“No society can surely be flourishing and happy, of which the far greater part of the members are poor and miserable.” Adam Smith
I have a BS in electrical engineering from the University of Michigan and worked in multiple roles at AT&T wireless from 1995-2007. In 2010 I matriculated to the MD/PhD program at WSU to pursue a career as a physician scientist. I intend to perform my residency in pathology and would like to focus my research on development of assays to identify disease states rapidly and efficiently. Currently, I have been contemplating the efficiency of graduate education, public funding of research and healthcare administration and am considering attempting to integrate these interests into my career.
Investigating the Mechanism of Isatin Cytotoxicity
Isatin has been identified in a diverse range of organisms, including microorganism, plants, invertebrates and vertebrates. In the species that have been investigated, the biosynthesis, metabolism and biological role of isatin is not fully understood. Over the past 40 years, one of the most studied biological roles of isatin is the ability of exogenous isatin to exhibit cytotoxic effects in multiple cancer cell lines, bacteria, fungi, algae and protozoa. To date, the mechanism of cytotoxicity is unknown.
In de novo purine biosynthesis, microbes convert the intermediate AIR (5-aminoimidazole ribonucleotide) to CAIR (4-carboxy-5-aminoimidazole ribonucleotide) via two enzymes – N5-CAIR synthetase and N5-CAIR mutase, while vertebrates utilize one enzyme, AIR carboxylase. A HTS identified compounds with an isatin (indole-2,3-dione) core as potential inhibitors of the microbial enzyme N5-CAIR synthetase. Investigation into the mechanism of inhibition suggests that the substrate, AIR, reacts with isatin in a reversible manner based on the following evidence. (1) Inhibition of the enzymatic assay is time dependent and is correlated to the incubation of the substrate with the inhibitor. (2) Inhibition of bromo isatins correlate with the reaction rates of bromo isatins with model 5-amino diazoles. (3) The products of methyl-isatin reacted with the model 5-amino diazoles have been characterized and exhibit a unique carbon-carbon reaction between isatin and the model 5-amino diazoles.
Prior research and the above findings provide the following hypothesis into the mechanism of action of isatin cytotoxicity: Isatin reacts with the de novo purine intermediate AIR and disrupts purine biosynthesis resulting in cytotoxicity. Further understanding of the mechanism of action will be useful to investigators pursuing isatin and istatin analogs as an anti-cancer agent.