The synthesis and structural characterization of N-para-ferrocenyl benzoyl dipeptide esters: The X-ray crystal structure of N-{para-(ferrocenyl)benzoyl}-l-alanine-glycine ethyl ester

A series ofN-para-ferrocenyl benzoyl dipeptide esters 2-5 were prepared by coupling para-ferrocenyl benzoic acid (1) to the dipeptide ethyl esters using the conventional 1,3-dicyclohexylcarbodiimide (DCC), 1-hydroxybenzotriazole (HOBt) protocol. The dipeptides employed in the synthesis were Ala-Gly(OEt) (2), Ala-Ala(OEt) (3), Ala-Leu(OEt) (4) and Ala-Phe(OEt) (5). The compounds were fully characterized by a range of NMR spectroscopic techniques, electrospray ionization mass spectrometry (ESI-MS) and tandem mass spectrometry (MS/MS). In addition the X-ray crystal structure of the l-alanine-glycine derivative 2 has been determined.     

The synthesis and structural characterization of novel N-meta-ferrocenyl benzoyl dipeptide esters: The X-ray crystal structure and in vitro anti-cancer activity of N-{meta-ferrocenyl)benzoyl}-l-alanine-glycine ethyl ester

A series of N-meta-ferrocenyl benzoyl dipeptide esters 2-5 have been prepared by coupling meta-ferrocenyl benzoic acid 1b to the dipeptide ethyl esters using the conventional 1,3-dicyclohexylcarbodiimide (DCC), 1-hydroxybenzotriazole (HOBt) protocol. The dipeptides employed in the synthesis were AlaGly(OEt) (2), AlaAla(OEt) (3), AlaLeu(OEt) (4) and AlaPhe(OEt) (5). The compounds were fully characterized by a range of NMR spectroscopic techniques, mass spectrometry (MALDI-MS, ESI-MS), and cyclic voltammetry (CV). In addition, the X-ray crystal structure and cytotoxicity of N-{meta-(ferrocenyl)-benzoyl}-l-alanine-glycine ethyl ester (2) towards lung cancer cells has been determined.     

Synthesis and structural characterization of N-para-ferrocenyl benzoyl amino acid ethyl esters and the X-ray crystal structures of the glycyl and (±)-2-aminobutyric acid derivative Fc-C6H4CONHCH(C2H5)CO2Et

A series of N-para-ferrocenyl benzoyl amino acid ethyl esters 1-8 have been prepared by coupling para-ferrocenyl benzoic acid with the amino acid esters using the conventional 1,3-dicyclohexylcarbodiimide (DCC), 1-hydroxybenzotriazole (HOBt) protocol. The amino acids employed in the synthesis were glycine, l-alanine, l-leucine, l-phenylalanine, β-alanine, 4-aminobutyric acid, (±)-2-aminobutyric acid and 2-aminoisobutyric acid. The compounds were fully characterized by a range of spectroscopic techniques such as NMR and mass spectrometry. In addition the X-ray crystal structures of the glycyl 1 and (±)-2-aminobutyrate 7 derivatives have been determined. Analysis of relevant fragments in crystal structures on the Cambridge Structural Database indicates a relative paucity of common fragments such as the α-aminobutyrate group in comparison to the glycyl moiety.     

Synthesis of the unnatural amino acid N-N-(ferrocene-1-acetyl)-l-lysine: A novel organometallic nuclease

The synthesis of a new unnatural amino acid, N^α-N^ε-(ferrocene-1-acetyl)-l-lysine, was achieved by coupling a ferroceneacetic acid molecule onto the side chain amine of a lysine. The structure of the compound provides options for incorporation of the molecule into peptides or large proteins. In addition, N^α-N^ε-(ferrocene-1-acetyl)-l-lysine exhibits nuclease activity. It is expected that incorporation of this ferrocenyl amino acid into any nucleic acid-binding protein will endow the protein with nuclease capability.     

Synthesis, structural characterization, in vitro anti-proliferative effect and cell cycle analysis of N-(ferrocenyl)benzoyl dipeptide esters

N-ortho, meta and para-(ferrocenyl)benzoyl dipeptide esters 2-10 were prepared by coupling ferrocenyl benzoic acids 1(ortho, meta and para) to the dipeptide ethyl esters GlyAbu(OEt) 2-4, GlyNva(OEt) 5-7 and GlyNle(OEt) 8-10 in the presence of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride and 1-hydroxybenzotriazole. The compounds were fully characterized by a range of NMR spectroscopic techniques, mass spectrometry and cyclic voltammetry. The cytotoxicity of 3, 6 and 9 versus H1299 lung cancer cells were 10.5 μM, 19.1 μM and 18.9 μM, respectively, whereas N-{meta-(ferrocenyl)-benzoyl}-glycine-l-alanine ethyl ester 11 and N-{para-(ferrocenyl)-benzoyl}-glycine-l-alanine ethyl ester 12 gave IC₅₀ values of 4.0 and 6.6 μM, respectively. Therefore, an increase in alkyl chain length of the second amino acid also increases the IC₅₀ values. Cell cycle analysis of N-{ortho-(ferrocenyl)-benzoyl}-glycine-l-alanine ethyl ester 13 suggests a block in the G2/M phase of the cell cycle.     

