Cyclopropane-derived peptidomimetics. Design, synthesis, and evaluation of novel enkephalin analogues

It is known that peptide mimics containing trans-substituted cyclopropanes stabilize extended conformations of oligopeptides, and molecular modeling studies now suggest that the corresponding cis-cyclopropane dipeptide isosteres could stabilize a reverse turn. To begin to assess this possibility, a series of cis-substituted cyclopropanes were incorporated as replacements of the Gly(2)-Gly(3) and Phe(4)-Leu(5) dipeptide subunits in Leu-enkephalin (H(2)N-Tyr-Gly-Gly-Phe-Leu-OH), which is believed to bind to opiod receptors in a conformation containing a beta-turn. General methods for the synthesis of the cyclopropane-containing dipeptide isosteres -XaaPsi[COcpCO]Yaa- and -XaaPsi[NHcpNH]Yaa-were developed by a sequence that featured the enantioselective cyclization of allylic diazoacetates catalyzed by the chiral rhodium complexes Rh(2)[(5S)-MEPY](4) and Rh(2)[(5R)-MEPY](4). A useful modification of the Weinreb amidation procedure was applied to the opening of the intermediate lactones with dipeptides, and a novel method for the synthesis of substituted diaminocyclopropanes was also developed. The Leu-enkephalin analogues were tested in a panel of binding and functional assays, and although those derivatives containing cyclopropane replacements of the Gly(2)-Gly(3) exhibited low micromolar affinity for the mu-receptor, analogues containing such replacements for the Phe(4)-Leu(5) subunit did not bind with significant affinity to any of the opioid receptors. These results are discussed.     

Cyclopropane-derived peptidomimetics. design, synthesis, and evaluation of novel Ras farnesyltransferase inhibitors

Trisubstituted cyclopropanes have previously been established as rigid replacements of dipeptide arrays in several biological systems. Toward further evaluating the utility of these dipeptide mimics in the design of novel CA(1)A(2)X-based inhibitors of Ras farnesyltransferase (FTase), the conformationally constrained, diastereomeric pseudopeptides CAbuPsi[COcpCO]FM 7-9, the flexible analogue CAbuPsi[CHOHCH(2)]FM (10), and the tetrapeptide CAbuFM (6) were prepared. The orientations of the two peptide backbone substituents and the phenyl group on the cyclopropane rings in 7-9were specifically designed to probe selected topological features of the hydrophobic binding pocket of the A(2) subsite of FTase. The syntheses of the requisite trisubstituted cyclopropane carboxylic acid 22 and the diastereomeric cyclopropyl lactones 32a,b featured diastereoselective intramolecular cyclopropanations of chiral allylic diazoacetates and a new method for introducing side chains onto the C-terminal amino acid of cyclopropane-derived dipeptide replacements via the opening of an N-Boc-aziridine with an organocuprate. These cyclopropane intermediates were then converted into the targeted FTase inhibitors 7-9 by standard peptide coupling techniques. The pseudopeptides 7-9 were found to be competitive inhibitors of Ras FTase with IC(50)s of 1055 nM for 7, 760 nM for 8, and 7200 nM for 9. The flexible analogue 10 of these constrained inhibitors exhibited a IC(50) of 320 nM and hence was slightly more potent than 7 and 8. All of these pseudopeptides were less potent than the tetrapeptide parent CAbuFM (6), which had an IC(50) of 38 nM. Because 7 and 8 are approximately equipotent, it appears that the orientation of the peptide backbone substituents on the cyclopropane rings in 7 and 8 do not have any significant effect on binding affinity and that multiple binding modes are possible without significant changes in affinity. On the other hand, this flexibility does not extend to the orientation of the side chain of the A(2) residue as 7 and 8 were both nearly 1 order of magnitude more potent than 9. Comparison of the relative potencies of 6 and 10 suggests that the amide linkage between the A(1) and the A(2) residues of CA(1)A(2)X-derived FTase inhibitors is important.     

