New anticancer drugs derived from plant hormones
Research focused on the primary mechanism of action of plant hormones cytokinins (N6-substituted adenine derivatives) in cell division cycle has showed that natural plant cytokinins are also rather non-specific inhibitors of various protein kinases. Surprisingly, among aromatic cytokinin derivatives, we have discovered a compound, 2-(2-hydroxyethylamino)-6-benzylamino-9-methylpurine, named „olomoucine“ (OC), which specifically inhibits some cyclin-dependent kinases (CDKs) at micromolar concentration. The total lack of the inhibitory effect of olomoucine on major kinases, such as cAMP- and cGMP-dependent kinases, protein kinase C, and others, suggests that OC might be a useful tool for cell cycle regulation studies. Finally, we have tested olomoucine and related analogues on different tumour cell lines. The average OC concentration that causes 50% growth inhibition is 1–60.6µM. The design and inhibitory activity of OC was further improved by modifications at positions 2, 6, and 9. This led to discovery of novel specific CDK inhibitors named roscovitine, olomoucine II and purvalanol A, which display an enhanced inhibitory activity toward CDK1, a higher selectivity toward some CDKs, an increased antimitotic activity at the G1/S and G2/M points of the cell cycle, and stronger and more selective antitumour effects. The compounds are also effective in vivo and one of them is already in clinical trials in USA and Europe (roscovitine → Seliciclib®, Cyclacel Pharmaceuticals Ltd, U.K.). Seliciclib® is currently in Phase IIb clinical trials as a single therapy in multiple myeloma and also in patients with Non-Small Cell Lung Cancer in combination with gemcitabine and cisplatin. Recently, we also discovered unusual activity of natural brassinosteroids.
Acknowledgements: This work is supported Ministry of Education, Youth, and Sports of the Czech Republic (via grants MSM 6198959216 and GAČR 301/08/1649)