Charge Transfer Properties of Benzo[b]thiophene Ferrocenyl Complexes

The synthesis of 2-ferrocenylbenzo[b]-thiophene, 3-ferrocenylbenzo[b]thiophene, 1,1-bis(2-indene)-ferrocene, and the two isomers of 1,1'-bis(2-benzo[b]-thiophene)ferrocene was efficiently achieved by using the palladium-catalyzed Negishi C,C cross-coupling reaction of the appropriate bromobenzo[b]thiophene derivative with ferrocenylzinc chloride. The accessibility of differently substituted benzo[b]thiophenes and a comparison with indene analogues allowed an in-depth investigation on how the geometric modifications and the presence of sulfur affect their physical properties. The molecular structure of 3-ferrocenylbenzo[b]-(t)hiophene has been determined by X-ray diffraction. Electrochemistry and UV-vis-NIR spectroscopy, in particular the appearance upon oxidation of a charge transfer absorption in the NIR region, are rationalized through quantum chemistry calculations and in the framework of the Hush theory

Hydrogen-bond-assisted, concentration-dependent molecular dimerization of ferrocenyl hydantoins

The synthesis and characterization of the ferrocenyl methylhydantoin 5-ferrocenyl-5-methylimidazolidine-2,4-dione, efficiently prepared through a Bucherer-Bergs reaction, and its derivatives carrying tert-butoxycarbonyl (Boc) protecting groups, namely 1,3-bis(tert-butoxycarbonyl)-5-ferrocenyl-S-methylirnidazolidine-2,4-dione and 1-(tert-butoxycarbonyl)-5-ferrocenyl-5-methylimidazolidine-2,4-dione, are reported. X-ray diffraction and ESI-mass spectrometry analyses of the ferrocenyl methylhydantoin revealed the presence of C=O center dot center dot center dot H-N intermolecularly hydrogen-bonded dimers. The mono-Boc derivative formed a hydrogen-bonded dimer in solution, as confirmed by H-1 NMR, FT-IR, and cyclic voltammetry experiments at different concentrations in CDCl3 or CHCl3

Effect on the conformation of a terminally blocked, (E) ß,y-unsaturated o-amino acid residue induced by carbon methylation

Peptides are well-known to play a fundamental therapeutic role and to represent building blocks for numerous useful biomaterials. Stabilizing their active 3D-structure by appropriate modifications remains, however, a challenge. In this study, we have expanded the available literature information on the conformational propensities of a promising backbone change of a terminally blocked d-amino acid residue, a dipeptide mimic, by replacing its central amide moiety with an (E) Cß-C¿ alkene unit. Specifically, we have examined by DFT calculations, X-ray diffraction in the crystalline state, and FT-IR absorption/NMR spectroscopies in solution the extended vs folded preferences of analogues of this prototype system either unmodified or possessing single or multiple methyl group substituents on each of its four -CH2-CH-CH-CH2– main-chain carbon atoms. The theoretical and experimental results obtained clearly point to the conclusion that increasing the number of adequately positioned methylations will enhance the preference of the original sequence to fold, thus opening interesting perspectives in the design of conformationally constrained peptidomimetics.Postprint (author's final draft

Helical foldamers incorporating photoswitchable residues for light-mediated modulation of conformational preference

An E unsaturated fumaramide linkage may be introduced into Aib peptide foldamer structures by standard coupling methods and photoisomerized to its Z (maleamide) isomer by irradiation with UV light. As a result of the photoisomerization, a new hydrogen-bonded contact becomes possible between the peptide domains located on either side of the unsaturated linkage. Using the fumaramide/maleamide linker to couple a chiral and an achiral fragment allows the change in hydrogen bond network to communicate a conformational preference, inducing a screw sense preference in the achiral domain of the maleamide-linked foldamers that is absent from the fumaramides. Evidence for the induced screw sense preference is provided by NMR and CD, and also by the turning on by light of the diastereoselectivity of a peptide chain extension reaction. The fumaramide/maleamide linker thus acts as a "conformational photo diode" that conducts stereochemical information as a result of irradiation by UV ligh

Facile and E-Selective Intramolecular Ring-Closing Metathesis Reactions in 3_(10)-Helical Peptides: A 3D Structural Study

The ring-closing metathesis reaction can be used to cross-link allylated serine residues situated at the i and i + 3 positions in 3_(10)-helical peptides containing the helicogenic amino acid, α-aminoisobutyric acid (Aib). An octapeptide with the sequence Boc-Aib-Aib-Aib-Ser(Al)-Aib-Aib-Ser(Al)-Aib-OMe was found to undergo a facile and >20:1 E-selective ring-closing metathesis (RCM) reaction catalyzed by the Grubbs second-generation catalyst to yield an 18-membered macrocycle. The formation of this cross-link does not significantly disturb the peptide's native 3_(10)-helicity, as judged by an X-ray diffraction study of the acyclic diene, the E-olefin RCM product, and its hydrogenated derivative. A heptapeptide system with the sequence Boc-Val-Ser(Al)-Leu-Aib-Ser(Al)-Val-Leu-OMe also underwent an efficient RCM reaction, albeit with diminished E-selectivity. It is apparent from these studies that a minimal, RCM-derived, macrocyclic constraint can be readily incorporated into 3_(10)-helical peptides

A study of a C Α, Β -didehydroalanine homo-oligopeptide series in the solid-state by 13 C cross-polarization magic angle spinning NMR

