ABSTRACT
Fluorescent chemosensors offer a direct means of measuring enzyme activity for cancer diagnosis, predicting drug resistance, and aiding in the discovery of new anticancer drugs. O6-methylguanine DNA methyltransferase (MGMT) is a predictor of resistance towards anticancer alkylating agents such as temozolomide. Using the fluorescent molecular rotor, 9-(2-carboxy-2-cyanovinyl)julolidine (CCVJ), we synthesized, and evaluated a MGMT fluorescent chemosensor derived from a chloromethyl-triazole covalent inhibitor, AA-CW236, a non-pseudosubstrate of MGMT. Our fluorescence probe covalently labelled the MGMT active site C145, producing a 18-fold increase in fluorescence. Compared to previous fluorescent probes derived from a substrate-based inhibitor, our probe had improved binding and reaction rate. Overall, our chloromethyl triazole-based fluorescence MGMT probe is a promising tool for measuring MGMT activity to predict temozolomide resistance.
Subject(s)
Antineoplastic Agents , Guanine/analogs & derivatives , Temozolomide , O(6)-Methylguanine-DNA Methyltransferase/genetics , DNA , Antineoplastic Agents, Alkylating/pharmacologyABSTRACT
It is well established that aberrant cellular biochemical activity is strongly linked to the formation and progression of various cancers. Assays that could aid in cancer diagnostics, assessing anticancer drug resistance, and in the discovery of new anticancer drugs are highly warranted. In recent years, a large number of small molecule-based fluorescent chemosensors have been developed for monitoring the activity of enzymes and small biomolecular constituents. These probes have shown several advantages over traditional methods, such as the ability to directly and selectively measure activity of their targets within complex cellular environments. This review will summarize recently developed fluorescent chemosensors that have potential applications in the field of cancer biology.
