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A new dipeptide receptor 9, which was designed de novo based on theoretical calculations, efficiently binds dipeptides in water with Kass > 104 M-1 by a combination of ion pairing and hydrogen bonds as can be shown by UV-titration and NMR experiments.
We report the first solid-state NMR, crystallographic, and quantum chemical investigation of the origins of the 13C NMR chemical shifts of the imidazole group in histidine-containing dipeptides. The chemical shift ranges for Cgamma and Cdelta2 seen in eight crystalline dipeptides were very large (12.7-13.8 ppm); the shifts were highly correlated (R2= 0.90) and were dominated by ring tautomer effects and intermolecular interactions. A similar correlation was found in proteins, but only for buried residues. The imidazole 13C NMR chemical shifts were predicted with an overall rms error of 1.6-1.9 ppm over a 26 ppm range, by using quantum chemical methods. Incorporation of hydrogen bond partner molecules was found to be essential in order to reproduce the chemical shifts seen experimentally. Using AIM (atoms in molecules) theory we found that essentially all interactions were of a closed shell nature and the hydrogen bond critical point properties were highly correlated with the N...H...O (average R2= 0.93) and Nepsilon2...H...N (average R2= 0.98) hydrogen bond lengths. For Cepsilon1, the 13C chemical shifts were also highly correlated with each of these properties (at the Nepsilon2 site), indicating the dominance of intermolecular interactions for Cepsilon1. These results open up the way to analyzing 13C NMR chemical shifts, tautomer states (from Cdelta2, Cepsilon1 shifts), and hydrogen bond properties (from Cepsilon1 shifts) of histidine residue in proteins and should be applicable to imidazole-containing drug molecules bound to proteins, as well.
The synthesis of dendritic dipeptides (4-3,4-3,5-4)12G2-CH(2)-Boc-L-Tyr-L-Ala-OMe and (4-3, 4-3,5-4)12G2-CH(2)-Boc-D-Tyr-D-Ala-OMe is described. These dendritic dipeptides self-assemble into porous elliptical and circular columns that in turn self-organize into centered rectangular columnar and hexagonal columnar periodic arrays. The transition from porous elliptical to porous circular columns is mediated in a reversible or irreversible way by the thermal history of the sample. A method to determine the dimensions of hollow elliptical and circular columns by the reconstruction of the small-angle powder X-ray diffractograms of the centered rectangular or hexagonal columnar lattices was elaborated. This technique together with wide-angle X-ray experiments performed on aligned fibers provided access to the structural and retrostructural analysis of elliptical supramolecular pores. This procedure is general and can be adapted for the determination of the dimensions of pores of any columnar shape.
Products of animal origin such as meat meal were commonly used as sources of protein and amino acids for the production of compound feeds. Because the feeding of such products is prohibited in Germany, the official feedstuff control of the government must evaluate feeds for the forbidden use of products of animal origin. Microscope examination is the official method to prove animal-originated adulterations of feeds. This paper proposes a high-performance liquid chromatography method for the determination of the dipeptide carnosine and related dipeptides (anserine and balenine) and shows the dependence of the contents of anserine, balenine, and carnosine in compound feeds on the content of meat meal in feeds. The presented method can complete and confirm the result of the microscopic method for evidence of components of animal origin in feeds.
A series of dipeptides which contained phosphonate analogs of proline and piperidine-2-carboxylic acid (homoproline) have been synthesized and tested as inhibitors of DPP-IV. The rates of inhibition of DPP-IV by these compounds are moderate, but the inhibitors are quite specific. The best inhibitor in the series is Ala-PipP(OPh-4-Cl)2 (13), which has a k(inact) of 0.353 s-1 and KI of 236 microM. The DPP-IV inhibitors Ala-ProP(OPh)2 (6), Ala-ProP(OPh-4-Cl)2 (12), and Ala-PipP(OPh-4-Cl)2 (13) do not inhibit trypsin, human leukocyte elastase (HLE), porcine pancreatic elastase (PPE), acetylcholinesterase, papain, and cathepsin B. However, compounds 12 and 13 inhibited chymotrypsin slowly. Most of these dipeptides containing a homoproline phosphonate residue (PipP) or a Pro phosphonate residue (ProP) at the P1 site are stable in a pH 7.8 buffer with half-lives of several hours to several days. DPP-IV inhibited by 6, 7 (Ala-PipP(OPh)2), 12, or 13 is quite stable, and no enzyme activity was recovered after removal of excess inhibitor and incubation in buffer for 1 day. Since the phosphonate inhibitors are specific toward DPP-IV and the inhibited enzymes are stable, they should be useful in establishing the biological functions of DPP-IV and may be useful therapeutically in the prevention of the rejection of transplanted tissue.
