A chloromethyl-triazole fluorescent chemosensor for O6-methylguanine DNA methyltransferase.

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.

Beyond ribose and phosphate: Selected nucleic acid modifications for structure-function investigations and therapeutic applications.

Over the past 25 years, the acceleration of achievements in the development of oligonucleotide-based therapeutics has resulted in numerous new drugs making it to the market for the treatment of various diseases. Oligonucleotides with alterations to their scaffold, prepared with modified nucleosides and solid-phase synthesis, have yielded molecules with interesting biophysical properties that bind to their targets and are tolerated by the cellular machinery to elicit a therapeutic outcome. Structural techniques, such as crystallography, have provided insights to rationalize numerous properties including binding affinity, nuclease stability, and trends observed in the gene silencing. In this review, we discuss the chemistry, biophysical, and structural properties of a number of chemically modified oligonucleotides that have been explored for gene silencing.