Novel bradykinin antagonist dimers for the treatment of human lung cancers.
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Amino Acid Sequence↗
Biomedical subjects
L Gera
Publications and source records attributed to L Gera.
A new type of bradykinin B2 receptor antagonists: bradykinin analogs with N-alkyl amino acids at position 2.
It is commonly assumed that bradykinin B2 receptor antagonists bind to a receptor site partially different from that for agonists. Thus, it is likely that there exists more than one key modification to convert bradykinin receptor agonists into antagonists. In this respect, [L-NMePhe2]-BK represents the basic structure of a new type of bradykinin B2 receptor antagonists without any replacement at position 7. This compound inhibits both in vitro bradykinin-induced contraction of the guinea pig lung strip and in vivo bradykinin-induced bronchoconstriction. Furthermore, this analog shows analgesic activity, blocks in a dose-dependent manner the bradykinin-induced Ca2+ release from macrophages and inhibits at a concentration of 10(-13) M the bradykinin-induced cytokine release from mononuclear cells. Combinations with structural modifications previously performed for other B2 receptor antagonists rather reduce than enhance the potency.
Amino Acid Sequence↗
A new generation of bradykinin antagonists.
Bradykinin B2 receptors are constitutively expressed, and require the entire peptide chain of bradykinin for recognition. Expression of B1 receptors is induced in inflammation; they recognize BK-(1-8). Heretofore blockade of all the actions of bradykinin required two different antagonists, one for each class of receptors. The new antagonists described here are full chain antagonists having high potency on B2 receptors, but they are also very potent antagonists for B1 receptors. They are highly resistant to kininases and show very long action in vivo. These antagonists contain the novel amino acid alpha-(2-indanyl)glycine (IgI) at positions 5 and 7. The peptide DArg-Arg-Pro-Hyp-Gly-Igl-Ser-DIgl-Oic-Arg (designated B9430) shows all these desirable characteristics. It represents a new class of bradykinin antagonist peptides.
Amino Acid Sequence↗
A new class of bradykinin antagonists containing indanylglycine.
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Amino Acid Sequence↗
A new class of potent bradykinin antagonist dimers.
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Amino Acid Sequence↗
New bradykinin antagonists having very high potency at B1 receptors.
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Amino Acid Sequence↗
Helix-forming tendencies of amino acids in short (hydroxybutyl)-L-glutamine peptides: an evaluation of the contradictory results from host-guest studies and short alanine-based peptides.
The helix propensities ("s-values") of amino acids measured using short alanine-based peptides are different, in both magnitude and rank order, from those found using random sequence copolymers of a "guest" amino acid and a (hydroxyalkyl)-L-glutamine "host". The origin of these differences is investigated here. In short alanine-based peptides containing 1-5 (hydroxybutyl)-, (hydroxypropyl)-, or (hydroxyethyl)-L-glutamines (HBQ, HPQ, and HEQ, respectively), we find the rank order of helix propensities to be Ala > HBQ > HPQ > HEQ, which is consistent with earlier results for HBQ, HPQ, and HEQ homopolymers and is attributed to helix-stabilizing hydrophobic interactions [Lotan, N., Yaron, A., & Berger, A. (1966) Biopolymers 4, 365-368]. The apparent s-values of nonpolar amino acids in a 17-residue, HBQ-based peptide cluster around 1, as they do in the host-guest studies, but in contrast to results with alanine-based peptides. The differences between the host-guest results and results obtained using alanine-based peptides may be rationalized in terms of side-chain interactions involving the hydroxyalkyl moiety.
Alanine↗
Effects of neuropeptide analogues on calcium flux and proliferation in lung cancer cell lines.
