NMR studies of transformations of aminoacid complexes of Pt(II) and Pd(II) in solution. 2. Bisalaninates

Synthetic procedures are suggested for diastereomers of Pt(II) and Pd(II) bischelates with alanine: cis- and trans-Pt(l-Ala)₂ , trans-Pt(l-Ala)fd-Ala), trans-Pd(l-Ala)₂ , and trans-Pd(l-Ala)(d-AIa). Methods of their isolation in individual solid state are proposed.¹H,¹³C, and¹⁹⁵Pt NMR spectral investigations are reported for the individual diastereomers and for M(Ala)₂ racemates in DMSO solution. The trans-isomers of Pd(II) bisalaninates in DMSO solution are transformed into an equilibrium mixture of cis- and trans-isomers. For Pt(II) complexes, the cis ↔ trans equilibrium was also found but the equilibration rate is much lower than that for Pd(II) bischelates for both cis- and trans-isomer. An equilibrium 2M(l-Ala)(d-Ala) ⇌ M(l-Ala)₂+M(d-Ala)₂ is also shown to exist. Translated fromZhurnal Strukturnoi Khimii, Vol. 41, No. 2, pp. 312–323, March–April, 2000.     

Oxidation of p-chlorotoluene and cyclohexene catalysed by polymer-anchored oxovanadium(IV) and copper(II) complexes of amino acid derived tridentate ligands

3-Formylsalicylic acid (Hfsal), covalently bound to chloromethylated polystyrene (PS) and cross-linked with 5% divinylbenzene reacts with d,l-alanine and l-isoleucine to give the Schiff-base tridentate ligands PS-H(2)fsal-d,l-Ala and PS-H(2)fsal-l-Ile, respectively. These anchored ligands upon reaction with VOSO(4) and Cu(CH(3)COO)(2).H(2)O form the complexes PS-[VO(fsal-d,l-Ala)(H(2)O)], PS-[Cu(fsal-d,l-Ala)(H(2)O)], PS-[VO(fsal-l-Ile)(H(2)O)] and PS-[Cu(fsal-l-Ile)(H(2)O)]. The structures of these immobilized complexes have been established on the basis of scanning electron micrographs, spectroscopic (infrared, electronic and EPR), thermogravimetric and elemental analysis studies. The oxidation of p-chlorotoluene and cyclohexene has been investigated using these complexes as the catalysts in the presence of H(2)O(2) as the oxidant. Reaction conditions have been optimised by considering the concentration of the oxidant, the amount of catalyst used and the temperature of the reaction mixture. Under the optimised conditions, p-chlorotoluene gave a maximum of 14% conversion using PS-[VO(fsal-d,l-Ala)(H(2)O)] as the catalyst, with the main products having a selectivity order of: p-chlorobenzaldehyde > p-chlorobenzylalcohol > p-chlorobenzoic acid > 2-methyl-5-chlorophenol > 3-methyl-6-chlorophenol. The oxidation of cyclohexene with PS-[VO(fsal-d,l-Ala)(H(2)O)] proceeds with 79% conversion, which is followed by PS-[VO(fsal-l-Ile)(H(2)O)] with 77% conversion, and the oxidation of cyclohexene by Cu-based catalysts occurs with considerably lower conversions (29-32%). The selectivity of the products follows the order: 2-cyclohexene-1-ol > cyclohexene oxide > cyclohexane-1,2-diol > 2-cyclohexene-1-one. Recycling studies indicate that these catalysts can be reused at least three times without any significant loss in their catalytic potential. However, EPR studies indicate that while the polymer supported V(iv)O-complexes do not change after being used, the EPR spectra of the Cu-complexes show significant changes. The corresponding non-polymer bound complexes [VO(fsal-d,l-Ala)(H(2)O)], [Cu(fsal-d,l-Ala)(H(2)O)], [VO(fsal-l-Ile)(H(2)O)] and [Cu(fsal-l-Ile)(H(2)O)] have also been prepared in order to compare their spectral properties and catalytic activities. The non-polymer bound complexes exhibit lower conversion, along with lower turn-over frequency as compared to their polymer-bound analogues. Several EPR, (51)V NMR and UV-vis studies have been undertaken to detect the intermediate species, and outlines for the mechanisms of the catalytic reactions are proposed.     

