidoadenosine Triphosphate with Cyclooctynes. Application to Living Cell Fluorescent Imaging. Bioconjug Chem 26:1519-32
Liang, Yong; Gloudeman, Jennifer; Wnuk, Stanislaw F (2014) Palladium-catalyzed direct arylation of 5-halouracils and 5-halouracil nucleosides with arenes and heteroarenes promoted by TBAF. J Org Chem 79:4094-103
Adhikary, Amitava; Kumar, Anil; Rayala, Ramanjaneyulu et al. (2014) One-electron oxidation of gemcitabine and analogs: mechanism of formation of C3' and C2' sugar radicals. J Am Chem Soc 136:15646-53

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