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PubMed1996

Novel mammalian cell cycle inhibitors, tryprostatins A, B and other diketopiperazines produced by Aspergillus fumigatus. II. Physico-chemical properties and structures.

Two novel diketopiperazines named tryprostatins A and B and a new natural product belonging to the diketopiperazine series, designated as demethoxyfumitremorgin C, together with four known diketopiperazines, fumitremorgin C, 12,13-dihydroxyfumitremorgin C, fumitremorgin B and verruculogen, are new M phase inhibitors of the mammalian cell cycle, which were isolated from the secondary metabolites of Aspergillus fumigatus. The structures of tryprostatins A, B and demethoxyfumitremorgin C were determined mainly by the use of spectroscopic methods especially by detailed analyses of their 1H and 13C NMR spectra with the aid of 2D NMR techniques including pulse field gradient heteronuclear multiple-bond correlation (PFG-HMBC) spectroscopy. Their absolute configurations were determined on the basis of the optical rotational values and CD spectra.

Aspergillus fumigatus↗
PubMed1986

Increased excretion of histidyl-L-proline diketopiperazine by infants receiving Pregestimil and Nutramigen formulas.

Histidyl-L-proline diketopiperazine is excreted in increased amounts by infants receiving Nutramigen or Pregestimil. When these formulas are discontinued, its excretion becomes undetectable. The compound was isolated from Nutramigen and Pregestimil, as well as from the urine of the infants receiving these formulas, and was identified by comparison with authentic histidyl-L-proline diketopiperazine standard in various chromatographic and electrophoretic systems. A neuropeptide widely distributed in the brain and gut and having a variety of biological functions, histidyl-L-proline diketopiperazine may have as-yet-undetermined effects on infants who are receiving these formulas.

Electrophoresis↗
PubMed1996

Novel CCK-B receptor agonists: diketopiperazine analogues derived for CCK4 bioactive conformation.

Recently, we proposed a CCK-B agonist bioactive conformation characterized by an 'S' shape of the peptidic backbone which was derived from structure-activity relationships and conformational analysis of CCK4 (Trp-Met-Asp-Phe-NH2) analogues. Using this template, we report here the synthesis of cyclic CCK4 analogues which contain, in place of the Trp-Met dipeptide, a diketopiperazine moiety resulting from a cyclization between Nle and N-substituted (D)Trp residues and coupled with a small linker to Asp-Phe-NH2. Some of these compounds displayed good affinities and selectivities for the CCK-B receptor. The results are discussed in terms of size, hydrophobicity and spatial orientation of the side-chains on the diketopiperazine ring. The most potent ligand exhibited potent and full CCK-B receptor agonist properties in promoting the hydrolysis of inositol phosphates (EC50 = 8 nM) in CHO cells, stably transfected with the rat brain CCK-B receptor. This compound was also shown to be a potent selective CCK-B/gastrin receptor agonist since, it increased gastric acid secretion measured in anesthetized rats on i.v. administration. These compounds provide a rigid template for the design of non-peptide CCK-B agonists, by modification of the remaining peptide moiety.

Animals↗
PubMed1993

Peptide-urea interactions as observed in diketopiperazine-urea cocrystal.

In order to develop a more complete understanding of urea induced protein denaturation we have investigated the crystal structure of urea with the cyclic dipeptide diketopiperazine. This structure, determined to an R factor of 8.1%, shows extensive hydrogen bonding between urea and the peptide groups of diketopiperazine. These studies support a model where hydrogen bonding plays an important contribution in urea-induced protein denaturation. In the companion paper we present thermodynamic data for urea-peptide interactions in aqueous solution that further support this model.

Crystallization↗
PubMed2006

The biological activity of the histidine-containing diketopiperazines cyclo(His-Ala) and cyclo(His-Gly).

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.

Animals↗
PubMed2000

Identification of proline-based diketopiperazines in roasted coffee.

Five proline-based diketopiperazines were identified in water extracts of roasted coffee proteins and roasted coffee itself. These are cyclo(pro-ile), cyclo(pro-leu), cyclo(pro-phe), cyclo(pro-pro), and cyclo(pro-val). The isolation included gel chromatography and solvent (CHCl(3)) extraction; in the case of roasted coffee brews, polyamide column chromatography was also used. The identification was achieved by LC-ESI-MS and -MS/MS by comparison of the retention time and the fragmentation pattern with reference compounds. As a second method GC-EI-MS was used. By both methods the presence of diketopiperazines in roasted coffee was unambiguously verified.