Design,synthesis and antimicrobial evaluation of thioglycosides of a novel class of 2-mercaptonicotinonitriles

A new class of thioglycosides comprising a diazenyl pyridine moiety was assembled from the regioselective reaction of the acetylated α-glycopyranosyl bromide with hitherto unreported 2-mercaptonicotinonitriles. Moreover, the deacetylation of S-glycoside derivatives utilizing of methanolic ammonia solution afforded the free hydroxy thioglycosides in quantitative yields. The identity of the newly obtained derivatives has been achieved via spectroscopic and elemental analyses. All of the newly synthesized derivatives exhibited significant antimicrobial activity towards certain selected microorganisms (bacteria and fungi). Generally, S-glycoside derivatives demonstrated outstanding antibacterial and antifungal activities. Amongst them, the acetylated derivatives showed the most distinguished antifungal and antibacterial activities with a promising minimum inhibitory concentration (MIC) values in comparison with the approved drugs; Amphotericin B and Cefotaxime.     

Parallel synthesis of bis-oxazole peptidomimetics

The parallel synthesis of bis-oxazole peptidomimetics starting from Boc-aminoacids and Serine-methyl ester is described. This work presents the synthesis of oxazole aminoacid building blocks in solution phase and their utilization for the solid phase peptide synthesis of a library of diverse bis-oxazole peptidomimetics in good overall yields.     

Enolate amination and derivatization of a pyrroloisoquinoline template: towards novel peptidomimetics

Pyrroloisoquinoline-based peptidomimetics are of significant interest in bioorganic chemistry as these targets are known to exhibit type II′ β-turn activity. In this paper we present a novel approach to such pyrroloisoquinoline templates based on a stereoselective N-acyliminium-mediated cyclization reaction to construct the heterocyclic core, coupled with an enolate amination protocol. We have applied both symmetrical and unsymmetrical electrophilic aminating reagents based on azodicarboxylate functionality, and demonstrate the utility of our approach in the synthesis of a peptide target.     

Three-step synthesis of cyclopropyl peptidomimetics

An efficient approach to novel cyclopropyl peptidomimetics has been developed. The synthetic route involves a cyclopropanation using ethyl (dimethylsulfuranylidene)acetate (EDSA) as the key step and affords a cyclopropyl peptidomimetic core in three steps from protected amino acid Weinreb amides.     

Solid-phase synthesis of sulfamate peptidomimetics

A synthetic method for the preparation of sulfamate peptidomimetics is described. The methodology allows sulfamoylation in the solid phase using sulfamoyl chloride in DMA, followed by the acylation of the corresponding sulfamoylated product. Following this approach, several derivatives have been prepared starting from distinct alcohol sources, including alpha-, beta-, and gamma-hydroxyacids and phenols. The presence of protected amino functions on the building blocks opens the possibility of the addition of more diversity. This approach, which is compatible with Fmoc/Boc/Alloc protection, provides a useful and efficient tool for the preparation of new sulfamate peptidomimetics.     

Fluorinated peptidomimetics: synthesis, conformational and biological features

Peptides modified with fluoroalkyl functions in key backbone positions have been scarcely studied so far. Thus, little is known about their synthesis, their structural and physico-chemical properties, and their biological features. Our interest in this field of research led to the development of stereocontrolled synthetic protocols, both in solution and in solid phase, for many different fluoroalkyl peptidomimetics, some of which are overviewed in this paper: (a) ψ[CH(CF₃)NH]-peptide mimics holding a great potential as hybrids between natural peptides and hydrolytic transition state analogs; (b) trifluoromethyl (Tfm) malic peptidomimetics as micromolar inhibitors of some matrix metalloproteinases; (c) bis-Tfm analogs of Pepstatin A, that are nanomolar and selective inhibitors of the protozoal aspartyl protease Plasmepsin II.     