The synthesis, structural characterization and in vitro anti-cancer activity of novel N-(3-ferrocenyl-2-naphthoyl) dipeptide ethyl esters and novel N-(6-ferrocenyl-2-naphthoyl) dipeptide ethyl esters

N-(3-ferrocenyl-2-naphthoyl) dipeptide esters (5-7) and N-(6-ferrocenyl-2-naphthoyl) dipeptide esters (8-10) were prepared by coupling either 3-ferrocenylnaphthalene-2-carboxylic acid 2 or 6-ferrocenylnaphthalene-2-carboxylic acid 4 to the dipeptide ethyl esters GlyAla(OEt) (5, 8), AlaGly(OEt) (6, 9), and AlaAla(OEt) (7, 10) using the standard N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC), 1-hydroxybenzotriazole (HOBt) protocol. All the compounds were fully characterized using a combination of ¹H NMR, ¹³C NMR, DEPT-135 and ¹H-¹³C COSY (HMQC) spectroscopy, electrospray ionization mass spectrometry (ESI-MS) and cyclic voltammetry (CV). In vitro, the cytotoxic effects of compounds 5-10 show improvements over the corresponding N-(ferrocenyl)benzoyl derivatives, with IC₅₀ values against the H1299 lung cancer cells ranging from 1.2 μM to 8.0 μM. N-(6-ferrocenyl-2-naphthoyl)-glycine-l-alanine ethyl ester 8 was found to be the most active derivative of the naphthoyl series so far, displaying an IC₅₀ value of 1.3 ± 0.1 μM. This value is slightly lower than that found for the clinically employed anti-cancer drug cisplatin (IC₅₀ = 1.5 ± 0.1 μM against H1299).     

Synthesis, structural characterisation and biological activity of novel N-(ferrocenylmethyl)benzene-carboxamide derivatives

A series of N-(ferrocenylmethyl)benzene-carboxamide derivatives (4a-f) have been synthesised by coupling ferrocenylmethyl amine 3 with benzoic acid and various substituted fluorobenzoic acids using the standard 1,3-dicyclohexylcarbodiimide (DCC), 1-hydroxybenzotriazole (HOBt) protocol. All compounds were fully characterised using a combination of ¹H NMR, ¹³C NMR, ¹⁹F NMR, DEPT-135, ¹H-¹H COSY and ¹H-¹³C COSY (HMQC) spectroscopy and electrospray ionisation mass spectrometry (ESI-MS). The compounds 4a, 4d, 4e and 4f exhibited cytotoxic effects on the MDA-MB-435-S-F breast cancer cell line. Single crystal X-ray crystallographic data for 4d is also presented.     

Synthesis and structural characterisation of redox-responsive N-ferrocenoyl amino acid esters; the X-ray crystal structure of N-ferrocenoyl alanine methyl ester; electrochemical anion recognition and H NMR complexation studies

The N-ferrocenoyl amino acid ester derivatives FcCOR {Fc=(η⁵-C₅H₅)Fe(η⁵-C₅H₄)} where R=Gly(OMe) 1, Gly(OEt) 2, Gly(OBn) 3, l-Ala(OMe) 4, l-Ala(OEt) 5, l-Leu(OMe) 6, l-Leu(OEt) 7, l-Leu(OBn) 8, l-Phe(OMe) 9 and l-Phe(OEt) 10, were prepared by coupling ferrocene carboxylic acid with the appropriate amino acid ester starting materials using the 1,3-dicyclohexylcarbodiimide (DCC), 1-hydroxybenzotriazole (HOBt) protocol and these have been characterised by spectroscopic techniques. The electrochemical anion sensing behaviour of compounds 1-10 with several anions using a platinum microdisk working electrode is described, together with ¹H NMR anion complexation studies. The X-ray single crystal structure of N-ferrocenoyl-l-alanine methyl ester 4 has been determined and contains two molecules which differ slightly in conformation in the asymmetric unit of space group P2₁ (No. 4); principal dimensions are amide N(H)CO 1.224(6) and 1.231(6) Å, ester CO 1.220(10) and 1.190(7) Å, with N-H?OC(amide) as the primary intermolecular hydrogen bond, N?O 2.992(6) and 2.971(6) Å and with graph set C(4).     

