During the last decade a series of benzothiazole derivatives based on the two lead compounds 2-(4-aminophenyl)benzothiazole and 4-(benzothiazol-2-yl)-4-hydroxy-2,5-cyclohexadien-1-one have been under rapid development as anti-tumor, antimicrobial, and antifungal agents and as radiopharmaceuticals for binding and in vivo imaging of A?-plaques, one of the earliest pathological processes in the development of Alzheimer's disease. Research on the mechanism of action of these compounds has lagged, and the reasons for their biological activity are not well understood. It is our hypothesis that the anti-tumor activity of these compounds is due to their conversion, by a series of metabolic and chemical reactions, into selective, electrophilic nitrenium or oxenium ions. This project will test of the ability of putative metabolites of the two lead benzothiazoles to generate reactive cations, and provide an evaluation of the ability of these ions to react with critical cellular nucleophiles. Selected ring substituted derivatives will also be examined to determine the effect of substituents on the chemistry of these compounds.
The specific aims of this proposal are: 1. To synthesize putative metabolites of the benzothiazoles, and to test the ability of these compounds to generate the reactive cations in aqueous solution. Kinetic analysis of the decomposition of the target compounds in aqueous media and trapping experiments with small anionic nucleophiles including N3- and Br- will be used to evaluate the hypothesis. Other reactions of these cations that may generate radical intermediates will also be examined. 2. To synthesize and test photoprecursors of the cations for use in mechanistic studies. Photo-generation may make it possible to directly detect and characterize the cations by fast spectroscopic methods after laser flash photolysis, and may make subsequent studies of these cations easier. 3. To study the reaction of the cations with cellular nucleophiles, particularly guanosine, which is known to be the main biological target of nitrenium ions derived from carcinogenic aromatic amines, and glutathione, which modulates the activity of the thiazole drug candidates. These studies will determine if the reactive intermediates are sufficiently selective to account for the biological activity of the drug candidates. 4. To examine the effects that ring substitution has on the chemistry of the putative metabolites. Ring substitution patterns that have been examined in drug candidates will be examined for their effects on the reactivity and selectivity of the reactive electrophilic cations by N3- trapping. Correlations between cation reactivity and biological endpoints will be examined. These studies will show to what extent the chemistry of the reactive cations governs the biological activity of the benzothiazole drug candidates.
Benzothiazole derivatives are being rapidly developed as anti-tumor, antimicrobial and antifungal agents, and also as radiopharmaceuticals for in vivo imaging of the plaques that are early indicators of Alzheimer's disease. Little is known of the chemistry of the metabolites of these compounds. This proposed study of the chemistry of these metabolites will make it possible to understand how these compounds function in their biological roles and may ultimately lead to the design of better drug candidates.
| Zhang, Yang; Chakraborty, Mrinal; Cerda-Smith, Christian G et al. (2013) Chemistry of ring-substituted 4-(benzothiazol-2-yl)phenylnitrenium ions from antitumor 2-(4-aminophenyl)benzothiazoles. J Org Chem 78:6992-7000 |
| Chakraborty, Mrinal; Jin, Kyoung Joo; Glover, Stephen A et al. (2010) Characterization of the 4-(benzothiazol-2-yl)phenylnitrenium ion from a putative metabolite of a model antitumor drug. J Org Chem 75:5296-304 |
| Chakraborty, Mrinal; Jin, Kyoung Joo; Brewer 3rd, Samuel C et al. (2009) Indirect and direct detection of the 4-(benzothiazol-2-yl)phenylnitrenium ion from a putative metabolite of a model anti-tumor drug. Org Lett 11:4862-5 |
