51V NMR spectroscopy is used to document, using speciation analysis, that one oxometalate is a more potent growth inhibitor of two Mycobacterial strains than other oxovanadates, thus demonstrating selectivity in its interaction with cells. Historically, oxometalates have had many applications in biological and medical studies, including study of the phase-problem in X-ray crystallography of the ribosome. The effect of different vanadate salts on the growth of Mycobacterium smegmatis (M. smeg) and Mycobacterium tuberculosis (M. tb) was investigated, and speciation was found to be critical for the observed growth inhibition. Specifically, the large orange-colored sodium decavanadate (V10O286-) anion was found to be a stronger inhibitor of growth of two mycobacterial species than the colorless oxovanadate prepared from sodium metavanadate. The vanadium(V) speciation in the growth media and conversion among species under growth conditions was monitored using 51V NMR spectroscopy and speciation calculations. The findings presented in this work is particularly important in considering the many applications of polyoxometalates in biological and medical studies, such as the investigation of the phase-problem in X-ray crystallography for the ribosome. The findings presented in this work investigate the interactions of oxometalates with other biological systems.

SMYD3 is a lysine methyltransferase that regulates the expression of over 80 genes and is required for the uncontrolled proliferation of most breast, colorectal, and hepatocellular carcinomas. The elimination of SMYD3 restores normal expression patterns of these genes and halts aberrant cell proliferation, making it a promising target for small molecule inhibition. In this study, we sought to establish a proof of concept for our in silico/in vitro hit-to-lead enzyme inhibitor development platform and to identify a lead small molecule candidate for SMYD3 inhibition. We used Schrodinger® software to screen libraries of small molecules in silico and the five compounds with the greatest predicted binding affinity within the SMYD3 binding pocket were purchased and assessed in vitro in direct binding assays and in breast cancer cell lines. We have confirmed the ability of one of these inhibitors, Inhibitor-4, to restore normal rates of cell proliferation, arrest the cell cycle, and induce apoptosis in breast cancer cells without affecting wildtype cell behavior. Our results provide a proof of concept for this fast and affordable small molecule hit-to-lead methodology as well as a promising candidate small molecule SMYD3 inhibitor for the treatment of human cancer.

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A major problem with patient treatments using anticancer compounds is accompanying bacterial infections, which makes more information on how such compounds impact bacterial growth desirable. In the following study, we investigated the growth effects of an anticancerous non-toxic Schiff base oxidovanadium(V) complex (N-(salicylideneaminato)-N′-(2-hydroxyethyl)ethane-1,2-diamine) coordinated to the 3,5-di-tert-butylcatecholato ligand on a representative bacterium, Mycobacterium smegmatis (M. smeg). We prepared the Schiff base V-complexes as reported previously and selected a few complexes to develop a V-complex series. Biological studies of M. smeg growth inhibition were complemented by spectroscopic studies using UV-Vis spectrophotometry and NMR spectroscopy to determine which complexes were intact under biologically relevant conditions. We specifically chose to examine (1) the growth effects of Schiff base oxidovanadium complexes coordinated to a catechol, (2) the growth effects of respective free catecholates on M. smeg, and (3) to identify complexes where the metal coordination complex was more potent than the ligand alone under biological conditions. Results from these studies showed that the observed effects of Schiff base V-catecholate complex are a combination of catechol properties including toxicity, hydrophobicity, and sterics.

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