Photochemical desulfurization of thiols and disulfides

A visible light-induced desulfurization process for thiols and disulfides using triethylphosphite and triethylborane is reported. The reaction can be effected on a range of organic molecules having either primary, secondary or tertiary thiol groups and disulfides without the need of protecting groups. Thus, after treating l-cystine 7, l-cystine dimethylester 8, thioctic amide 9 and glutathione disulfide 10, first with tributylphosphine, later with triethylborane/triethylphosphite under irradiation in a one-pot reaction, the corresponding desulfurized compounds l-Ala, l-Ala, 1-octanamide and γ-l-Glu-l-Ala-Gly, respectively, are prepared in high yields with retention of configuration.     

Molecularly imprinted cavities template the macrocyclization of tetrapeptides

Cavities formed using cyclic tetrapeptides (CTPs) or heat-induced conformers act as templates for cyclization; the cavities bind to linear tetrapeptides and enforce turn conformations to enhance cyclization to constrained CTPs.     

Synthesis of CF3-containing tetrapeptide surrogates via Ugi reaction/dipolar cycloaddition sequence

A convenient synthetic pathway to novel functionalized tetrapeptides containing the 1,2,3-triazole moiety is described. The target molecules were obtained by the reaction of fluorinated α-amino acids or α-aminophosphonates with azidopeptides via Cu(I)-catalyzed Huisgen cycloaddition reaction (click chemistry). The synthesized tetrapeptides may find important applications in biomedical chemistry as potential drugs.     

Structure, histone deacetylase, and antiprotozoal activities of apicidins B and C, congeners of apicidin with proline and valine substitutions

[structure: see text]. Isolation and structure elucidation of two novel cyclic tetrapeptides that show a variety of potent antiprotozoal activities by reversibly inhibiting HDAC have been reported. These are the new members of a unique family of cyclic tetrapeptides that do not require the electrophilic alpha-epoxyketone moiety of HC-toxin, trapoxin A, or chlamydocin for their potent activities against HDAC and the malarial parasite.     

Interactions of Ni(II) and Cu(II) ions with the hydrolysis products of the C-terminal -ESHH- motif of histone H2A model peptides. Association of the stability of the complexes formed with the cleavage of the -E-S- bond

We studied the interactions of Ni(II) and Cu(II) ions with the synthetic tetrapeptides SHHK- and SAHK-, which were blocked by amidation making them more realistic models of the hydrolysis peptidic products of the hexapeptides models of H2A histone. A combination of potentiometric and spectroscopic techniques (UV/Vis, CD, NMR and EPR) suggested that at pH > 7 both tetrapeptides coordinated equatorially through the imidazole ring of His in position 3, the N-terminal amino group and the two amide nitrogens existing between these groups {NH2, 2N-, NIm} forming 4N square-planar complexes. While in the case of the CuH(-1)L complex with SHHK- a possible axial coordination of the imidazole ring of His in position 2 was suggested, in the case of the analogous NiH(-1)L complex a completely different interaction of the same ring with metal ions was observed. As expected these complexes have the same structures with the hydrolysis products produced from the Ni(II)- or Cu(II)-assisted hydrolysis of previously studied hexapeptide models of the C-terminal of histone H2A, due to their predominance at pH > 7.4. In addition, the competition plots presented herein showed that the synthetic tetrapeptides SHHK- and SAHK- have higher affinity towards Ni(II) and Cu(II) ions than the previously studied hexapeptides, suggesting that metal ions remain bound to the peptidic products during the hydrolysis cleavage. Thus, it can be concluded that the stability of Ni(II) or Cu(II) complexes with the synthetic tetrapeptides and consequently with the real hydrolysis peptidic products is the driving force of the hydrolysis reaction of H2A histone blocked hexapeptide models, presented in previous studies.     

