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Relevant academic research and scientific papers

Biocompatible Photoinduced Alkylation of Dehydroalanine for the Synthesis of Unnatural α-Amino Acids

A site-selective alkylation of dehydroalanine to access protected unnatural amino acids is described. The protocol is characterized by the wide nature of alkyl radicals employed, mild conditions, and functional group compatibility. This protocol is further extended to access peptides, late-stage functionalization of pharmaceuticals, and enantioenriched amino acids.

Direct modification of tripeptides using photoinduced decarboxylative radical reactions

In order to explore the applicability of photoinduced electron transfer (PET) promoted decarboxylative reactions to the direct modification of peptides, a study was performed to assess the influence of amino acid side chains on photoreactions of N-terminal protected tripeptides. Photoinduced decarboxylation reactions of tripeptides, which are composed of central amino acids that possess alkyl, phenyl, thioether, hydroxy, and amide containing side chains, in the presence or absence of acrylonitrile and a thiol were found to proceed smoothly to give the corresponding radical addition, H-abstraction, and substitution products. Although photoreactions of tripeptides containing central amino acids with phenol and indole (Tyr and Trp) moieties do not take place efficiently, appropriate protection of these groups enables the substrates to undergo smooth photoinduced decarboxylative reactions.

Highly stereoselective synthesis of natural-product-like hybrids by an organocatalytic/multicomponent reaction sequence

In an endeavor to provide an efficient route to natural product hybrids, described herein is an efficient, highly stereoselective, one-pot process comprising an organocatalytic conjugate addition of 1,3-dicarbonyls to α,β-unsaturated aldehydes followed by

Synthesis and electrochemical studies of disubstituted ferrocene/dipeptide conjugates with sulfur-containing side chains

A series of 1 1'-disubstituted ferrocenoyl peptides incorporating dipeptide sidearms has been synthesized and studied electrochemically. The target peptides include ferrocene as an electrochemical reporter, sulfur-containing amino acids (L-methionine, S-methyl-L-cysteine, S-trityl-L-cysteine, S-benzhydryl-L- cysteine) as metal binding agents, and amino acids with non-polar side chains (L-alanine, L-valine, L-phenylalanine) as spacers between reporter and metal binding groups. Ferrocene/dipeptide conjugates were prepared using solution phase peptide synthesis methods employing a BOC-protecting group strategy and HBTU- (O-(benzotriazol-1-yl)-N, N, N', N'-tetramethyluronium hexafluorophosphate) mediated peptide coupling. The electrochemical properties of these 1, 1'-substituted ferrocenoyl peptides have been characterized using cyclic voltammetry. All exhibit fully reversible one electron oxidation steps; forward sweep half wave peaks (EF), reverse sweep half wave peaks (ER), peak separations (DEP) and half wave potentials (E1/2) are reported. Finally, towards the goal of utilizing ferrocenoyl peptides to detect heavy metals in solution, the response of these ferrocene/dipeptide conjugates to metal cations (zinc(II), mercury(II), cadmium(II), lead(II), silver(I)) has been examined. Monitoring changes in the potential of the Fe(II)/Fe(III) redox couple to follow peptide/metal interactions, we have probed the influence of the spacer unit between the redox reporter and the metal-binding amino acid, and shown that these systems respond to mercury(II) more strongly than to other heavy metal ions.

Dechalcogenative allylic selenosulfide and disulfide rearrangements: Complementary methods for the formation of allylic sulfides in the absence of electrophiles. Scope, limitations, and application to the functionalization of unprotected peptides in aqueous media

Primary allylic selenosulfates (seleno Bunte salts) and selenocyanates transfer the allylic selenide moiety to thiols giving primary allylic selenosulfides, which undergo rearrangement in the presence of PPh3 with the loss of selenium to give allylically rearranged allyl alkyl sulfides. This rearrangement may be conducted with prenyl-type selenosulfides to give isoprenyl alkyl sulfides. Alkyl secondary and tertiary allylic disulfides, formed by sulfide transfer from allylic heteroaryl disulfides to thiols, undergo desulfurative allylic rearrangement on treatment with PPh3 in methanolic acetonitrile at room temperature. With nerolidyl alkyl disulfides this rearrangement provides an electrophile-free method for the introduction of the farnesyl chain onto thiols. Both rearrangements are compatible with the full range of functionality found in the proteinogenic amino acids, and it is demonstrated that the desulfurative rearrangement functions in aqueous media, enabling the derivatization of unprotected peptides. It is also demonstrated that the allylic disulfide rearrangement can be induced in the absence of phosphine at room temperature by treatment with piperidine, or simply by refluxing in methanol. Under these latter conditions the reaction is also applicable to allyl aryl disulfides, providing allylically rearranged allyl aryl sulfides in good yields.

Synthesis, pharmacological evaluation, and molecular modeling studies of novel peptidic CAAX analogues as farnesyl-protein-transferase inhibitors

Fifteen analogues of the C-terminal CA1A2X motif were synthesized and evaluated for their inhibition potency against farnesyltransferase (FTase). Replacement of the A2 residue by phenylalanine or tyrosine-derived analogues, in which a different number of methyl groups were introduced on the aromatic ring, resulted in compounds less active than the reference compound CVFM against FTase except for compounds I and VI (IC50 = 1 μM and 2.5 μM, respectively) that were comparable to CVFM and compound IV (IC50 = 0.1 μM), which was 6-fold more active than the reference compound. Because pseudopeptidic derivatives I-IX were inactive in the cellular assays, the N-formyl- and methyl-ester derivatives (compounds X-XV) were synthesized and tested on different cell lines, showing, in some cases, activity and appreciable selectivity against transformed cells. To rationalize the obtained results, molecular modeling experiments were carried out suggesting the molecular basis of FTase inhibition by these products.

Phe*-Ala-based pentapeptide mimetics are BACE inhibitors: P2 and P3 SAR.

We describe herein the syntheses and evaluation of a series of C-termini pyridyl containing Phe*-Ala-based BACE inhibitors (5-19). In conjunction with four fixed residues at the P1 (Phe), P1' (Ala), P2' (Val), and P2' cap (Pyr.), rather detailed SAR modifications at P2 and P3 positions were pursued. The promising inhibitors emerging from this SAR investigation, 12 and 17 demonstrated very good enzyme potency (IC(50)=45 nM) and cellular activity (IC(50)=0.4 microM).