Coffee↗
PubMed1997

Design, synthesis, and dopamine receptor modulating activity of diketopiperazine peptidomimetics of L-prolyl-L-leucylglycinamide.

The diketopiperazine "C5" conformational mimic has been incorporated into the L-prolyl-L-leucylglycinamide (PLG, 1) structure and into the bicyclic lactam PLG peptidomimetic structure 3 to give compounds 5 and 6, respectively. These analogues were designed to explore the idea that the N-terminal "C5" conformation, which was found in the crystal structure of 2 and which was mimicked in 4 by the diketopiperazine function, was a factor in the high potency of these two agents. Through the use of the [3H]spiroperidol/N-propylnorapomorphine (NPA) D2 receptor competitive binding assay, both 5 and 6 were found to increase the affinity of the dopamine receptor for agonists and both were found to increase the percentage of D2 receptors which existed in the high-affinity state. These effects were observed when Gpp(NH)p was either absent or present, and they were analogous to the effects observed previously for PLG and the PLG peptidomimetics 2 and 4. However, the potency seen with 5 and 6 was less than that seen for 2 and 4, suggesting that while the N-terminal "C5" conformation may play a role in the potency of the gamma-lactam peptidomimetics of PLG, it does not appear to be the primary factor. In the 6-hydroxydopamine-lesioned animal model of Parkinson's disease, 5 altered apomorphine-induced rotational behavior in a dose-dependent manner. The maximum effect occurred at a dose of 0.01 mg/kg i.p. and resulted in a 52.27 +/- 13.96% (p < 0.001, n = 7) increase in rotations compared to apomorphine administered alone.

Animals↗
PubMed2006

Convergent synthesis of complex diketopiperazines derived from pipecolic acid scaffolds and parallel screening against GPCR targets.

A convergent approach to highly functionalized diketopiperazines (DKPs) using enantioenriched pipecolic acids is described. Scandium triflate-catalyzed [4 + 2] aza-annulation was employed to produce stereochemically well-defined building blocks. A resin "catch and release" strategy was devised to convert annulation products to pipecolic acid monomers. Complex diketopiperazines were efficiently assembled utilizing one-pot cyclodimerization of pipecolic acids. Massively parallel screening of the complex DKPs against a panel of molecular targets identified novel ligands for a number of G-protein-coupled receptors (GPCRs).

Aza Compounds↗
PubMed1997

Opioid diketopiperazines: refinement of the delta opioid antagonist pharmacophore.

Bioactive models for a delta opioid receptor antagonist are proposed based on the structurally rigid, diketopiperazine containing cyclo 2',6'-dimethyl-L-tyrosyl (Dmt)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (Tic). Monte Carlo conformational analysis of c(Dmt-Tic) generated three low energy clusters (I-III) of conformers. The lowest energy conformer representing cluster I superimposed best with the X-ray crystal structures of c(Tyr-Tic), an inactive diketopiperazine with similar framework as c(Dmt-Tic), with H-Tyr-Tic-NH2, a dipeptide of moderate delta opioid affinity and lacking bioactivity, and with H-Tyr-Tic-Phe-Phe-OH (TIPP), a selective and potent delta opioid receptor antagonist. Clusters I and II superimposed best with three different overlays of naltrindole, a potent delta opiate antagonist, and with two other H-Tyr-Tic-NH delta opioid antagonist pharmacophores proposed by Temussi et al. (1994) and Wilkes and Schiller (1995). The 3-dimensional topography of these two clusters of c(Dmt-Tic) conformations may represent bioactive models for interaction of an antagonist at delta opioid receptors. Cluster I conformers exhibited gauche- (- 64 degrees) and gauche+ (53 degrees) orientations of the side chains Dmt and Tic, respectively, while cluster II contained trans (179 degrees) and gauche+ (62 degrees) orientations of those side-chains. Aromatic ring distances were 5.4 A for cluster I conformations and 8.2 A for cluster II structures. Orientation about the peptide bond N-C' was cis (- 5 degrees and 3 degrees) for both clusters, respectively. These structural features may provide optimal alignment of the physicochemical moieties important for delta opioid receptor interaction, such as the hydrophobic methyl groups of Dmt, hydrogen bonding of the dimethyltyrosine hydroxyl group within the receptor pocket and cation-pi interactions involving the aromatic rings of Dmt and Tic, as profiled by the three point attachment hypothesis.

