Biological activity of selected tyrosine-containing 2,5-diketopiperazines
Kilian, G.; Jamie, H.; Brauns, S.C.A.; Dyason, K.; Milne, P.J.
Die Pharmazie 60(4): 305-309
2005
ISSN/ISBN: 0031-7144 PMID: 15881613 Document Number: 592423
The study investigates two cyclic dipeptides, cyclo(Tyr-Tyr) (cTT) and cyclo(Phe-Tyr) (cPT) with respect to their biological activity. Investigations using the whole-cell patch-clamp technique testing the effects of 100 mu M cyclic dipeptide on ion channels, revealed reversible voltage-dependant blockade for cTT, while cPT exhibited irreversible time-dependant blockade of L-type calcium channels. The isolated retrogradely-perfused rat heart was used to determine the effects of 100 mu M of either cTT or cPT on heart rate (HR), coronary flow rate (CFR), left ventricular systolic pressure (LVSP) and cardiac conduction speed. Results indicated opposing effects for the two compounds, where cTT increased HR and CF while cPT decreased HR, CF, LVSP as well as conduction speed. Other biological investigations included opioid binding and anti-neoplastic assays. Competitive binding curves, using tritiated DAMGO, revealed significant binding to mu-opioid receptors with IC50 values for cTT and cPT being 0.82 mu M and 69.7 mu M respectively. Anti-neoplastic activity was tested using three cultured cell lines: HT-29, MCF-7 and HeLa which were exposed to 2.5 mM cyclic dipeptide or 0.1 mM melphalan as a positive control. While cTT showed little activity against these lines, cPT resulted in as much as a 75.6% growth inhibition of MCF-7 cells, while also being active against HeLa (73.4% inhibition) and HT-29 (60.6%). The results indicate potential biological activity, showing a need for more investigation into tyrosine containing cyclic dipeptides and their analogues as potential bioactive compounds.