An investigation into the biological activity of the selected histidine-containing diketopiperazines cyclo(His-Phe) and cyclo(His-Tyr).

Although cyclic diketopiperazines have been known since the beginning of the century, only now have they attracted considerable interest with respect to their biological activity. The aim of this study was to determine if the diketopiperazines cyclo(L-histidyl-L-phenylalanyl) (cyclo(His-Phe)) and cyclo(L-histidyl-L-tyrosyl) (cyclo(His-Tyr)) have significant biological activity relevant to the treatment of cardiovascular-related disease states, cancer and infectious diseases. Haematological studies were performed, including thrombin substrate binding, blood clotting time, platelet adhesion, platelet aggregation and fibrinolysis assays. A cytotoxicity screening utilizing a tetrazolium-based assay on the cell lines HeLa, WHCO3, and MCF-7 was performed. The whole-cell patch-clamp technique was used to investigate ion-channel activity in ventricular myocytes of rats, and isolated rat heart studies were performed to investigate the cardiac effects involving heart rate and coronary flow rate. Cyclo(His-Tyr) produced a significant prolongation of blood clotting time, slowing of clot lysis and inhibition of ADP-induced platelet adhesion and aggregation (P < 0.05). Cyclo(His-Phe) showed significant (P < 0.05) anti-tumour activity, causing greatest reduction of cell viability in cervical carcinoma cells. Preliminary results from patch-clamp studies indicate that both diketopiperazines caused blocking of sodium and calcium ion channels, but opening of inward rectifying potassium ion channels. In the rat isolated heart studies, cyclo(His-Phe) caused a gradual reduction in heart rate (P = 0.0027) and a decrease in coronary flow rate (P = 0.0017). Cyclo(His-Tyr) significantly increased the heart rate (P = 0.0016) but did not cause any significant change of coronary flow rate (P > 0.05). Cyclo(His-Tyr) showed notable (P < 0.05) antibacterial activity and both diketopiperazines showed excellent antifungal activity (P < 0.05). These observations reveal diketopiperazines to be ideal lead compounds for the rational design of an agent capable of preventing metastasis, inhibiting tumour growth, and as potential chemotherapeutic, antiarrhythmic and antihypertensive agents, as well as potential antibacterial and antifungal agents.
AuthorsK McCleland, P J Milne, F R Lucieto, C Frost, S C Brauns, M Van De Venter, J Du Plessis, K Dyason
JournalThe Journal of pharmacy and pharmacology (J Pharm Pharmacol) Vol. 56 Issue 9 Pg. 1143-53 (Sep 2004) ISSN: 0022-3573 [Print] England
PMID15324483 (Publication Type: Comparative Study, Journal Article, Research Support, U.S. Gov't, Non-P.H.S.)
Chemical References
  • Diketopiperazines
  • Dipeptides
  • Piperazines
  • histidylphenylalanine
  • Histidine
  • Animals
  • Cell Line, Tumor
  • Diketopiperazines
  • Dipeptides (chemistry, pharmacology)
  • HeLa Cells
  • Heart Rate (drug effects, physiology)
  • Histidine (chemistry, pharmacology)
  • Humans
  • In Vitro Techniques
  • Male
  • Microbial Sensitivity Tests (statistics & numerical data)
  • Myocytes, Cardiac (drug effects, physiology)
  • Piperazines (chemistry, pharmacology)
  • Rats
  • Rats, Long-Evans
  • Rats, Sprague-Dawley

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