A one-step synthesis of N-Fmoc-4-O-[O′,O″-di-tert-butyl-2-(2-fluoromalonyl)]-l-tyrosine from commercially available starting material

A one-step high yield synthesis from commercially available starting material is reported for the novel phosphotyrosyl mimetic, N^α-Fmoc-4-O-[O′,O″-di-tert-butyl-2-(2-fluoromalonyl)]-l-tyrosine. The conditions employed for this transformation may also be applicable for the direct electrophilic fluorination of other N^α-Fmoc-protected amino acids.     

Synthesis of isotopomers of N-(tert-butoxycarbonyl)-4-cyano-l-phenylalanine methyl ester: choice of cyanation solvent

N-(tert-butoxycarbonyl)-4-cyano-l-phenylalanine methyl ester and three isotopomers (C¹⁵N, ¹³CN, and ¹³C¹⁵N) were successfully synthesized in two steps to expand the utility of the nitrile symmetric stretch vibration of this modified amino acid as a vibrational reporter of local environments. The choice of cyanation solvent directly impacted the level of isotopic enrichment of the isotopomers. The commonly used solvent acetonitrile resulted in an isotopic enrichment of only ∼80% with a cyanation reaction time of 4.5 h, however, the cyanation solvent N,N-dimethylformamide afforded the isotopomers with >98% isotopic enrichment.     

(4R)-4-Hydroxy-1-nitroso-l-proline: synthesis, X-ray structure, ab initio and conformational calculations

4-Hydroxy-l-proline, an amino acid, an important component of collagen, was transformed into its N-nitroso-derivative, (4R)-4-hydroxy-1-nitroso-l-proline, 1 by butylnitrite in the acidic medium. The structure is a cyclic hydroxy-N-nitrosoacid with the carboxyl and hydroxyl groups trans to each other. The carboxyl group is in the syn-conformation. In the structure, the neutral molecules are connected via classical intermolecular O-H?O hydrogen bonds involving the hydroxyl and carboxyl groups [O?O=2.6251(14) Å], and form chains along the a-axis direction. The chains are linked into sheets via O-H?O hydrogen bond, [O?O=2.6813(15) Å] with participation of oxygen atom of nitroso group. Ab initio calculations based on density functional theory at the B3LYP/6-311++G(d, p) level of theory were performed to analyze the influence of 4-hydroxy-l-proline (Hyp) nitrosation on the conformation of the synthesized N-nitroso-compound. The geometry optimization of 1 and initial 4-hydroxy-l-proline was carried out in the gas phase and in solution using the polarizable continuum model. The single-point calculation was performed for the crystal structure of 1. The most stable conformer of 1 is observed in an aqueous solution. In this state, the pyrrolidine ring adopts an envelope conformation, which is also maintained in the gas phase. The twisted conformation of the pyrrolidine ring is present in all states of Hyp and in the crystal structure of 1. In 1 the interchange of five-membered ring conformation in solution and in the gas phase in comparison with the crystal is accompanied by an increase of the dipole moment of the molecule, which is maximal in solution.     

Novel optically active poly(amide-imide)s from N,N-(4,4-carbonyldiphthaloyl)-bis-l-phenylalanine diacid chloride and aromatic diamines by microwave irradiation

3,3^′,4,4^′-benzophenonetetracarboxylic dianhydride (4,4^′-carbonyldiphthalic anhydride) (1) was reacted with l-phenylalanine (2) in a mixture of acetic acid and pyridine (3:2) and the resulting imide-acid [N,N^′-(4,4^′-carbonyldiphthaloyl)-bis-l-phenylalanine diacid] (4) was obtained in high yield. The compound (4) was converted to the N,N^′-(4,4^′-carbonyldiphthaloyl)-bis-l-phenylalanine diacid chloride (5) by reaction with thionyl chloride. A new facile and rapid polycondensation reaction of this diacid chloride (5) with several aromatic diamines such as 4,4^′-diaminodiphenyl methane (6a), 2,4-diaminotoluene (6b), 4,4^′-sulfonyldianiline (6c), p-phenylenediamine (6d), 4,4^′-diaminodiphenylether (6e), m-phenylenediamine (6f), benzidine (6g) and 2,6-diaminopyridine (6h) was developed by using a domestic microwave oven in the presence of a small amount of a polar organic medium such as o-cresol. The polymerization reactions proceeded rapidly, compared with the conventional solution polycondensation, and was completed within 7 min, producing a series of optically active poly(amide-imide)s with high yield and inherent viscosity of 0.22-0.52 dl/g. All of the above polymers were fully characterized by IR, elemental analyses and specific rotation. Some structural characterization and physical properties of this optically active poly(amide-imide)s are reported.     

