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The peptide coupling reactions allowing the incorporation of trifluoromethyl substituted oxazolidine-type pseudoprolines (CF 3-ΨPro) into peptide chains have been studied. While standard protocols can be used for the peptide coupling reaction at the C-terminal position of the CF3-ΨPro, acid chloride activation has to be used for the peptide coupling reaction at the N-terminal position to overcome the decrease of nucleophilicity of the CF3-ΨPro. We demonstrate that the N-amidification of a diastereomeric mixture of CF3-ΨPro using Fmoc-protected amino acid chloride without base gave the corresponding dipeptides as a single diastereomer (6 examples). The ratio of the cis and trans amide bond conformers was determined by NMR study, highlighting the role of the Xaa side chains in the control of the peptide backbone conformation. Finally a tripeptide bearing a central CF3-ΨPro has been successfully synthesized.

The outcome of ring-expansion reactions based on amino/hydroxyacid side-chain insertion is strongly dependent on ring size. This manuscript, which builds upon our previous work on Successive Ring Expansion (SuRE) methods, details efforts to better define the scope and limitations of these reactions on lactam and β-ketoester ring systems with respect to ring size and additional functionality. The synthetic results provide clear guidelines as to which substrate classes are more likely to be successful and are supported by computational results, using a density functional theory (DFT) approach. Calculating the relative Gibbs free energies of the three isomeric species that are formed reversibly during ring expansion enables the viability of new synthetic reactions to be correctly predicted in most cases. The new synthetic and computational results are expected to support the design of new lactam- and β-ketoester-based ring-expansion reactions.

The apelin receptor generates increasing interest as a potential target across several cardiovascular indications. However, the short half-life of its cognate ligands, the apelin peptides, is a limiting factor for pharmacological use. In this study, we systematically explored each position of apelin-13 to find the best position to cyclize the peptide, with the goal to improve its stability while optimizing its binding affinity and signaling profile. Macrocyclic analogues showed a remarkably higher stability in rat plasma (half-life >3 h versus 24 min for Pyr-apelin-13), accompanied by improved affinity (analogue 15, Ki 0.15 nM and t1/2 6.8 h). Several compounds displayed higher inotropic effects ex vivo in the Langendorff isolated heart model in rats (analogues 13 and 15, maximum response at 0.003 nM versus 0.03 nM of apelin-13). In conclusion, this study provides stable and active compounds to better characterize the pharmacology of the apelinergic system.

The design of constrained peptides is of prime importance in the development of bioactive compounds and for applications in supramolecular chemistry. Due to its nature, the peptide bond undergoes a spontaneous cis-trans isomerism, and the cis isomers are much more difficult to stabilize than the trans forms. By using oxazolidine-based pseudoprolines (ψPro) substituted by a trifluoromethyl group, we show that the cis peptide bond can be readily switched from 0% to 100% in Xaa-ψPro dipeptides. Our results prove that changing the configuration of the Cα in Xaa or in ψPro is sufficient to invert the cis:trans populations while changing the nature of the Xaa side chain finely tuned the conformers ratio. Moreover, a strong correlation is found between the puckering of the oxazolidine ring and the peptide bond conformation. This finding highlights the role of the trifluoromethyl group in the stabilization of the peptide bond geometry. We anticipate that such templates will be very useful to constrain the backbone geometry of longer peptides.

Four Merrifield resin-supported thiourea organocatalysts derived from l-proline were synthesized and found to be efficient catalysts for the direct asymmetric aldol reaction between ketone and aromatic aldehydes. The catalysts exhibited high catalytic activity, diastereoselectivity and excellent enantioselectivity at room temperature with a low loading (only 2 mol %). They also retained unchanged enantioselectivities even after being reused for at least four cycles.

Phenolic L-prolinamide was allowed to participate in enzymatic polymerization with horseradish peroxidase as the catalyst, generating immobilized L-prolinamide. The catalytic performance of the resultant polymer-supported L-prolinamide for direct asymmetr

(Chemical Equation Presented) Recoverable (Sa)-binam-L- prolinamide in combination with benzoic acid is used as catalysts in the direct aldol reaction between cycloalkyl, alkyl, and α-functionalized ketones and aldehydes under solvent-free reac

As an alternative approach to the graft modification of polymers to fabricate polymer-supported chiral organocatalysts in a bottom-up fashion, L-prolinamide functionalized polymers were prepared by general solution homopolymerization or copolymerization of L-proline functionalized styrene monomer in the presence of 1,4-divinylbenzene as the crosslinking agent. The catalytic performance of the as-prepared heterogeneous catalysts towards the direct enantioselective aldol reaction of ketones with a series of aromatic aldehydes was explored. Our findings indicate that the as-prepared heterogeneous catalysts can afford relevant aldol addition products with good yields (up to 96%), high diastereoselectivities (up to 8:92 dr) and excellent enantiomeric excess (up to 96%); they also exhibit good recyclability, retaining high yield and rate as well as good selectivity after several cycles.