Diketopiperazines↗
PubMed1990

Diketopiperazine-mediated peptide formation in aqueous solution.

Though diketopiperazines (DKP) are formed in most experiments concerning the prebiotic peptide formation, the molecules have not been paid attention in the studies of chemical evolution. We have found that triglycine, tetraglycine or pentaglycine are formed in aqueous solution of glycine anhydride (DKP) and glycine, diglycine or triglycine, respectively. A reaction of alanine with DKP resulted in the formation of glycylglycylalanine under the same conditions. These results indicate that the formation of the peptide bonds proceeds through the nucleophilic attack of an amino group of the amino acids or the oligoglycines on the DKP accompanied by the ring-opening. The formation of glycine anhydride, di-, tri- and tetraglycine was also observed in a mixed aqueous solution of urea and glycine in an open system to allow the evaporation of ammonia. A probable pathway is proposed for prebiotic peptide formation through diketopiperazine on the primitive Earth.

Amino Acid Sequence↗
PubMed1998

Cellular origin of chlorinated diketopiperazines in the dictyoceratid sponge Dysidea herbacea (Keller).

The tropical marine sponge Dysidea herbacea (Keller) contains the filamentous unicellular cyanobacterium Oscillatoria spongeliae (Schulze) Hauck as an endosymbiont, plus numerous bacteria, both intracellular and extracellular. Archaeocytes and choanocytes are the major sponge cell types present. Density gradient centrifugation of glutaraldehyde-fixed cells with Percoll as the support medium has been used to separate the cyanobacterial symbiont from the sponge cells on the basis of their differing densities. The protocol also has the advantage of separating broken from intact cells of O. spongeliae. The lighter cell preparations contain archaeocytes and choanocytes together with damaged cyanobacterial cells, whereas heavier cell preparations contain intact cyanobacterial cells, with less than 1% contamination by sponge cells. Gas chromatography/mass spectrometry analysis has revealed that the terpene spirodysin is concentrated in preparations containing archaeocytes and choanocytes, whereas nuclear magnetic resonance analysis of the symbiont cell preparations has shown that they usually contain the chlorinated diketopiperazines, dihydrodysamide C and didechlorodihydrodysamide C, which are the characteristic metabolites of the sponge/symbiont association. However, one symbiont preparation, partitioned by a second Percoll gradient, has been found to be devoid of chlorinated diketopiperazines. The capability to synthesize secondary metabolites may depend on the physiological state of the symbiont; alternatively, there may be two closely related cyanobacterial strains within the sponge tissue.

Animals↗
PubMed1981

Histidyl-proline diketopiperazine decreases food intake in rats.

Histidyl-proline diketopiperazine was found to suppress food intake during stress-induced eating (10(-6)--10(-8) mol), starvation-induced eating (10(-8) mol) and over an 8 h period of spontaneous eating (10(-8) mol). In contrast, other cyclic piperazines failed to alter food ingestion. The suppressive effect of histidyl-proline diketopiperazine was antagonized by the enkephalin analogue, D-Ala-Met-enkephalin, in equimolar concentrations.

Animals↗
PubMed1987

Plasma and urine diketopiperazine concentrations in normal adults ingesting large quantities of aspartame.

In aqueous solution, aspartame can cyclicize to form its corresponding diketopiperazine (3-carboxymethyl-6-benzyl-2,5-diketopiperazine; DKP) and methanol. We measured plasma and urinary concentrations of DKP in samples obtained from six normal adult subjects ingesting 2.2 mg DKP/kg body weight. The DKP was administered as part of a dose of 200 mg aspartame/kg body weight. DKP concentrations in plasma were below the detection limit (less than 1 microgram/ml) of the high-pressure liquid chromatographic method at each time interval after ingestion at which they were measured. Mean (+/- SD) total urinary DKP excreted during the first 24-hr period after dosing was 6.68 +/- 1.30 mg (4.83 +/- 0.23% of the ingested DKP dose). Approximately 44% of the total DKP excreted was excreted in the first 4 hr after dosing.

