The Development of Small Molecule Inhibitors of Pathogenic Pathways
The development of small molecule inhibitors of pathogenic pathways: Small molecules that block critical pathways can slow both viral replication and the spread of cancer. For example, we have shown that thoughtfully designed sulfones can serve as non-hydrolizable surrogates of phosphates. Aromatic vinyl sulfones have been developed as potent inhibitors of HIV integrase, an enzyme that integrates viral DNA into host DNA. By inhibiting this process, viral replication is slowed. Applying this same chemical technology to the synthesis of sugar nucleotide analogs has led to inhibitors of enzymes that are critical for the expression of cell surface polysaccharides that are highly correlated with tumor metastasis.
a. Meadows, D.C., T.B. Mathews, T.W. North, M.J. Hadd, C.L. Kuo, N. Neamati, and J. Gervay-Hague. Synthesis and Biological Evaluation of Geminal Disulfones as HIV-1 Integrase Inhibitors. J. Medicinal Chem. 2005, 48: 4526-4534. DOI: 10.1021/jm049171v
b. Meadows, D.C., T. Sanchez, N. Neamati, T.W. North, J. Gervay- Hague. Ring substituent effects on biological activity of vinyl sulfones as inhibitors of HIV-1. Bioorganic & Medicinal Chemistry Letters. 2007, 15(2): 1127-37. DOI:10.1016/j.bmc.2006.10.017
c. Duong, Y.T., D.C. Meadows, I.K. Srivastava, J. Gervay-Hague, T.W. North. Direct inactivation of human immunodeficiency virus type 1 by a novel small-molecule entry inhibitor, DCM205. Antimicrobial Agents and Chemotherapy. 2007, 51(5): 1780-6. DOI:10.1128/AAC.01001-06
d. Wong, J. H., U. Sahni, Y. Li, X. Chen, and J. Gervay-Hague. “Synthesis of Sulfone-based Nucleotide Isosteres: Identification of CMP-Sialic Acid Synthetase Inhibitors” Organic and Biomolecular Chemistry, First published as an Advance Article on the web 17th November 2008. DOI: 10.1039/B819155G