基于多元线性回归的血管紧张素转化酶抑制肽定量构效关系建模研究

利用氨基酸结构描述符SVHEHS分别对血管紧张素转化酶(Angiotensin I-converting Enzyme,ACE)竞争性抑制二肽、三肽、四肽序列表征后,建立结构与活性的多元线性回归(MLR)模型。ACE抑制二肽模型的相关系数、交叉验证相关系数、均方根误差、外部验证相关系数分别为0.851、0.781、0.327、0.792;三肽模型分别为0.805、0.717、0.339、0.817;四肽模型分别为0.792、0.553、0.393、0.630。研究表明,运用该描述符建立的ACE抑制肽MLR模型拟合、预测能力均较好,能较好解释ACE抑制肽的活性与结构间的关系。     

Synthesis of dinitrophenyltetrapeptides as chromophoric substrates of endoproteinases

The synthesis has been performed of ten tetrapeptides of the general formula Dnp-Gly-Gly-X-Arg-OH, where X = Val, Phe, Abu, Asp (OBu^t), Asp, Met, D-Phe, Ser, Thr, or Trp. The synthesis was carried out with Dnp-Gly-Gly-ONp, activated esters of protected amino acids, and arginine with an unprotected carboxy group. The coefficients of molar extinction of the tetrapeptides at 660 nm are given. It has been shown that the peptides can be used to determine the activities of neutral and alkaline proteinases from various sources, the peptides with X = Phe, Met, and Abu exhibiting the highest sensitivity to enzymatic hydrolysis.All-Union Scientific-Research Institute of Ultrapure Biopreparations, Leningrad. Translated from Khimiya Prirodnykh Soedinenii, No. 4, pp. 499–504, July–August, 1983.     

Cyclic tetrapeptides via the ring contraction strategy: chemical techniques useful for their identification

Cyclic tetrapeptides are a class of natural products that have been shown to have broad ranging biological activities and good pharmacokinetic properties. In order to synthesise these highly strained compounds a ring contraction strategy had previously been reported. This strategy was further optimised and a suite of techniques, including the Edman degradation and mass spectrometry/mass spectrometry, were developed to enable characterisation of cyclic tetrapeptide isomers. An NMR solution structure of a cyclic tetrapeptide was also generated. To illustrate the success of this strategy a library of cyclic tetrapeptides was synthesised.     

Difficult macrocyclizations: new strategies for synthesizing highly strained cyclic tetrapeptides

[reaction: see text] Cyclic tetrapeptides are an intriguing class of natural products. To synthesize highly strained cyclic tetrapeptides we developed a macrocyclization strategy that involves the inclusion of 2-hydroxy-6-nitrobenzyl (HnB) group at the N-terminus and in the "middle" of the sequence. The N-terminal auxiliary performs a ring closure/ring contraction role, and the backbone auxiliary promotes cis amide bonds to facilitate the otherwise difficult ring contraction. Following this route, the all-L cyclic tetrapeptide cyclo-[Tyr-Arg-Phe-Ala] was successfully prepared.     

Microwaves enhance cyclisation of tetrapeptides

Head-to-tail cyclisation tetrapeptides can be improved using microwave dielectric heating. Cyclisation occurs rapidly at millimolar dilution giving the product in higher purity and yields if compared with standard conditions. The reaction can be applied to sequences containing at least one d-amino acid.     

α-Aminoisobutyric acid modified protected analogues of β-amyloid residue 17-20: a change from sheet to helix

The strong intermolecular interactions mediated by short hydrophobic sequences (e.g., 17-20, -l-Leu-l-Val-l-Phe-l-Phe-) in the middle of Aβ are known to play a crucial role in the neuropathology of Alzheimer's disease. FTIR, TEM and Congo red binding studies indicated that a series of l-Ala substituted terminally protected peptides related to the sequence 17-20 of the β-amyloid peptide, adopted β-sheet conformations. However, the Aib-modified analogues disrupt the β-sheet structure and switch over to a 3₁₀ helix with increasing number of Aib residues. X-ray crystallography shed some light on the change from sheet to helix at atomic resolution.     

A photochemical route for efficient cyclopeptide formation with a minimum of protection and activation chemistry

An elaborated protocol is described which allows the efficient transformation of di-, tri-, and tetrapeptides into cyclopeptides with a minimum of protection and activation chemistry using the photoinduced electron transfer initiated decarboxylation of N-phthaloyl peptides resulting in C-C coupling between the initially formed carbon radicals.     

Synthesis of cyclic peptides constrained with biarylamine linkers using Buchwald-Hartwig C-N coupling

In this paper, we describe the synthesis of conformationally constrained cyclic peptides with biarylamine linkers for peptidomimetics using palladium-catalyzed intramolecular Buchwald-Hartwig C-N coupling. We have prepared a variety of di-, tri-, and tetrapeptides (16-22-membered) in good yields using this reaction.     

