title: Biological activity of selected tyrosine-containing 2,5-diketopiperazines.
abstract: 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 microM 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 microM 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 micro-opioid receptors with IC50 values for cTT and cPT being 0.82 microM and 69.7 microM 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.
authors.affiliation: Cyclic Dipeptide Research Unit, University of Port Elizabeth, South Africa.
authors.forename: G
authors.initials: G
authors.lastname: Kilian
authors.forename: H
authors.initials: H
authors.lastname: Jamie
authors.forename: S C A
authors.initials: SC
authors.lastname: Brauns
authors.forename: K
authors.initials: K
authors.lastname: Dyason
authors.forename: P J
authors.initials: PJ
authors.lastname: Milne
mesh_terms: D000465:Algorithms; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D001667:Binding, Competitive / Q000187:drug effects; D001923:Brain Chemistry / Q000187:drug effects; D015220:Calcium Channels / Q000187:drug effects; D002317:Cardiovascular Agents / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D045744:Cell Line, Tumor; D003326:Coronary Circulation / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D004354:Drug Screening Assays, Antitumor; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / Q000378:metabolism; D006321:Heart / Q000187:drug effects; D006329:Heart Conduction System / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D018408:Patch-Clamp Techniques; D010879:Piperazines / Q000138:chemical synthesis* / Q000494:pharmacology*; D015221:Potassium Channels / Q000187:drug effects; D051381:Rats; D020318:Rats, Long-Evans; D017450:Receptors, Opioid, mu / Q000187:drug effects / Q000378:metabolism; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D015220:Calcium Channels; D002317:Cardiovascular Agents; D010879:Piperazines; D015221:Potassium Channels; D017450:Receptors, Opioid, mu; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D014443:Tyrosine