Background: Agro-waste derived solvent media act as a greener process for the peptide bond formation using Nα-Fmoc-amino acid chloride and amino acid ester salt with in situ neutralization and coupling under biphasic condition. The Fmoc-amino acid chlorides are prepared by the reported procedure of freshly distilled SOCl2 with dry CH2Cl2. The protocol found many added ad-vantages such as neutralization of amino acid ester salt and not required additional base for the neu-tralization, and directly coupling take place with Fmoc-amino acid chloride gave final product dipeptide ester in good to excellent yields. The protocol occurs with complete stereo chemical integrity of the configuration of substrates. Here, we revisited Schotten-Baumann condition, instead of using inorganic base. Objective: To develop green protocol for the synthesis of peptide bond using Fmoc-amino acid chloride with amino acid esters salt. Methods: The final product isolated is analyzed in several spectroscopic and analytical techniques such as FT-IR,1H-,13C-NMR, Mass spectrometry and RP-HPLC to check stereo integrity and puri-ty of the product. Conclusion: The present method developed greener using natural agro-waste (lemon fruit shell ash) derived solvent medium for the reaction and not required chemical entity.

Dimers for use in synthesis of peptidomimetics are described. Uses of dimers as synthons in synthesis of azapeptides and other peptidomimetics, azapeptides and other peptidomimetics synthesized from the dimers and uses of azapeptides and other peptidomimetics are also described.

Thioesters, thiocarbamates, thiocarbazates, semithiocarbazates, peptides, aza-amino acid conjugates, and azapeptides; and a chemoselective and site-specific functionalization protocol of protected thiocarbazates and semithiocarbazates are described. The protocol features the use of Mitsunobu reaction to alkylate specifically the nitrogen atom close to the acylthiol moiety with alcohols to produce protected mono-substituted thiocarbazates that can be stored for months, activated under mild conditions at low temperature using halonium reagents and integrated orthogonally to make substituted semicarbazides that can be used, e.g., as synthons in synthesis of aza-amino acid conjugates, azapeptides and other peptidomimetics. Methods for preparing and using ureases, carbazides, semicarbazides, beta-peptides, azapeptides, and other peptidomimetics and azapeptide conjugates, and uses of ureases, carbazides, semicarbazides, beta-peptides, azapeptides in drug discovery, diagnosis, inhibition, prevention and treatment of diseases are also described.

The present invention provides a compound having the structure of Formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, or isomer thereof, for the controlled delivery and release of Agent.

Macrocyclic lactones can be prepared from lactams and hydroxyacid derivatives via an efficient 3- or 4-atom iterative ring expansion protocol. The products can also be expanded using amino acid-based linear fragments, meaning that macrocycles with precise

A successive ring-expansion protocol is reported that enables the controlled insertion of natural and non-natural amino acid fragments into lactams. Amino acids can be installed into macrocycles via an operationally simple and scalable iterative procedure, without the need for high dilution. This method is expected to be of broad utility, especially for the synthesis of medicinally important cyclic peptide mimetics.

The total synthesis and stereochemical structural elucidation of JBIR-39, containing four nonproteinogenic piperazic acid (Piz) residues, is reported. The synthesis includes Sc(OTf)3-catalyzed acylation of a Piz(γ-OTBS) derivative with piperazi

Verruculogen and fumitremorgin A are bioactive alkaloids that contain a unique eight-membered endoperoxide. Although related natural products such as fumitremorgins B and C have been previously synthesized, we report the first synthesis of the more complex, endoperoxide-containing members of this family. A concise route to verruculogen and fumitremorgin A relied not only on a hydroperoxide/indole hemiaminal cyclization, but also on the ability to access the seemingly simple starting material, 6-methoxytryptophan. An iridium-catalyzed C-H borylation/Chan-Lam procedure guided by an N-TIPS group enabled the conversion of a tryptophan derivative into a 6-methoxytryptophan derivative, proving to be a general way to functionalize the C6 position of an N,C3-disubstituted indole for the synthesis of indole-containing natural products and pharmaceuticals.

