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1.
Int J Mol Sci ; 25(9)2024 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-38732028

RESUMO

The development of turn-based inhibitors of protein-protein interactions has attracted considerable attention in medicinal chemistry. Our group has synthesized a series of peptides derived from an amino-functionalized ferrocene to investigate their potential to mimic protein turn structures. Detailed DFT and spectroscopic studies (IR, NMR, CD) have shown that, for peptides, the backbone chirality and bulkiness of the amino acid side chains determine the hydrogen-bond pattern, allowing tuning of the size of the preferred hydrogen-bonded ring in turn-folded structures. However, their biological potential is more dependent on their lipophilicity. In addition, our pioneering work on the chiroptical properties of aminoferrocene-containing peptides enables the correlation of their geometry with the sign of the CD signal in the absorption region of the ferrocene chromophore. These studies have opened up the possibility of using aminoferrocene and its derivatives as chirooptical probes for the determination of various chirality elements, such as the central chirality of amino acids and the helicity of peptide sequences.


Assuntos
Aminoácidos , Compostos Ferrosos , Metalocenos , Peptídeos , Compostos Ferrosos/química , Aminoácidos/química , Metalocenos/química , Peptídeos/química , Ligação de Hidrogênio , Estereoisomerismo
2.
Int J Mol Sci ; 23(20)2022 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-36293089

RESUMO

Considering the enormous importance of protein turns as participants in various biological events, such as protein-protein interactions, great efforts have been made to develop their conformationally and proteolytically stable mimetics. Ferrocene-1,1'-diamine was previously shown to nucleate the stable turn structures in peptides prepared by conjugation with Ala (III) and Ala-Pro (VI). Here, we prepared the homochiral conjugates of ferrocene-1,1'-diamine with l-/d-Phe (32/35), l-/d-Val (33/36), and l-/d-Leu (34/37) to investigate (1) whether the organometallic template induces the turn structure upon conjugation with amino acids, and (2) whether the bulky or branched side chains of Phe, Val, and Leu affect hydrogen bonding. Detailed spectroscopic (IR, NMR, CD), X-ray, and DFT studies revealed the presence of two simultaneous 10-membered interstrand hydrogen bonds, i.e., two simultaneous ß-turns in goal compounds. A preliminary biological evaluation of d-Leu conjugate 37 showed its modest potential to induce cell cycle arrest in the G0/G1 phase in the HeLa cell line but these results need further investigation.


Assuntos
Diaminas , Dipeptídeos , Humanos , Metalocenos/química , Ligação de Hidrogênio , Células HeLa , Cristalografia por Raios X , Estereoisomerismo , Dipeptídeos/química , Peptídeos/química , Aminoácidos/química , Conformação Proteica
3.
Int J Mol Sci ; 22(24)2021 Dec 16.
Artigo em Inglês | MEDLINE | ID: mdl-34948332

RESUMO

The concept of peptidomimetics is based on structural modifications of natural peptides that aim not only to mimic their 3D shape and biological function, but also to reduce their limitations. The peptidomimetic approach is used in medicinal chemistry to develop drug-like compounds that are more active and selective than natural peptides and have fewer side effects. One of the synthetic strategies for obtaining peptidomimetics involves mimicking peptide α-helices, ß-sheets or turns. Turns are usually located on the protein surface where they interact with various receptors and are therefore involved in numerous biological events. Among the various synthetic tools for turn mimetic design reported so far, our group uses an approach based on the insertion of different ferrocene templates into the peptide backbone that both induce turn formation and reduce conformational flexibility. Here, we conjugated methyl 1'-aminoferrocene-carboxylate with homo- and heterochiral Pro-Ala dipeptides to investigate the turn formation potential and antiproliferative properties of the resulting peptidomimetics 2-5. Detailed spectroscopic (IR, NMR, CD), X-ray and DFT studies showed that the heterochiral conjugates 2 and 3 were more suitable for the formation of ß-turns. Cell viability study, clonogenic assay and cell death analysis showed the highest biological potential of homochiral peptide 4.