Investigation of the conformations of four tetrapeptides by nuclear magnetic resonance and circular dichroism spectroscopy, and conformational energy calculations.

Proton nuclear magnetic resonance and circular dichroism studies were carried out on aqueous solutions of the tetrapeptide Asp-Lys-Thr-Gly (which appears as a bend at residues 35-38 of alpha-chymotrypsin) and its sequence variants Gly-Thr-Asp-Lys, Asp-Lys-Gly-Thr, and Lys-Thr-Gly-Asp; the N and C termini of all four tetrapeptides were blocked with CH3CO and NHCH3 groups, respectively. The spectroscopic data suggest that bend conformations may exist, to some extent, among the distributions of conformations in the first, third, and fourth, but not in the second, tetrapeptide. This result is consistent with empirical probabilities for the prediction of bend conformations in proteins. Conformational energy calculations on these four tetrapeptides support the indications from the experimental data. It thus appears that, because of short-range interactions, the tendency toward bend formation exists in short peptides, provided that both the composition and amino acid sequence are energetically favorable for bend formation.     

Ferrocene-dipeptide conjugates derived from aminoferrocene and 1-acetyl-1′-aminoferrocene: synthesis and conformational studies

In this study we present the synthesis and conformational analysis of mono- and disubstituted ferrocene bioconjugates bearing dipeptide chains (Boc-AA-AA-Fn-X, AA=Gly, l-Ala, l-Val). The conformational preferences of novel aminoferrocene derived conjugates with X=H, as well as their 1-acetyl analogues (X=COMe), were investigated by spectroscopic techniques (IR, NMR and CD) and corroborated by DFT calculations. Chirally organized structures, stabilized through intrachain hydrogen bonds, prevail in solution when X=H. The resulting 10-membered hydrogen-bond ring is destabilized by heteroannular introduction of an acetyl group when X=COMe.     

Photochemical desulfurization of l-cysteine derivatives

Thiol groups can be reductively eliminated at room temperature by a photochemical method which makes use of triethylboron, triethylphosphite and visible light. Thus, after treating l-Cys 1a, d-Pen 1b, l-Cys-OMe 1c and glutathione (γ-l-Glu-l-Cys-Gly) 3, the corresponding desulfurized compounds l-Ala 2a, d-Val 2b, l-Ala-OMe 2c and γ-l-Glu-l-Ala-Gly 4, respectively, are prepared in high yields and with retention of configuration.     

Diazonamide studies. A direct synthesis of the indole bis-oxazole fragment from tri- and tetra-peptides using biomimetic oxidative cyclizations

The oxidation of several readily prepared tryptophan containing tri- and tetrapeptides with DDQ results in a biomimetic cyclization and direct formation of the indole bis-oxazole fragment of diazonamide A, establishing that such a transformation is a viable route when considering the biosynthetic formation of the heterocyclic core of the natural product.     

Solid-phase synthesis of a farnesylated CaaX peptide library: inhibitors of the Ras CaaX endoprotease

A solid-phase method, based on Kaiser's p-benzophenone oxime resin, was developed for the synthesis of a series of N-acetyl-S-(E, E-farnesylated) Ca(1)a(2)X tetrapeptides as potential inhibitors of recombinant Ras and a-factor converting enzyme (RCE). N-Acetyl-S-(E, E-farnesyl)-L-cysteine was coupled to resin-bound a(1)a(2) dipeptide using HOBt/DCC activation in conjunction with N-BOC chemistry. The protected farnesylated tripeptide was cleaved from the resin with simultaneous addition of the X residue by treating the resin-bound farnesylated Ca(1)a(2) tripeptide with L-amino acid benzyl ester tosylates under mildly acidic conditions. The benzyl ester was saponified, and the resulting carboxylate precipitated by ether to afford a library of tetrapeptides as a mixture of diastereomers at the cysteine center. The peptides were evaluated as inhibitors of recombinant yeast RCE endoprotease (yRCE) to obtain information about the affinity of the enzyme for the a(1)a(2)X portion of the Ca(1)a(2)X moiety.