N-Sulfanylethylanilide (SEAlide) peptides 1, obtainable using Fmoc-based solid-phase peptide synthesis (Fmoc SPPS), function as crypto-thioesters in native chemical ligation (NCL), yielding a wide variety of peptides/proteins. Their acylating potential with N-terminal cysteinyl peptides 2 can be tuned by the presence or absence of phosphate salts, leading to one-pot/multifragment ligation, operating under kinetically controlled conditions. SEAlide peptides have already been shown to be promising for use in protein synthesis; however, a widely applicable method for the synthesis of N-Fmoc amino acyl-N- sulfanylethylaniline linkers 4, required for the preparation of SEAlide peptides, is unavailable. The present study addresses the development of efficient condensation protocols of 20 naturally occurring amino acid derivatives to the N-sulfanylethylaniline linker 5. N-Fmoc amino acyl aniline linkers 4 of practical use in NCL chemistry, except in the case of the proline- or aspartic acid-containing linker, were successfully synthesized by coupling of POCl3- or SOCl2-activated Fmoc amino acid derivatives with sodium anilide species 6, without accompanying racemization and loss of side-chain protection. Furthermore, SEAlide peptides 7 possessing various C-terminal amino acids (Gly, His, Phe, Ala, Asn, Ser, Glu, and Val) were shown to be of practical use in NCL chemistry.

We report the solid-phase total synthesis of the antifungal highly modified cyclic depsipeptide petriellin A. The synthesis confirms earlier reports on the absolute configuration of the natural product. The solid-phase approach resulted in a protected lin

Antifibrinolytic agents are required during complex surgeries to decrease bleeding; their pro-thrombotic potency and efficacy in causing hemostasis has attracted much attention. To discover new inhibitors of urokinase with high selectivity for antifibrinolytic effects over pro-thrombotic effects, the 12-position of (5aS,12S,14aS)- and (5aS,12R,14aS)-5,14-dioxo-1,2,3,5,5a,6,11, 12,14,14a-decahydro-5H,14H-pyrolo[1,2:4,5]pyrazino[1,2:1,6]pyrido[3,4-b]indoles were modified with L-Ala, L-Asp, L-Phe, L-Trp, L-Lys, L-Ser, Gly, and L-Leu to provide 16 (5aS,12S,14aS) and (5aS,12R,14aS) derivatives. In a murine bleeding model, the (5aS,12S,14aS) derivatives containing L-Ala, L-Asp, L-Phe, and L-Trp induced blood coagulation for the treated mice; they also stimulated thrombus formation in a rat thrombosis model, but the other derivatives inhibited thrombosis. The most potent compound, the L-Asp derivative, showed a good therapeutic window: the minimum effective dose for coagulation was -1, whereas at 10nmolkg-1, no pro-thrombotic effect was observed. This type of coagulation action was correlated with a mechanism of urokinase inhibition, and these results could lead to the discovery of novel urokinase inhibitors. Stop the clot: Small molecular antifibrinolytic agents in clinical use such as tranexamic acid carry the risk of prompting thrombus formation. Herein we present an investigation of pyrolo[1,2:4,5]-1,4-dioxopyrazino[1,2:1,6]pyrido[3,4-b]indoles (DAPPP), some of which show strong hemostatic activities invivo. The most potent compound, 5c, has a good therapeutic window for antifibrinolytic therapy.

Provided herein are compounds and methods of synthesis thereof. The compounds set forth herein are useful for the treatment, prevention, and/or management of various disorders, such as neurological disorders, neurodegenerative disorders, neuropsychiatric disorders, disorders of cognition, learning or memory, gastrointestinal disorders, lower urinary tract disorder, and cancer. Compounds set forth herein modulate the activity of metabotropic glutamate receptor 5 (mGluR5) in the central nervous system or the periphery. Pharmaceutical formulations containing the compounds and their methods of use are also provided herein.

Prodrugs have proven to be very useful in enhancing aqueous solubility of sparingly water-soluble drugs, thereby increasing in vivo efficacy without a need of special excipients. In vitro and in vivo evaluations of a number of amino acid prodrugs of 1, a previously identified potent tubulin polymerization inhibitor and cytotoxic against various cancer cell lines led to the discovery of 3·HCl (l-valine attached) which is highly efficacious in mouse xenografts bearing human cancer. Pharmacokinetic analysis in rats revealed that compound 1 was released immediately upon administration of 3·HCl intravenously, with rapid clearance of 3·HCl indicating the effective cleavage of prodrug. Compound 3·HCl (CKD-516) has now been progressed to phase 1 clinical trial.

