Messing with microtubules

ATLANTA—Because of their pivotal role in so many cell growth functions, microtubules are popular targets for anti-cancer drugs. Unfortunately, drug resistance and toxicity can be significant problems. With this in mind, researchers at Emory University School of Medicine, the Indian Institute of Technology-Bombay, and the University of Delhi recently developed a series of halogenated analogs of the low-toxicity microtubule-binding drug noscapine.

They presented their work in Biochemical Pharmacology.

Initially, the researchers had to overcome the challenges of halogenating the aromatic constituents of noscapine, and were able to develop methods that offered high yields under mild conditions necessary for the easily hydrolysable noscapine. They then tested the new compounds for the ability to bind tubulin. Using spectrophotometry, the researchers found that each of the analogues exhibited higher affinities than noscapine. Furthermore, they noted that each of the compounds had higher antiproliferative activity in human cancer cell lines than the original compound, and the bromoderivative was 40-fold more active.

They then used fluorescence-activated cell sorting (FACS) to monitor at what stage the compounds halted cell cycling and whether the analogues had apoptotic activity. They found that the fluorinated, chlorinated and brominated derivatives each induced accumulation at the G₂/M phase of the cell cycle. And using FACS and confocal microscopy, the researchers noted signs indicative of apoptosis. The researchers suggest that the results warrant further preclinical and clinical testing of the analogues.