Small cell lung cancers (SCLC) and some non-small cell lung cancers (NSCLC) have neuroendocrine features which include production of a variety of neuropeptides, cell surface expression of the receptors for these peptides, and autocrine stimulation by the peptides. Previous studies showed that some peptide antagonists and anti-peptide antibodies inhibited the growth of SCLC cell lines which expressed receptors for the specific peptide. We and others showed that the heterogeneity of peptide receptor expression and responsiveness was a major potential obstacle for developing therapeutic uses of peptide antagonists. In this manuscript we evaluated the effects of 11 peptide antagonists (3 bombesin-specific, 2 cholecystokinin-specific, 1 arginine vasopressin (AVP)-specific, and 5 substance P derivatives with broad specificity) on peptide-induced calcium mobilization and growth of SCLC and NSCLC cell lines. For each antagonist, we determined the dose-response effects, specificity of peptide antagonism, and biological stability in serum using Indo-1AM-based flow cytometric assays. We found that the three bombesin antagonists, S30, SC196, and L336,175, varied in potency from 10 nM to 10 microM, varied in serum stability from 6 h to more than 24 h, and had no effect on the calcium response elicited by other peptides. None of these compounds effectively inhibited the growth of SCLC cell lines in [3H]dThd and cell growth assays in vitro. Similarly, the three cholecystokinin and AVP antagonists were highly specific for cholecystokinin and AVP, respectively, had widely varying potency, but had little inhibitory effect on SCLC growth in vitro. In contrast, the five substance P derivatives inhibited the calcium response to bombesin, AVP, bradykinin, and fetal bovine serum. None of these five antagonists were as potent as the six specific antagonists described above, but they were more effective in inhibiting the growth of SCLC cell lines in vitro. These substance P derivatives inhibited the growth of peptide-sensitive SCLC cell lines more efficiently than their inhibition of peptide-insensitive NSCLC or breast cancer cell lines. Relatively high concentrations of these substance P derivatives were required to inhibit in vitro growth, even in the absence of added peptide. It is likely that more potent broad spectrum antagonists, toxins, or radiolabeled stable antagonists will need to be developed for maximal clinical development of this type of anti-growth factor therapy.
Amino Acid Sequence↗
A CD and an NMR study of multiple bradykinin conformations in aqueous trifluoroethanol solutions.
CD and nmr studies have been carried out on aqueous trifluoroethanol (TFE) solutions of bradykinin (BK) and a bradykinin antagonist. The CD results exhibit a striking effect of TFE on the spectra of BK, with sequence Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg, and the BK antagonist, with sequence D-Arg-Arg-Pro-Hyp-Gly-Thi-D-Ser-D-Cpg-Cpg-Arg [where Hyp is 4-hydroxy-L-proline; Thi refers to beta-(2-thienyl)-L-alanine and Cpg refers to alpha-cyclopentylglycine). The effect of increasing concentration of TFE in water on the difference ellipticity at 222 nm was examined and showed that BK may be a mixture of at least two different conformers, one of which largely forms when the TFE concentration is increased beyond 80%. The linear extrapolation of 100% of the difference ellipticity of BK at low TFE concentrations yields a value in agreement with that shown by the BK antagonist, indicating that the conformation of BK at the lower TFE concentrations is similar to that of the BK antagonist. The conformational analysis was carried out using both one-dimensional and two-dimensional 1H-nmr techniques. The total correlation spectroscopy (TOCSY) spectrum of BK in a 60/40% (v/v) TFE/H2O solution at 10 degrees C and a nuclear Overhauser effect spectroscopy (NOESY) spectrum that shows only sequential H alpha (i)-NH(i + 1) or the H alpha (i)-H delta delta' (i + 1) NOEs indicate that the majority of the molecules adopt an all-trans extended conformation. The TOCSY for BK in the 95/5% (v/v) TFE/H2O solution shows that there are two major conformations in the solution with about equal population. The NOESY experiment shows two new important cross peaks for one conformation, namely Pro2 (alpha)-Pro3 (alpha) and the Pro2 (alpha)-Gly4(NH), indicating a cis Pro2-Pro3 bond and a type VI beta-turn between residues Arg1 and Gly4 involving cis proline at position 3, respectively. The low temperature coefficient of Gly4 for this conformation suggests the presence of an intramolecular hydrogen bond, therefore a type VIa beta-turn is present. The other conformation is all trans and extended. The BK antagonist shows difference CD spectra in TFE solutions referred to H2O that are superficially indicative of a beta-bend.(ABSTRACT TRUNCATED AT 400 WORDS)
Amino Acid Sequence↗
Proton magnetic resonance studies of bradykinin antagonists.