A facile route for the synthesis of novel S-linked 1,3,5-triazine tethered peptidomimetics

An efficient one-pot synthesis of N^α-protected S-linked 1,3,5-triazine tethered peptidomimetics is described. The protocol involves a three-component condensation reaction employing N^α-protected amino alkyl isothiouronium salt, formaldehyde and amino acid ester or aryl amine as reactants. Various aryl amines with substitutions and amino acids with simple as well as bifunctional side chains were employed to obtain triazine tethered peptidomimetics in good yield.     

The serine-proline turn: a novel hydrogen-bonded template for designing peptidomimetics

Serine-Proline (SP) dipeptide motifs have been shown to form unique hydrogen-bonding patterns in protein crystal structures. Peptides were designed to mimic these patterns by forming the 6 + 10 and the 9 + 10 hydrogen-bonded rings. Factors that contribute to the formation of SP turns include controlling backbone flexibility and amino acid chirality along with creating a hydrophobic environment around the intramolecular hydrogen bonds.     

Expedient synthesis of pseudo-Pro-containing peptides: towards constrained peptidomimetics and foldamers

The reaction of sulfonyl peptides containing L- or D-configured Ser or Thr with bis(succinimidyl) carbonate in the presence of a catalytic amount of a base affords, in solution or in the solid phase, the corresponding peptides with one or two, consecutive or alternate oxazolidin-2-ones (Oxd). The Oxd ring can be regarded to as a pseudo-Pro with an exclusively trans conformation of the preceding peptide bond; homochiral Oxd-containing peptides adopt extended conformations, while the presence of a D-configured Oxd favours folded conformations.     

Solid-phase synthesis of 1,3-azole-based peptides and peptidomimetics

[reaction: see text] We report highly efficient two-step procedures for the synthesis of 1,3-oxazole-, thiazole-, and imidazole-containing peptides on solid phase from dipeptides composed of C-terminal threonine, serine, cysteine, or diaminopropionic acid by using different cyclodehydration procedures followed or preceded by oxidation. The methods are compatible with Fmoc solid-phase peptide synthesis conditions and with N-Fmoc, N-Boc, N-Cbz, and N-Alloc protecting groups.     

Pt-tetraethynylethene molecular scaffolding: synthesis and characterization of a novel class of organometallic molecular rods

The series of monodisperse Pt-bridged TEE oligomers 3a-f was prepared by oxidative Glaser-Hay oligomerization of monomer 7 under end-capping conditions. These novel molecular rods extend in length from 3.3 nm (monomeric 3a) to 12.1 nm (hexameric 3 f). Their isolation was achieved by high performance gel permeation chromatography (GPC), and their purification was best monitored by analytical GPC in combination with matrix-assisted laser-desorption-ionization mass spectrometry (MALDI-TOF MS). The mass spectra of each oligomer revealed the molecular ion or its sodium complex as parent ion together with a clean, highly characteristic fragmentation pattern. Delayed addition of the end-capping reagent PhC(triple bond)CH to the oligomerization mixture afforded polymer 10 with an average of approximately 32 repeat units and a remarkably narrow molecular weight distribution (Mw/Mn=1.06), which is indicative of a living polymerization process. UV/Vis spectral data as well as measurements of the second hyperpolarizability gamma by third harmonic generation (THG) revealed a nearly complete lack of pi-electron delocalization along the oligomeric backbone. The Pt atoms act as true insulating centers, and the Pt-C(sp) bonds hardly possess any pi character. The synthesis of the molecular rods 3a-f provides another demonstration of the power of oxidative acetylenic homocouplings for the preparation of unusual nanoarchitecture.     