A series of analogs of Ac-CCK-7 [Ac-Tyr(SO3H)-Met28-Gly29-Trp-Met-Asp- Phe-NH2, (1)] were prepared in which the Met28-Gly29 dipeptide was replaced by omega-aminoalkanoic acids. Compounds were assessed in binding assays using homogenated rat pancreatic membranes and bovine striatum as the source of CCK-A and CCK-B receptors, respectively, and for anorectic activity after intraperitoneal administration to rats. The analog incorporating 4-aminobutanoic acid (5) was only 8 times less potent than 1 in the pancreatic binding assay, was more potent in the striatal binding assay, and was more potent than 1 in reducing food intake in rats. Using a bioactive cyclic analog of Ac-CCK-7 as a template, several rigid spacers were designed and tested as substitutes for the Met28-Gly29 dipeptide. The analogs incorporating 3-aminobenzoic acid (20) and (1S)-trans-2-aminocyclopentanecarboxylic acid (26) proved highly effective in the binding assays and as anorectic agents. We hypothesize that for stimulation of CCK-A receptors, the main function of the N-terminal tripeptide of Ac-CCK-7 is to orient the tyrosine sulfate with respect to Trp30 and that the bioactive arrangement of these elements lies among those which are readily available to both 20 and 26. NOESY and distance-constrained molecular dynamics experiments carried out on 20 and 26 identified conformations in which the relative orientation of the tyrosine hydroxide and the alpha-carbon atom of tryptophan were similar, providing the basis for further drug design efforts.
The dipeptide N-[[[2'S-(2' alpha, 3' beta, 4' beta)]-2'-carboxy-4'-(1"-methylethenyl)-3'-pyrrolidinyl)acetyl]-L- glutamic acid (6) has been synthesized by a route that involves the selective protection of the alpha-carboxyl function of kainic acid. This dipeptide inhibits the stimulation of Na+ fluxes induced in brain slices by the neuroexcitant N-methyl-D-aspartic acid. Administered intracerebroventricularly, it is also effective in protecting mice from picrotoxin-induced convulsions with an ED50 of 0.17 mumol.
One of the pattern recognition techniques, the SIMCA method, has been applied to structure-taste studies on L-aspartyl dipeptides (L-Asp-NH-R). The sweet and bitter taste class models of the peptides were obtained by using five structural descriptors, such as molar refractivity, and four kinds of STERIMOL parameters. The classification rates were calculated to be 87% and 81% for sweet and bitter peptides, respectively. The SIMCA method has also suggested that two factors, shape and size, of the C-terminal amino acid moiety R in the dipeptides are extremely important to model their taste qualities.
The synthesis of a series of renin inhibitors in which the P2 and P3 amino acids are replaced with the hydroxyethylene dipeptide isostere is reported. In vitro evaluation of the inhibitors has revealed that this isostere is an acceptable amide-bond replacement in which activity is maintained and stability is enhanced. Structure-activity relationships of this series resemble but do not parallel those of the corresponding dipeptide-containing inhibitors.
Eight L-aspartyl dipeptides derived from heterocyclic glycine esters were prepared and evaluated as sweeteners. The fenchyl esters of L-aspartyl-2-furyl-, 2- and 3-thienyl-, and imidazolylglycine were all potently sweet with the D-2-furylglycine (+)-beta-fenchyl ester being the most potent at 16,500 times the potency of sucrose. The requirement for a planar heterocyclic group directly attached to the glycine carbon atom was demonstrated by the observation that the tetrahydrofuryl and beta-thienylalanine fenchyl esters were not sweet. The heteroaromatic glycine esters join the phenylglycine esters as a novel class of dipeptide sweeteners with very high potency.