A simple, efficient and racemization free method for the synthesis of peptides employing Fmoc-amino acid chlorides mediated by HOAtDCHA as a co-coupling agent has been described. This protocol is successfully employed in the synthesis of the pentapeptide H-Pro-Gly-VaI-GIy-VaI-OH (PGVGV), and ss-casomorphin (H-Tyr-Pro-Phe-Pro-Gly-OH) in 85 and 80% yields, respectively.

Tryprostatin A is an inhibitor of breast cancer resistance protein, consequently a series of structure-activity studies on the cell cycle inhibitory effects of tryprostatin A analogues as potential antitumor antimitotic agents have been carried out. These

Incorporation of the extremely hindered amino acid N-benzylaminoisobutyric acid into dipeptides under microwave irradiation with commercial zinc dust is described. A comparative survey of various methodologies for hindered peptide couplings was undertaken

The syntheses of aminoalkyloxazoline and pyrrolidinyloxazoline ligands, each of which bear a pair of chiral centres, by both known and new routes are reported. Variable temperature NMR studies show that the known stepwise syntheses of the pyrrolidinyl compounds are not complicated by epimerization; however, coordination of one of the aminoalkyl derivatives to Pt(II) under conditions of prolonged heating to 80°C does give mixtures of diastereomeric N,N′-chelated complexes that result from inversion of the chiral centre associated with the aminoalkyl fragment. A new synthesis of pyrrolidinyloxazoline ligands that involves the Zn-catalyzed cyclization of Cbz-protected 2-cyanopyrrolidine and β-amino alcohols is also reported. This procedure offers the advantages of economy, shorter time, and fewer purification steps over the previously reported synthesis. In addition, the crystal structure of an enantiopure Pd(II) complex of an N.N′-chelated pyrrolidinyloxazoline is disclosed. This compound has a pseudo-C2 axis of symmetry, which may make it suitable for asymmetric catalytic applications.

A general method for the formation of benzoxazoles via a copper-catalyzed cyclization of ortho-haloanilides is reported. This approach complements the more commonly used strategies for benzoxazole formation which require 2-aminophenols as substrates. The reaction involves an intramolecular C-O cross-coupling of the ortho-haloanilides and is believed to proceed via an oxidative insertion/reductive elimination pathway through a Cu(I)/Cu(III) manifold. The reaction is also applicable to the formation of benzothiazoles. A variety of ligands including 1,10-phenanthroline and N,N′- dimethylethylenediamine were shown to provide ligand acceleration/stabilization in the reaction. Optimal conditions for cyclization used a catalyst combination of CuI and 1,10-phenanthroline (10 mol %). The method was amenable to a parallel-synthesis approach, as demonstrated by the synthesis of a library of benzoxazoles and benzothiazoles substituted at various positions in the ring. Most examples utilized the cyclization of ortho-bromoanilides, but orthoiodoanilides and ortho-chloroanilides also undergo a reaction under these conditions. The rate of reaction of the ortho-haloanilides follows the order I > Br > Cl, consistent with oxidative addition being the rate-determining step.

Because of their negligible vapor pressures and large dipoles, ionic liquids are excellent media for microwave-accelerated organic reactions. Using low-power microwave irradiation in the new [bdmim][PF6] ionic liquid with temperature controlled at 60°C, a three-step synthesis (Pictet-Spengler, Schotten-Baumann, and intramolecular ester amidation) of tetrahydro-β-carbolinediketopiperazines starting from tryptophan methyl ester was achieved with good isolated yields (49-69%) in only 5 min.

Chemotherapy of prostate cancer with antimitotic agents such as vinblastine and doxorubicin is only marginally effective, due to dose-limiting systemic toxicity. Herein we report the development of peptidyl conjugate 5 of the cytotoxic agent vinblastine (

The synthesis of Fmoc amino acid azides starting from the corresponding protected amino acid and sodium azide (NaN3) by the mixed anhydride method using isobutoxycarbonyl chloride (IBC-Cl) or by the acid chloride method is described. Isolated as crystalli

A new one-pot procedure for the preparation of pentafluorophenyl and 3,4-dihydro-4-oxo-1,2,3-benzotriazine-3-yl esters of Nα-9-fluorenylmethyloxycarbonyl amino acids bearing no side chain protecting groups is described. The method gives the desired activated esters in high yield and purity without use of the highly allergenic DCC.

The recently described FMOC/4-AMP technique for rapid continous solution synthesis of peptides involving coupling by crystalline FMOC amino acid chlorides and deblocking via 4-(aminomethyl)piperidine (4-AMP) has been extended to the synthesis of a varied

Fmoc amino acid chlorides are described as stable, easily synthesized coupling agents and shown to be useful in a novel method of rapid, repetitive peptide synthesis