Bradykinin (BK) is a peptide hormone with sequence Arg1-Pro2-Pro3-Gly4-Phe5-Ser6-Pro7-Phe8-Arg9 and has been implicated in a multitude of pathophysiological processes such as the ability to lower systemic blood pressure and stimulate pain. BK analogues having bulky, beta-branched D-aliphatic residues at position 7 combined with bulky L-aliphatic residues at position 8 have now been observed to be strong antagonists. Conformational studies based on two-dimensional nmr experiments in methanol/water (80/20 v/v) were carried out on several such active antagonists in a polar solvent. Included in this study were the very active antagonists, [D-Arg0,Hyp3,Thi5,D-Cpg7,Cpg8]-BK [Cpg: alpha-cyclo-pentyl-glycine; Hyp: trans-4-hydroxy-L-proline; Thi: beta-(2-thienyl)-L-alanine] (I), [D-Arg0,Hyp3,D-Cpg7,Cpg8]-BK (II), as well as its variant with D-Cpg7 replaced by Cpg7, namely [D-Arg0,Hyp3,Cpg7,Cpg8]-BK (III). A turn-like structure, which coexists with the extended conformation, was observed between residues 2 and 5 for the most active antagonists I and II, in direct correlation with the peptide activities. No turn-like structure was found for residues 6-9. In peptide III, a turn-like structure was not identified. The existence of a turn at the C-terminal end of bradykinin and its analogues has been predicted by empirical calculations and supported by nmr measurements. But the present nmr study on the most active antagonists (I, II) does not support this hypothesis. Instead, the data suggest that a turn-like structure between residues 2 and 5 could be important for antagonist activity. Finally, one weak inhibitor [D-Cpg7]-BK (IV) showed no defined secondary structure.
Amino Acid Sequence↗
The aggregation properties of some bradykinin analogs.
Bradykinin (BK) is a peptide hormone with sequence Arg1-Pro2-Pro3-Gly4-Phe5-Ser6-Pro7-Phe8-Arg9 and has been implicated in a multitude of pathophysiological processes such as the ability to lower systemic blood pressure and stimulate pain. Bulky, beta-branched D-aliphatic residues at position 7 combined with bulky L-aliphatic residues at position 8 have now been observed to yield strong antagonists. Nuclear magnetic resonance studies have been carried out on many of these molecules with a view to determining their solution conformations. However, two such analogs, namely DArg-[Hyp3, Thi5, DSer6, DCpg7, Cpg8]-BK [I] and DArg-[Hyp3, DSer6, DCpg7, Cpg8]-BK [II] (Cpg = alpha-cyclopentyl-glycine; Hyp = 4-hydroxy-L-proline, Thi = beta-(2-thienyl)-L-alanine), have exhibited an abnormal, non-linear temperature dependence for the amide NH proton of Cpg8. The NH of Arg9 also shows a slightly non-linear temperature dependence at higher temperatures above 25 degrees C. In addition, a very slow exchange rate for the NH protons of DCpg7, Cpg8 and Arg9 indicated aggregation of these two analogs, which was confirmed using the circular dichroism experiments.
Amino Acid Sequence↗
Synthesis and stability of 3-nitro-2-pyridinesulfenyl chloride (NpysCl).