Side-chain homologues of sweet trifluoroacetyl-alpha-L-aspartyl-p-cyanoanilide have been synthesized and tasted. Removal of the trifluoroacetyl group only changes the potency of sweet taste, not the taste property. These results have been compared with the structure-taste relationships of dipeptide sweeteners. An informative discontinuity of taste effects was found to exist with novel aminomalonyl dipeptide derivatives. The results are explained on topochemical grounds.
A series of analogues of the analgesic dipeptide derivative H-Lys-Trp(NPS)-OMe has been designed to determine the influence of the (2-nitrophenyl)sulfenyl (NPS) moiety on the activity. The syntheses and antinociceptive effects of these analogues of general formula H-Lys-Trp(R)-OMe [R = phenylsulfenyl (PS) (9); R = (2-carbomethyoxyphenyl)sulfenyl (CmPS) (10); R = (4-nitrophenyl)sulfenyl (pNPS) (11); R = (2,4-dinitrophenyl)sulfenyl (DNPS) (12); R = [2-(acetylamino)-2-carbomethoxyethyl]sulfenyl (AacCmES) (13); R = [2-(acetylamino)phenyl]sulfenyl (AacPS) (17); R = tert-butylsulfenyl (t-BuS) (23); R = (2-carbomethoxyethyl)sulfenyl (CmES) (24)] are described. Reaction of Z-Lys(Z)-Trp-OMe (3) with PS-, CmPS-, pNPS-, DNPS-, and AacCmES-Cl afforded the corresponding 2-(sulfenyl)tryptophan derivatives, which on treatment with boron-tris(trifluoroacetate)/trifluoroacetic acid or trimethylsilyl iodide in acetonitrile (Me3SiI/CH3CN) provided 9-13, respectively. Sulfenylation of 3 with NPS-Cl gave Z-Lys(Z)-Trp(NPS)-OMe, which, on catalytic hydrogenation of the nitro group using 10% Pd/C followed by acetylation of the resulting amino function and removal of the protecting Z groups, gave 17. Condensation of 2-(tert-butylsulfenyl)- and 2-[(2-carbomethoxyethyl)sulfenyl]tryptophan methyl ester, obtained by reaction of methyl 3a-hydroxy-1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]indole-2-carboxyla te with the corresponding thiol, with Z-Lys(Z)-OSu afforded Z-Lys(Z)-Trp(t-BuS)-OMe and Z-Lys(Z)-Trp(CmES)-OMe, which on treatment with Me3SiI/CH3CN provided 23 and 24, respectively. Intracerebroventricular administration of 10 elicited a naloxone-reversible antinociceptive effect in mice similar to that of H-Lys-Trp(NPS)-OMe. No analgesia was however found with the phenylsulfenyl or acyclic sulfenyl substituted dipeptides 9, 11, and 17 or 13, 23, and 24. The Trp(DNPS)-containing analogue was neurotoxic. Structure-activity studies indicate that the role of the NPS and CmPS moieties could be related to the adoption of a preferential active conformation.
The design and synthesis of renin inhibitors that incorporate the novel dipeptide isostere (4S,5S)-5-amino-6-cyclohexyl-4-hydroxyhex-1-ene-2-carboxylic acid as a transition-state analogue are described. Titanium-promoted condensation of dilithiated N-alkylmethacrylamides with protected amino aldehydes results in efficient preparation of protected dipeptide analogues 7 and 8. Incorporation of 7 into the partial sequence of angiotensinogen affords potent in vitro inhibitors of human renin. Further chemical manipulation of the unsaturated amide moiety allows the study of structure-activity relationships in both the P1' and P2' sites. Details of the syntheses, stereochemical determinations, and in vitro renin inhibition are presented.
