Robert Vince - Research
Research Details
Anti-microbial Drugs (Antibiotics)
Over the years, bacteria have increasingly developed resistance to traditional antibiotics. Research on new antibiotics to fight infections caused by these super-resistant bacteria is currently underway in our labs, using two approaches.
The first approach is to find new ways to block the ability of the bacteria to manufacture their vital cell walls. We are working on designing new antibiotic molecules that are simpler than the standard penicillins and are designed to overcome the resistance associated with penicillin-type drugs.
The second approach is to produce a synthetic equivalent to the naturally-produced vancomycin drug. Vancomycin is considered the last defense in the treatment of resistant bacterial infections. We believe an equivalent can be designed that will not only kill resistant bacteria, but can be easily produced in the laboratory.
Anti-viral Drugs
Following the identification of a human retrovirus (HIV) as the etiologic agent of the Acquired Immunodeficiency Syndrome (AIDS), an intense effort was made to identify drugs for the treatment of this debilitating, lethal disease. Ongoing research in our laboratory deals with the development of anti-viral agents and has focused on the design of anti-HIV drugs. In response to the initial project for a very large-scale anti-HIV drug screening and AIDS drug development program at the National Cancer Institute, researchers in our lab developed a series of carbocyclic nucleoside analogs. These compounds have design features compatible with action as DNA chain terminators and are structurally analogous to natural nucleosides, the only difference being that a methylene group replaces the oxygen atom of the carbohydrate ring. The studies showed that these analogs, called carbovirs, which lack a labile glycosidic bond, are stable to hydrolytic cleavage while retaining the therapeutically useful interaction with enzymes involved in DNA and RNA synthesis. As a result, several of the carbocyclic nucleosides inhibited the infectivity and replication of HIV in T-cells and led to the development of the commercially available anti-HIV drug, Ziagen®.
Other approaches to the design of anti-AIDS drugs at the Center for Drug Design include:
- Create a new protease inhibitor to block the ability of the virus to produce essential proteins
- Construct integrase enzyme inhibitors designed to prevent the virus from integrating its own DNA into the DNA of human cells
Other areas of focus for our anti-viral programs are Herpes, Hepatitis B, and Hepatitis C.
Cancer Therapy
Several anti-cancer projects are ongoing based on our extensive history of nucleoside analog production. In fact, the development of our anti-viral program and the successful design of the AIDS drug, was a spin off of our anti-cancer drug program. Since most of the successful anti-tumor drugs are nucleoside analogs, we continue to work in this area for the discovery of new cancer drugs.
We have recently initiated a program to study Vitamin C in cancer chemoprevention and treatment. The Vitamin C molecule has important and interesting anti-oxidant properties (free radical elimination) but is vulnerable to metabolism and elimination from the body. We have found some interesting unrelated properties of Vitamin C that have potential for anti-cancer and cancer chemopreventive applications. We are studying these properties and will use our results to redesign the molecule into a more stable and effective potential drug.
Recent Publications
Design and synthesis of sulfoximine based inhibitors for HIV-1 protease. Raza A, Sham YY, Vince R. Bioorg Med Chem Lett. 2008, 18(20):5406-10. Abstract
Design, synthesis and biological evaluation of glutathione peptidomimetics as components of anti-Parkinson prodrugs. More SS, Vince R. J Med Chem. 2008, 51(15):4581-8. Abstract
Design and synthesis of dual inhibitors of HIV reverse transcriptase and integrase: introducing a diketoacid functionality into delavirdine. Wang Z, Vince R. Bioorg Med Chem. 2008, 16(7):3587-95. Abstract
Synthesis of pyrimidine and quinolone conjugates as a scaffold for dual inhibitors of HIV reverse transcriptase and integrase. Wang Z, Vince R. Bioorg Med Chem Lett. 2008, 18(4):1293-6. Abstract
Discovery of potent HIV-1 protease inhibitors incorporating sulfoximine functionality. Lu D, Vince R. Bioorg. Med. Chem. Lett. 2007, 17(20):5614-9. Abstract
Rationally designed dual inhibitors of HIV reverse transcriptase and integrase. Wang Z, Bennett EM, Wilson DJ, Salomon C, Vince R. J. Med. Chem. 2007, 50(15): 3416-19. Abstract
Design, synthesis, and binding studies of bidentate Zn-chelating peptidic inhibitors of glyoxalase-I. More SS, Vince R. Bioorg. Med. Chem. Lett. 2007, 17(13): 3793-7. Abstract
A metabolically stable tight-binding transition-state inhibitor of glyoxalase-I. More SS, Vince R. Bioorg. Med. Chem. Lett. 2006, 16(23): 6039-42. Abstract
Synthesis and biological evaluation of carboacyclic nucleosides with (Z) and (E)-9-[4,4-bis(hydroxymethyl)]-2-butenyl side chain. Tang Y, Muthyala R, Vince R. Bioorg. Medicinal Chem. 2006, 14(17): 5866-75. Abstract
Synthesis and biological evaluation of purine derivatives incorporating metal chelating ligands as HIV integrase inhibitors. Li X, Vince R. Bioorg. Medicinal Chem. 2006, 14(16): 5742-55. Abstract
Conformationally restrained carbazolone-containing alpha,gamma-diketo acids as inhibitors of HIV integrase. Li X, Vince R. Bioorg. Medicinal Chem. 2006, 14(9): 2942-55. Abstract
Synthesis of Conformationally Restricted 2',3'-exo-methylene Carbocyclic Nucleosides Built on a Bicyclo[2',3']hexane Template. Bhushan RG, Vince R. Bioorg. Medicinal Chem. 2002, 10: 2325-33. Abstract
Synthesis and Biological Evaluation of Endocyclic-2',3'-didehydro-2',3'-dideoxymethanecarba Adenosine. Quirk Dorr DR, Vince R. Nucleosides, Nucleotides, and Nucleic Acids 2002, 21: 665-80. Abstract
Metabolism of O6-Propyl and N6-Propyl-Carbovir in CEM Cells. Parker WB, Shaddix SC, Rose LM, Pham PT, Hua M, Vince R. Nucleosides, Nucleotides and Nucleic Acids 2000: 19, 795-804. Abstract
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