3-Nitro-2-pyridinesulfenyl chloride (NpysCl) is the starting material for the synthesis of N-, O- and S-Npys-protected amino acids. Two efficient, novel synthetic routes to NpysCl are described. The stability of NpysCl was determined in a variety of solvents, with and without base, to determine the most suitable solvent and base for the synthesis of N-Npys amino acids. The syntheses of Npys-Ala and Boc-Lys(Npys) tert-butylammonium salt are also described.
Alanine↗
Pseudopeptide analogs of bradykinin and bradykinin antagonists.
Over 100 reduced-bond analogs of bradykinin and bradykinin antagonists were designed, synthesized, and assayed in the classic smooth muscle and blood pressure assays in a further study of the structure-activity relationships of bradykinin. Both potent BK-like agonists and antagonists of BK activity were found among the reduced-bond analogs.
Amino Acid Sequence↗
Bradykinin antagonists do not require a D-aromatic amino acid residue at position 7.
More than 200 new analogs of bradykinin have been synthesized and assayed. Analogs containing a D-aliphatic amino acid residue at position 7 and an L-aliphatic residue at position 8 are very potent antagonists of BK action on classical systems. Thus the "conventional wisdom" that a D-aromatic amino acid residue is required at sequence position 7 of BK antagonists must be modified.
Amino Acid Sequence↗
Practical approach to solid-phase synthesis of C-terminal peptide amides under mild conditions based on a photolysable anchoring linkage.
Several 3-nitro-4-(N-protected aminomethyl)benzoic acids; with protection provided by tert.-butyloxycarbonyl (Boc), 9-fluorenylmethyloxycarbonyl (Fmoc), trifluoroacetyl (Tfa), dithiasuccinoyl (Dts), or phthaloyl (Phth), have been prepared by reproducible routes. Synthesis of Dts-handle 6 illustrates some particularly novel and efficient chemistry, and is preferred over more intricate routes to Boc-handle 3 and Fmoc-handle 4. The five handles were each evaluated for their application to the synthesis of peptide amides. Coupling onto amino-functionalized supports provided a general starting point for peptide chain assembly. The handle amino function was deblocked (Boc, Fmoc, Dts), the C-terminal residue was coupled as its N alpha-protected free acid, and ultimately the ortho-nitrobenzylamide anchorage linkage was cleaved photolytically to give the corresponding amide. Starting with handles 3, 4, and 6, several free and protected peptide amides were synthesized.
Amides↗
[Critical analysis of osteosynthesis of fractures of the femoral diaphysis].
Authors analyse the osteosyntheses of 98,417 segmental fractures of the femoral diaphysis. Beside the 72 per cent of excellent and good results in 19 per cent complications were found, especially after using plate osteosynthesis. In spite of the fact that Kuentscher nailing seems to be the method of choice in this paper the problem is not analysed from the viewpoint of indication but from that of the causes of prolonged healing. On the basis of their own experiences they call attention to the danger of complications. They think the choice of the most suitable method of treatment of very great importance and also the regular control, the aftertreatment and readiness to cooperation of the patients.
Adolescent↗
Synthesis and stereochemistry of 8,13-diaza-2,3-dimethoxygona-1,3,5(10),9(11)-tetraen-12-one and D-homo derivatives.
From the condensation reaction of O-methylbutyrolactim (2), O-methylvalerolactim (3), O-methylcaprolactim (4) and O-methyl-4-t-butylcaprolactim (5) with ethyl 6,7-dimethoxy-alpha-[1-(1,2,3,4-tetrahydro-isoquinolyl)] acetate (1), 8,13-diaza-2,3-dimethoxygona-1,3,5(10),9(11)-tetraen-1 2-one (6) D-homo-derivatives (7-9), and medium-sized ring cyclic diamides (10,11) were obtained. The stereoselective reduction of compounds 6-9 by Adam's platinum catalyst afforded 8,13-diaza-2,3-dimethoxygona-1,3,5(10)-trien-12-one (12) and its D-homo derivatives (13-15). The structures of the compounds obtained were established by NMR and X-ray crystallographic analyses.
Azasteroids↗