Assuntos
Ácidos Carboxílicos/química , Ácidos Carboxílicos/farmacologia , Proliferação de Células/efeitos dos fármacos , Compostos Ferrosos/química , Compostos Ferrosos/farmacologia , Peptidomiméticos/química , Peptidomiméticos/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Cristalografia por Raios X/métodos , Dipeptídeos/química , Dipeptídeos/farmacologia , Células HeLa , Humanos , Células MCF-7 , Peptídeos/química , Peptídeos/farmacologia , Estrutura Secundária de Proteína , Estereoisomerismo
4.
Chemistry ; 23(43): 10372-10395, 2017 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-28543826

RESUMO

A series of peptides that contain homo- and heterochiral Ala-Pro sequences attached to the turn-inducing ferrocene-1,1'-diamine scaffold were synthesized. The effects of the backbone chirality and the N-terminal group (Boc/Ac) on the conformational properties of the novel peptidomimetics were thoroughly explored by IR, NMR, and CD spectroscopy and the experimental observations were corroborated by DFT studies in solution. The most stable conformers of the homochiral peptides adopted the interstrand hydrogen-bond patterns, realized through ten- and thirteen-membered rings. The common feature of the most stable conformers of the heterochiral peptides was the adoption of the turn-like structures that feature the simultaneous intra- (seven-membered) and interstrand (sixteen-membered) hydrogen-bonded rings. An exchange of two N-terminal groups had a somewhat larger influence on the distribution of the hydrogen-bond patterns in homochiral than in heterochiral derivatives. The homochiral peptides that contain pyridine moieties as metal coordination sites formed 1:1 complexes with divalent metal ions, which included Zn2+ , Cd2+ , Cu2+ and Fe2+ .


Assuntos
Compostos Ferrosos/química , Metalocenos/química , Peptídeos/química , Sequência de Aminoácidos , Sítios de Ligação , Dicroísmo Circular/métodos , Cristalografia por Raios X/métodos , Dipeptídeos/química , Compostos Ferrosos/síntese química , Ligação de Hidrogênio , Metalocenos/síntese química , Metais/química , Modelos Moleculares , Ressonância Magnética Nuclear Biomolecular/métodos , Peptídeos/síntese química , Ligação Proteica , Estrutura Secundária de Proteína , Piridinas/química , Espectrometria de Massas por Ionização por Electrospray/métodos , Espectroscopia de Infravermelho com Transformada de Fourier/métodos , Estereoisomerismo , Relação Estrutura-Atividade
5.
Molecules ; 19(8): 12852-80, 2014 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-25153883

RESUMO

Our previous studies showed that alteration of dipeptides Y-Fca-Ala-OMe (III) into Y-Ala-Fca-OMe (IV) (Y=Ac, Boc; Fca=1'-aminoferrocene-1-carboxylic acid) significantly influenced their conformational space. The novel bioconjugates Y-Fca-Pro-OMe (1, Y=Ac; 2, Y=Boc) and Y-Pro-Fca-OMe (3, Y=Boc; 4, Y=Ac) have been prepared in order to investigate the influence of proline, a well-known turn-inducer, on the conformational properties of small organometallic peptides with an exchanged constituent amino acid sequences. For this purpose, peptides 1-4 were subjected to detailed spectroscopic analysis (IR, NMR, CD spectroscopy) in solution. The conformation of peptide 3 in the solid state was determined. Furthermore, the ability of the prepared conjugates to inhibit the growth of estrogen receptor-responsive MCF-7 mammary carcinoma cells and HeLa cervical carcinoma cells was tested.


Assuntos
Antineoplásicos/farmacologia , Ácidos Carboxílicos/química , Compostos Ferrosos/química , Oligopeptídeos/farmacologia , Prolina/análogos & derivados , Prolina/síntese química , Antineoplásicos/química , Sobrevivência Celular/efeitos dos fármacos , Dicroísmo Circular , Cristalografia por Raios X , Ensaios de Seleção de Medicamentos Antitumorais , Células HeLa , Humanos , Ligação de Hidrogênio , Concentração Inibidora 50 , Células MCF-7 , Oligopeptídeos/química , Prolina/farmacologia , Estrutura Secundária de Proteína
6.
Amino Acids ; 42(1): 285-93, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-21082204

RESUMO

A simple and practical general synthetic protocol towards orthogonally protected tHyAsp derivatives fully compatible with Fmoc solid-phase peptide synthetic methodology is reported. Our approach includes enantioresolution of commercially available D: ,L: -tHyAsp racemic mixture by co-crystallization with L: -Lys, followed by ion exchange chromatography yielding enantiomerically pure L: -tHyAsp and D: -tHyAsp, and their selective orthogonal protection. In this way N ( α )-Fmoc protected tHyAsp derivatives were prepared ready for couplings via either α- or ß-carboxylic group onto the resins or the growing peptide chain. In addition, coupling of tHyAsp via ß-carboxylic group onto amino resins allows preparation of peptides containing tHyAsn sequences, further increasing the synthetic utility of prepared tHyAsp derivatives.


