title: The biological activity of the histidine-containing diketopiperazines cyclo(His-Ala) and cyclo(His-Gly).
abstract: Two cyclic dipeptides, cyclo(His-Ala) and cyclo(His-Gly,) were synthesized from their linear counterparts and their structures elucidated using standard elucidation techniques. Molecular modeling and predictive NMR results indicated that the majority of energetically favourable conformers adopted a boat conformation with respect to the diketopiperazine ring. Cyclo(His-Ala), at concentrations of 100 microM inhibited the growth, in vitro, of various cancer cell lines, including HT-29, MCF-7 and HeLa carcinoma cells while cyclo(His-Gly) inhibited the growth of MCF-7 cells. While the antibacterial potential of these two compounds was limited, both cyclic dipeptides significantly inhibited the growth of C. albicans. Both compounds at a concentration of 100 microM resulted in a decrease in heart rate, coronary flow rate and left ventricular systolic pressure in the isolated rat heart. Inhibition of thrombin, amounting to a 63.3% and 36.7% reduction in the rate of fibrin formation, was noted for cyclo(His-Ala) and cyclo(His-Gly), respectively. While cyclo(His-Ala) showed no notable effects on platelet aggregation, cyclo(His-Gly) significantly inhibited both pathways tested with greatest effects on thrombin-induced platelet aggregation, yielding an IC(50) of 0.0662 mM (R(2)=0.989). The results of the anticancer and hematological studies indicate that histidine-containing diketopiperazines have potential as a novel group of cytotoxic agents with antithrombotic effects.
authors.affiliation: Cyclic Peptide Research Unit, Department of Pharmacy, Box 77000, Nelson Mandela Metropolitan University, Port Elizabeth 6031, South Africa. flucietto@yahoo.co.uk
authors.forename: F R
authors.initials: FR
authors.lastname: Lucietto
authors.forename: P J
authors.initials: PJ
authors.lastname: Milne
authors.forename: G
authors.initials: G
authors.lastname: Kilian
authors.forename: C L
authors.initials: CL
authors.lastname: Frost
authors.forename: M
authors.initials: M
authors.lastname: Van De Venter
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D054659:Diketopiperazines; D004354:Drug Screening Assays, Antitumor; D006339:Heart Rate / Q000187:drug effects; D006639:Histidine / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D015394:Molecular Structure; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010974:Platelet Aggregation / Q000187:drug effects; D013917:Thrombin / Q000187:drug effects
chemical_list: D000900:Anti-Bacterial Agents; D054659:Diketopiperazines; D010456:Peptides, Cyclic; D010879:Piperazines; D006639:Histidine; D013917:Thrombin