Gemini pyridinium surfactants: synthesis and conductometric study of a novel class of amphiphiles1

A new series of pyridinium cationic gemini surfactants was prepared by quaternization of the 2,2'-(alpha,omega-alkanediyl)bispyridines with N-alkylating agents, whose reactivity is briefly discussed. Particularly useful was the use of long-chain alkyl triflates (trifluoromethanesulfonates) for both overcoming the sterical hindrance in the pyridines and obtaining higher synthetic yields. Well-known 4,4'-(alpha,omega-alkanediyl)bis(1-alkylpyridinium) structures showed narrow temperature ranges for practical applications, due to their high Krafft points, while the new 2,2'-(alpha,omega-alkanediyl)bis(1-alkylpyridinium) series, accounted for good surface active properties. Due to the Krafft points below 0 degrees C, they could be exploited as solutions in water at any temperature. The characterization of the behavior of the series was performed by conductivity measurements. Some of the proposed structures exhibited unusual surface active behavior, which was interpreted in terms of particular conformational arrangements.     

Imino sulfinamidines: synthesis and coordination chemistry of a novel class of chiral bidentate ligands

The new imino sulfinamidine ligand PhS(NHt-Bu)=NC(Me)=N(C6H3-2,6-iPr2), LH (11) was synthesized from N-(2,6-diisopropylphenyl)acetamidine (9) and N-tert-butyl phenylsulfinimidoyl chloride (10). Reaction of LH (11) with ZnEt2 or AlMe3 gave the complexes LZnEt (12) and LAlMe2 (13), respectively. The structures of 12 and 13 were determined by X-ray diffraction and were shown to contain L as a kappa2-N1,N5 bidentate ligand in a six-membered chelate. Formation of the magnesium complex (LMgN(TMS)2 x L2Mg) (14) from 11, MgI2, and KN(SiMe3)2 highlighted a secondary coordination mode of L, binding through the sulfinamidine nitrogens in a four-membered chelate.     

Csp-tellurium copper cross-coupling: synthesis of alkynyl tellurides a novel class of antidepressive-like compounds

We present here the results on the synthesis of functionalized alkynyl tellurides using the reaction of vinyl, alkynyl, and aryl tellurides with several alkynyl iodides catalyzed by copper iodide. The reaction proceeded cleanly under mild reaction conditions, at room temperature, in the absence of base and ligand giving alkynyl tellurides in acceptable yields. The obtained compounds 3a-c and 3m-o were screened for antidepressive-like activity using the tail suspension test (TST) in mice. Compounds 3a-c and 3m-o administered at 10 mg/kg by oral route produced a significant antidepressant-like effect on the TST in mice.     

A novel class of inhibitors for human steroid 5alpha-reductase: synthesis and biological evaluation of indole derivatives. II

In a search for novel nonsteroidal inhibitors of human prostatic 5alpha-reductase, we found a new series of indole derivatives that showed potent inhibitory activities for the human enzyme. Among them, 4-[(1-benzyl-1H-indol-5-yl)oxyl-3-chlorobenzoic acid (2d, YM-32906) showed more potent inhibitory activity than finasteride with an IC50 value of 0.44 nM. 3-Chloro-4-[[1-(4-phenoxybenzyl)-1H-indol-5-yl]oxy]benzoic acid (2m) showed inhibitory activities for both human and rat prostatic 5alpha-reductase with IC50 values of 2.1 and 73 nM, respectively. The synthesis and structure-activity relationships of these indole derivatives are presented.     

Solid-phase synthesis of constrained terminal and internal lactam peptidomimetics

Lactams are key components of many peptidomimetic structures. Five- and six-membered lactam peptidomimetics with hydrogen or amino acid side chains at the alpha-position can be constructed from peptide precursors during a solid-phase synthesis. There is no significant racemization of remote stereocenters during synthesis.     

Solid-phase synthesis of 1,2,3, 4-tetrahydro-beta-carboline-containing peptidomimetics

A solid-phase method for the synthesis of 1,2,3, 4-tetrahydro-beta-carboline-containing peptidomimetics has been developed. The key step in the strategy is the Pictet-Spengler condensation of a resin-bound tryptophan-containing fragment with an Fmoc-amino aldehyde.