Assuntos
Ácido Aspártico/análogos & derivados , Ácido Aspártico/síntese química , Ácido Aspártico/química , Estrutura Molecular , Estereoisomerismo
7.
Food Chem ; 187: 236-42, 2015 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-25977022

RESUMO

The aim of the present study was to examine changes in phenolic compounds during refining of rapeseed oil. In crude rapeseed oil, 4-vinylsyringol (canolol) is the dominant phenolic compound, accounting for 85% of total phenolics. Refining decreased the total amount of phenolic compounds by 90%. NMR and MS analyses of edible rapeseed oil phenolic extracts identified 4-vinylsyringol dimer as the dominant phenolic compound. This phenolic compound appears to form through acid-catalyzed dimerization-aromatic substitution of 4-vinylsyringol monomers. Analysis of rapeseed oils from different stages of the refining process suggest that 4-vinylsyringol dimer forms during the neutralization phase, when H3PO4 acts as a catalyst, or during bleaching, when acid-activated bleaching earth acts as the catalyst. Whether 4-vinylsyringol forms during one or the other phase appears to depend on the phospholipid content of the crude oil. These insights may be useful for designing rapeseed oil refining processes that maximize levels of 4-vinylsyringol dimer.


Assuntos
Manipulação de Alimentos/métodos , Óleos de Plantas/química , Pirogalol/análogos & derivados , Cromatografia Líquida de Alta Pressão , Ácidos Graxos Monoinsaturados , Análise de Alimentos , Espectroscopia de Ressonância Magnética , Polifenóis/análise , Pirogalol/análise , Óleo de Brassica napus , Espectrometria de Massas em Tandem
8.
Dalton Trans ; 44(37): 16405-20, 2015 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-26308626

RESUMO

A novel synthetic approach toward a poorly explored bioorganometallic consisting of ferrocene-1,1'-diamine bearing structurally and chirally diverse amino acid sequences is reported. Until now, ferrocene-1,1'-diamine was suitable for accommodating only identical amino acid sequences at its N-termini, leading to the symmetrically disubstituted homochiral products stabilized through a 14-membered intramolecular hydrogen-bonded ring as is seen in antiparallel ß-sheet peptides. The key step of the novel synthetic pathway is the transformation of Ac-Ala-NH-Fn-COOH (5) (Fn = 1,1'-ferrocenylene) to orthogonally protected Ac-Ala-NH-Fn-NHBoc (7). The spectroscopic analysis (IR, NMR, CD) of the novel compounds, corroborated with DFT studies, suggests the interesting feature of the ferrocene-1,1'-diamine scaffold. The same hydrogen-bonding pattern, i.e. a 14-membered hydrogen-bonded ring, was determined both in solution and in the solid state, thus making them promising, yet simple scaffolds capable of mimicking ß-sheet peptides. In vitro screening of potential anticancer activity in Hep G2 human liver carcinoma cells and Hs 578 T human breast cancer cells revealed a cytotoxic pattern for novel compounds (150-500 µM) with significantly decreased cell proliferation.


Assuntos
Aminoácidos/química , Antineoplásicos/química , Diaminas/química , Compostos Ferrosos/química , Antineoplásicos/síntese química , Antineoplásicos/toxicidade , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Cristalografia por Raios X , Células Hep G2 , Humanos , Ligação de Hidrogênio , Espectroscopia de Ressonância Magnética , Metalocenos , Conformação Molecular , Peptídeos/química
9.
Chem Commun (Camb) ; (17): 2004-5, 2004 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-15340643

RESUMO

The unnatural organometallic amino acid 1'-aminoferrocene-1-carboxylic acid (Fca) induces a turn structure in a tetrapeptide with anti-parallel strands which is stabilized by two intra-molecular hydrogen bonds in the solid state and in solution.


Assuntos
Aminoácidos/química , Ácidos Carboxílicos/química , Compostos Ferrosos/química , Oligopeptídeos/química , Compostos Organometálicos/química , Dicroísmo Circular , Cristalografia por Raios X , Ligação de Hidrogênio , Espectroscopia de Ressonância Magnética , Metalocenos , Modelos Químicos , Estrutura Secundária de Proteína
10.
Carbohydr Res ; 346(5): 678-84, 2011 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-21316038

RESUMO

The two structurally interesting bioorganometallic analogues of muramyldipeptide (MDP) with potential immunomodulatory activity were synthesized starting from the O-protected N-acetylmuramic acid (MurNAc), L- or D-Ala and 1'-aminoferrocene-1-carboxylic acid (Fca). They were fully characterized by IR, (1)H NMR, (13)C NMR and CD spectroscopy as well as by FD mass spectrometry.