Non-ionic surfactant modified ligand exchange chromatography using copper (II) complex of N,N-dimethyl-l-phenylalanine as the chiral additive for enantioselective amino acids separation

The influence of non-ionic surfactants on the selectivity and retention in the ligand exchange chromatography for the enantioselective separation of racemic mixtures of the amino acids dl-methionine, dl-leucine, dl-valine and dl-tyrosine applying chiral mobile phases was investigated, whereas five different surfactants were tested as modifiers. The experiments were carried out using a commercially available non-chiral RP-C8 column and the copper (II) complex of N,N-dimethyl-l-phenylalanine as the chiral additive. Varying the surfactant concentrations the retention factors and the selectivity could be controlled and in general no negative influence on the separation (due to surfactant adsorption on the non-chiral stationary phase) occurred. Changing the temperature the van’t Hoff plots were obtained and the thermodynamic parameters calculated. Temperature had influence on the selectivity for each surfactant and lowered the retention times as expected.     

Study on biodegradable polymers: synthesis and characterization of poly(DL-lactic acid-co-l-lysine) random copolymer

Poly(DL-lactic acid-co-l-lysine) (PLAL) random copolymer was obtained by copolymerization of amino acid-N-carboxy anhydride with lactic acid anhydrosulphite in the presence of an initiator. The structures of the poly(DL-lactic acid-co-ε-cbz-l-lysine) and PLAL were characterized by IR, ¹H-NMR, ¹³C-NMR and elemental analysis. Different initiators were used to initiate the ring-opening copolymerization. Good agreement between calculated and actual compositions was observed in most cases when using dibutylzinc as initiator. The solubility of PLAL was discussed.     

Thermal phase transitions of solid chiral N,N′-carbonyl-bis-(l-amino acids) and their methyl and benzyl esters

Compounds derived from different N,N′-carbonyl-bis-(l-amino acids) and their methyl and benzyl esters were synthesized and characterized by elemental analysis, infrared and nuclear magnetic resonance. The amino acids used were valine, leucine, phenylglycine and phenylalanine. All compounds revealed complex thermal behaviour as proved by differential scanning calorimetry, X-ray powder diffractometry and optical birefringence observation by polarizing microscope. Above isotropization temperature N,N′-carbonyl-bis-(l-amino acids) decomposed. The number and kinds of thermal phase transitions of investigated esters vary from a simple phase transition and melting to a complex polymorphism, and strongly depends on molecular structure. One to four phase transitions have been observed upon heating. Phase transition temperatures showed considerable variation with choice of the supstituent on symmetric carbons and therminal carboxylic groups. The results are discussed in terms of the architecture of investigated molecules that hinder mesomorphism.     

Chiral self-assembly of triorganotin complexes: Syntheses, characterization, crystal structures and antitumor activity of organotin(IV) complexes containing (R)-(+)-methylsuccinic acid, (S)-(+)-methylglutaric acid and l-(−)-malic acid ligands

Six new chiral triorganotin(IV) complexes, {(R₃Sn)₂[C₃H₆(COO)₂]}_n (R = Me: 1; Bu: 2), {(R₃Sn)₂[C₄H₈(COO)₂]}_n (R = Me: 3; Bu: 4), and {(R₃Sn)₂[C₂H₄O(COO)₂]}_n (R = Me: 5; Bu: 6) have been prepared by treatment of (R)-(+)-methylsuccinic acid, (S)-(+)-methylglutaric acid and l-(−)-malic acid, with the corresponding R₃SnCl (R = Me, Bu) and sodium ethoxide in methanol. All the complexes were characterized by elemental analysis, FT-IR, NMR (¹H, ¹³C, ¹¹⁹Sn) spectroscopy and TGA. Except for 3, all of the complexes were also characterized by X-ray crystallography. The structural analyses reveal that complexes 1 and 5 have 2D network structures in which (R)-(+)-methylsuccinic acid and l-(−)-malic acid act as tetradentate ligands coordinated to trimethyltin(IV) ions. Complexes 2 and 4 have 3D metal-organic framework structures in which the deprotoned acids serve as tetradentate ligands. Complex 6 adopts a 1D zigzag chain structure and forms a 2D supramolecular framework through intermolecular C-H?O interactions. In addition, the antitumor activities of complexes 1-6 have been studied. We also have measured the specific rotation of the chiral dicarboxylic acids and the organotin derivatives.