Adult↗
PubMed1981

TRH and histidyl-proline diketopiperazine inhibit cholesterol synthesis in dog intestine.

Low concentrations of thyrotropin-releasing hormone and one of its metabolites, histidyl-proline diketopiperazine, are shown to have an inhibitory effect on the activation of 3-hydroxy-3-methylglutaryl coenzyme A reductase which occurs during organ culture of canine intestinal mucosa. Somatostatin and vasoactive intestinal polypeptide, in contrast, are shown to have no effect. Thyrotropin-releasing hormone, recently shown to be present in gut mucosa, may be a physiological regulator of intestinal cholesterol synthesis. Histidyl-proline diketopiperazine, an active metabolite of the hormone, is possibly the active agent since its inhibitory effect was observed at a concentration as low as 10(-12) M. These observations demonstrate an effect on intestinal metabolism by a neurotransmitter-like hormone at potentially physiologic concentrations.

Animals↗
PubMedDate not supplied

Microwave-assisted solid-phase synthesis of 2,5-diketopiperazines: solvent and resin dependence.

Solid-phase synthesis of diketopiperazines (DKPs) was preformed using various combinations of resins (polystyrene, TentaGel, ArgoGel, and PEGA) and solvents (toluene, tert-butyl alcohol, water, and toluene/2-butanol (1:4, v/v). The DKPs were synthesized from solid-phase bound dipeptides via intramolecular aminolysis. Both thermal and microwave-assisted solid-phase synthesis of DKPs gave high yields of products independently of resin and organic solvent used; however, only the PEGA resin resulted in high yields of DKPs in water independent of heating method. The short reaction times, high yields, and the possibility to run reactions in water when an appropriate resin is used makes the microwave-assisted solid-phase synthesis the method of choice. The method should be suitable for solid-phase synthesis of diketopiperazine-based libraries.

Combinatorial Chemistry Techniques↗
PubMed2005

2,5-diketopiperazines as potent, selective, and orally bioavailable oxytocin antagonists. 2. Synthesis, chirality, and pharmacokinetics.

A short stereoselective synthesis of a series of chiral 7-aryl-2,5-diketopiperazines oxytocin antagonists is described. Varying the functionality and substitution pattern of substituents in the 7-aryl ring and varying the chirality of this exocyclic ring have produced potent oxytocin antagonists (pK(i) > 8.5). SAR and pharmacokinetic profiling of this series of (3R,6R,7R)-2,5-diketopiperazines together with the introduction of an ortho F group in the 7-aryl ring to improve rat pK has culminated in the 2',4'-difluorophenyldiketopiperazine derivative 37, a highly potent oxytocin antagonist against the human oxytocin receptor (pK(i) = 8.9) that has >1000-fold selectivity over all three vasopressin receptors V1a, V2, and V1b. It has good bioavailability (46%) in the rat and moderate bioavailability (13-31%) in the dog and is more active in vivo in the rat than atosiban (rat DR(10) = 0.44 mg/kg iv).

Administration, Oral↗
PubMed2006

2,5-diketopiperazines as potent, selective, and orally bioavailable oxytocin antagonists. 3. Synthesis, pharmacokinetics, and in vivo potency.

A short, efficient, and highly stereoselective synthesis of a series of (3R,6R,7R)-2,5-diketopiperazine oxytocin antagonists and their pharmacokinetics in rat and dog is described. Prediction of the estimated human oral absorption (EHOA) using measured lipophilicity (CHI log D) and calculated size (cMR) has allowed us to rank various 2,5-diketopiperazine templates and enabled us to focus effort on those templates with the greatest chance of high bioavailability in humans. This rapidly led to the 2',4'-difluorophenyl-dimethylamide 25 and the benzofuran 4 with high levels of potency (pK(i)) and good bioavailability in the rat and dog. Dimethylamide 25 is more potent (>20-fold) than 4 in vivo and has a high degree of selectivity toward the vasopressin receptors, >10,000 for hV1a/hV1b and approximately 500 for hV2. It has a good Cyp450 profile with no time dependent inhibition and was negative in the genotoxicity screens with a satisfactory oral safety profile in rats.

Administration, Oral↗