The fully extended peptide conformation (2.0 5 -helix) has been investigated for the first time in the solid-state by 13 C cross-polarization magic angle spinning NMR. The compounds examined are members of a terminally protected, homo-oligopeptide series (from monomer through hexamer) based on C Α, Β -didehydroalanine. Copyright © 2004 European Peptide Society and John Wiley & Sons, Ltd.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/35198/1/551_ftp.pd

Peptide delta-turn: Literature survey and recent progress

Among the various types of a-peptide folding motifs, delta-turn, which requires a central cis-amide disposition, has been one of the least extensively investigated. In particular, this main-chain reversal topology has been studied in-depth neither in linear/cyclic peptides nor in proteins. This Minireview article assembles and critically analyzes relevant data from a literature survey on the d-turn conformation in those compounds. Unpublished results from recent conformational energy calculations and a preliminary solution-state analysis on a small model peptide, currently ongoing in our laboratories, are also briefly outlined.Postprint (published version

Anticancer gold(III) peptidomimetics: from synthesis to in vitro and ex vivo biological evaluation

Five new Au(III)‐peptidodithiocarbamato complexes of the type [AuIIIBr2(dtc‐AA1‐AA2‐OR] (AA1=Sar, L/D‐Pro; AA2=L/D‐Ala, Aib; R=OtBu, TEG), differing in the amino acidic sequence and/or the chiral amino acid configuration, were designed to enhance the tumor selectivity and bioavailability. The gold(III)‐based moiety was functionalized to exploit the targeting properties of the peptidomimetic ligand towards two peptide transporters (namely, PEPT1 and PEPT2), up‐regulated in several tumor cells. The compounds were synthesized and fully characterized, mainly by means of elemental analysis, mono‐ and bidimensional NMR spectroscopy, FT‐IR and UV‐Vis spectrophotometries. The crystal structures of three compounds were also solved by X‐ray diffraction. In vitro cytotoxicity studies using a panel of human tumor cell lines (A549, MCF‐7, A2780, H1975, H460 and A431) showed that the dtc‐Pro‐Aib‐OtBu derivative is very effective, with GI50 values much lower than those of Cisplatin. It was thus selected for evaluating the stability under physiological conditions and possible interaction with serum albumin as well as for PARP‐1 enzyme inhibition assays and preliminary ex vivo toxicity experiments on healthy rat tissues

Comparative conformational analysis of peptides based on the two Cα-tetrasubstituted, Cβ-branched, chiral α-amino acids (αMe)Dip and (αMe)Val

For the first time a number of terminally protected model peptides (to the pentamer level) of the sterically demanding α-amino acid Cα-methyl,Cα-diphenylmethylglycine, (αMe)Dip, in combination with either Ala or Gly residues, have been synthesized (by solution methods) and fully characterized. In a parallel synthesis the corresponding peptides based on the related α-amino acid Cα-methyl,Cα-isopropylglycine, (αMe)Val, have also been prepared. The results of a comparative conformational analysis, performed by using FTIR absorption, 1H NMR, and X-ray diffraction techniques, favour the conclusion that, in contrast to the potent β-turn and 310-helix promoter (αMe)Val, (αMe)Dip may induce either a folded or a fully extended conformation. These findings indicate that, despite the common Cα-methylated and Cβ-branched features, (αMe)Dip and (αMe)Val are characterized by partially divergent conformational bias.The Padova authors gratefully acknowledge M.U.R.S.T., the Ministry of University and Scientific and Technological Research, and the National Council of Research (C.N.R.) of Italy for their continuous support of this research. The Zaragoza and Padova authors are also grateful to the Spain-Italy exchange program “Accion Integrada” HI 97-20/“Azioni Integrate” 1997/1999.Peer reviewe

(αMe)Nva: stereoselective syntheses and preferred conformations of selected model peptides

Using different stereoselective chemical and chemoenzymatic approaches we synthesized the chiral, Cα-methylated α-amino acid l-(αMe)Nva with a short, linear side-chain. A set of terminally protected model peptides to the pentamer level containing either (αMe)Nva or Nva in combination with Ala and/or Aib was prepared using solution methods and characterized fully. Two (αMe)Nva peptides were also synthesized using side-chain hydrogenation of the corresponding Cα-methyl, Cα-allylglycine (Mag) peptides. A detailed solution and crystal-state conformational analysis based on FT-IR absorption, 1H NMR and X-ray diffraction techniques allowed us to define that: (i) (αMe)Nva is an effective β-turn and 310-helix former; and (ii) the relationship between (αMe)Nva chirality and the screw sense of the turn/helix formed is that typical of protein amino acids, i.e. l-(αMe)Nva induces the preferential formation of right-handed folded structures. In more general terms, this study reinforced previous conclusions that peptides based on α-amino acids with a Cα-methyl substituent and a Cα-linear alkyl substituent are characterized by a strong tendency to fold into turn and helical structures.The Padova authors gratefully acknowledge M.U.R.S.T., the Ministry of University and Scientific and Technological Research, and C.N.R., the National Council of Research of Italy for their continuous support. The Zaragoza authors acknowledge the Direccion General de Investigacion Cientifica y Tecnica (PB94±0998) for financial support. The Zaragoza and Padova authors are also grateful to the Spain-Italy exchange program Accion Integrada HI 97-20/AzioniIntegrate 1997/99.Peer reviewe