The synthesis of MDP (muramyl dipeptide) or nor-MDP (normuramyl dipeptide) conjugates modified at the peptide part with batracylin (BAT) or batracylin derivatives is described. Batracylin was synthesized by our modified method (Scheme 3). The synthesis of BAT via this modified route now appears to be feasible on a multigram scale. Preliminary screening data obtained at the National Cancer Institute (NCI, Bethesda, MD) have revealed that the conjugates did not expose any cytotoxic activity even at 10(-4)-10(-8) M or microg/mL. During tests performed at Medical University of Gdansk, Poland, two analogues 11c and 11e reduced the proliferation of Ab melanoma cells in vitro compared with batracylin alone (Table 2, Figure 1).
We describe the design, the conformational behavior, and the biological activity at the mu-opioid receptor of new morphiceptin analogues. In these analogues a recently described dipeptide mimetic structure replaces both the N- and the C-terminal Xaa-Pro dipeptide of morphiceptin. Conformational investigation on the most active analogue, compared to the parent peptide, indicates a high degree of structural tolerance within the mu-opioid receptor binding site. In fact, our results indicate that only the location and the relative orientation of the side chains of the aromatic pharmacophoric residues represent the indispensable structural features for mu-receptor binding. To reach such topological arrangement, opioid peptides can adopt different conformations and configurations. In particular, opioid peptides bearing a proline residue as spacer between the two aromatic residues can adopt, in the active state, both cis and trans configurations at the Tyr(1)-Pro(2) amide bond, each of them with the appropriate backbone and side chains orientations.
L,L-Type and L,D-type (E)-alkene dipeptide isosteres (EADIs) that have unnatural side chains at the alpha-position were synthesized by the combination of stereoselective aziridinyl ring-opening reactions and organozinc-copper-mediated anti-S(N)2' reactions toward a single substrate of gamma,delta-cis-gamma,delta-epimino (E)-alpha,beta-enoate. The utility of this methodology was demonstrated by the stereoselective synthesis of a set of diastereomeric EADIs of L-Arg-L/D-3-(2-naphthyl)alanine (Nal) that is contained in a small CXCR4 antagonist FC131 [cyclo(-D-Tyr-Arg-Arg-Nal-Gly-)]. Furthermore, a (Nal-Gly)-type EADI was synthesized by samarium diiodide (SmI(2))-induced reduction of a gamma-acetoxy-alpha,beta-enoate. Several FC131 analogues, in which these EADIs were inserted for reduction of their peptide character, were synthesized with analogues containing reduced amide-type dipeptide isosteres to investigate the importance of these amide bonds for anti-HIV and CXCR4-antagonistic activity.
Family 18 chitinases play an essential role in a range of pathogens and pests. Several inhibitors are known, including the potent inhibitors argadin and allosamidin, and the structures of these in complex with chitinases have been elucidated. Recent structural analysis has revealed that CI-4 [cyclo-(L-Arg-D-Pro)] inhibits family 18 chitinases by mimicking the structure of the proposed reaction intermediate. Here we report the high-resolution structures of four new CI-4 derivatives, cyclo-(L-Arg-L-Pro), cyclo-(Gly-L-Pro), cyclo-(L-His-L-Pro), and cyclo-(L-Tyr-L-Pro), in complex with a family 18 chitinase. In addition, details of enzyme inhibition and in vivo activity against Saccharomyces cerevisiae are presented. The structures reveal that the common cyclo-(Gly-Pro) substructure is sufficient for binding, allowing modification of the side chain of the nonproline residue. This suggests that design of cyclic dipeptides with a view to increasing inhibition of family 18 chitinases should be possible through relatively accessible chemistry. The derivatives presented here in complex with chitinase B from Serratia marcescens provide further insight into the mechanism of inhibition of chitinases by cyclic dipeptides as well as providing a new scaffold for chitinase inhibitor design.
A series of substituted monocyclic and bicyclic azepinones were incorporated as dipeptide surrogates in mercaptoacetyl dipeptides with the desire to generate a single compound which would potently inhibit both angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP). Many of these compounds displayed excellent potency against both enzymes. Two of the most potent compounds, monocyclic azepinone 2n and bicyclic azepinone 3q, demonstrated a high level of activity versus ACE and NEP both in vitro and in vivo.