Microtubule-Destabilising Actions of Piperlongumine and Analogues

Piperlongumine is a natural amide alkaloid isolated from the plant species Piper longum L. It is known to be cytotoxic^[1] and has been reported to selectively kill cancer cells by targeting the stress response to reactive oxygen species (ROS).^[2] The use of small molecules to target cancer by altering cell levels of ROS is emerging area of research and there is huge potential for further exploration in this area.^[3]

Piperlongumine is structurally similar to a number of microtubule-destabilizing agents, including combretastatin A-4 and related chalcones. This project focuses on the effects of piperlongumine on tubulin, a protein that is the main constituent of microtubules. The synthesis of analogues of piperlongumine was carried out to establish a structure-activity relationship for microtubule-destabilizing activity. The novel compounds were screened for their antiproliferative effects in breast cancer cells and normal breast cells. The effect of the piperlongumine analogues on ROS levels was also investigated.

References:

[1]          Bezerra, D. P.; Militao, G. C. G.; de Castro, F. O.; Pessoa, C.; de Moraes, M. O.; Silveira, E. R.; Lima, M. A. S.; Elmiro, F. J. M.; Costa-Lotufo, L. V.,  Toxicology in Vitro 2007, 21, 1-8.

[2]          Raj, L.; Ide, T.; Gurkar, A. U.; Foley, M.; Schenone, M.; Li, X.; Tolliday, N. J.; Golub, T. R.; Carr, S. A.; Shamji, A. F.; Stern, A. M.; Mandinova, A.; Schreiber, S. L.; Lee, S. W., Nature 2011, 475, 231-234.

[3]          Schumacker, P. T., Cancer cell 2006, 10, 175-176.