Assuntos
Ácidos Carboxílicos/química , Compostos Ferrosos/química , Ácidos Murâmicos/química , Peptídeos/química , Peptídeos/síntese química , Dicroísmo Circular , Ligação de Hidrogênio , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Metalocenos , Estrutura Molecular
11.
Acta Crystallogr C ; 62(Pt 12): m610-1, 2006 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-17148899

RESUMO

The title compound, [Fe(C6H5O2)(C10H13O2)], contains a heteroannularly substituted ferrocene unit, with the two substituents, viz. 3-(methoxycarbonyl)propyl and carboxyl, both capable of forming O-H...O hydrogen bonds. The keto ester group is stereochemically hindered by the trimethylene spacer and does not participate in intramolecular hydrogen-bond formation. Instead, the carboxy groups form self-complementary intermolecular hydrogen bonds [O...O = 2.650 (2) A], which join the molecules into centrosymmetric dimers with a graph-set descriptor R(2)2(8).

12.
Chemistry ; 12(19): 4965-80, 2006 Jun 23.
Artigo em Inglês | MEDLINE | ID: mdl-16721886

RESUMO

We present a detailed structural study of peptide derivatives of 1'-aminoferrocene-1-carboxylic acid (ferrocene amino acid, Fca), one of the simplest organometallic amino acids. Fca was incorporated into di- to pentapeptides with D- and L-alanine residues attached to either the carboxy or amino group, or to both. Crystallographic and spectroscopic studies (circular dicroism (CD), IR, and NMR) of about two dozen compounds were used to gain a detailed insight into their structures in the solid state as well as in solution. Four derivatives were characterized by single-crystal X-ray analysis, namely Boc-Fca-Ala-OMe (16), Boc-Fca-D-Ala-OMe (17), Boc-Fca-beta-Ala-OMe (18), and Boc-Ala-Fca-Ala-Ala-OMe (21) (Boc=tert-butyloxycarbamyl). CD spectroscopy is an extremely useful tool to elucidate the helical chirality of the metallocene core. Unlike in all other known ferrocene peptides, the helical chirality of the ferrocene is governed solely by the chirality of the amino acid attached to the N terminus of Fca. Depending on the degree of substitution of both cyclopentadiene (Cp) rings, different hydrogen-bonding patterns are realized. (1)H NMR and IR spectroscopy, together with the results from X-ray crystallography, give detailed information regarding not only the hydrogen-bonding patterns of the compounds, but also the equilibria between different conformers in solution. Differences in chemical shifts of NH protons in dimethyl sulfoxide ([D(6)]DMSO) and CDCl(3), that is, the variation ratio (vr), is used for the first time as a measure of the hydrogen-bonding strength of individual COHN bonds in ferrocenoyl peptides. In dipeptides with one intramolecular hydrogen bond between the pendant chains, for example, in dipeptide 16, an equilibrium between hydrogen-bonded and open forms is observed, as testified by a vr value of around 0.5. Higher peptides, such as tetrapeptide 21, are able to form two intramolecular hydrogen bonds stabilizing one single conformation in CDCl(3) solution (vr approximately 0). Due to the low barrier of Cp-ring rotation, new and unnatural hydrogen-bonding patterns are emerging. The systematic work described herein lays a solid foundation for the rational design of metallocene peptides with unusual structures and properties.


Assuntos
Ácidos Carboxílicos/química , Compostos Ferrosos/química , Peptídeos/química , Dicroísmo Circular , Cristalografia por Raios X , Indicadores e Reagentes , Espectroscopia de Ressonância Magnética , Metalocenos , Modelos Moleculares , Conformação Molecular , Espectrofotometria Infravermelho , Espectroscopia de Infravermelho com Transformada de Fourier , Estereoisomerismo
13.
Acta Crystallogr C ; 59(Pt 2): m55-7, 2003 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-12574647

RESUMO

Heteroannularly substituted ferrocene derivatives can act as model systems for various hydrogen-bonded assemblies of biomolecules formed, for instance, by means of O-H...O and N-H...O hydrogen bonding. The crystal structure analysis of 1'-(tert-butoxycarbonylamino)ferrocene-1-carboxylic acid, [Fe(C(10)H(14)NO(2))(C(6)H(5)O(2))] or (C(5)H(4)COOH)Fe(C(5)H(4)NHCOOC(CH(3))(3), reveals two independent molecules within the asymmetric unit, and these are joined into discrete dimers by two types of intermolecular hydrogen bonds, viz. O-H...O and N-H...O. The -COOH and -NHCOOR groups are archetypes for dimer formation via two eight-membered rings. The O-H...O hydrogen bonds [2.656 (3) and 2.663 (3) A] form a cyclic carboxylic acid dimer motif. Another eight-membered ring is formed by N-H...O hydrogen bonds [2.827 (3) and 2.854 (3) A] between the N-H group and an O atom of another carbamoyl moiety. The dimers are assembled in a herring-bone fashion in the bc plane.

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