Dina Scarpi

Structural diversity of bicyclic amino acids

Summary.Over the years biomedical research has been constantly oriented towards the development of new therapeutics based on bioactive peptides and their analogues. In particular, the generation of compounds having structures and functions similar to bioactive peptides, named “peptidomimetics”, raised much interest among organic and medicinal chemists due to the possibility by using such compounds to improve both potency and stability of peptidic lead compounds. In the context of this research area, unnatural amino acids are of great interest in drug discovery, and their use as new building blocks for the development of peptidomimetics with high diversity level and possessing high-ordered structures is of special interest. In particular, medicinal chemistry has taken advantage of the use of amino acid homologues and of cyclic and polycyclic templates to introduce elements of diversity for the generation of new molecules as drug candidates. Bicyclic amino acids have been developed as reverse turn mimetics and dipeptide isosteres, and the constraint imposed by their structures has been reported as a tool for controlling the conformational preferences of modified peptides. Moreover, synthetic efforts have been driven to the generation of diverse structures based on the modulation of ring size and scaffold decoration by suitable functional groups. Herein is reported an overview of different classes of bicyclic amino acids, taking into account the strategies to achieve structurally diverse templates, and some implications in medicinal chemistry are also disclosed.

Low molecular weight, non-peptidic agonists of TrkA receptor with NGF-mimetic activity

Exploitation of the biologic activity of neurotrophins is desirable for medical purposes, but their protein nature intrinsically bears adverse pharmacokinetic properties. Here, we report synthesis and biologic characterization of a novel class of low molecular weight, non-peptidic compounds with NGF (nerve growth factor)-mimetic properties. MT2, a representative compound, bound to Trk (tropomyosin kinase receptor)A chain on NGF-sensitive cells, as well as in cell-free assays, at nanomolar concentrations and induced TrkA autophosphorylation and receptor-mediated internalization. MT2 binding involved at least two amino-acid residues within TrkA molecule. Like NGF, MT2 increased phosphorylation of extracellular signal-regulated kinase1/2 and Akt proteins and production of MKP-1 phosphatase (dual specificity phosphatase 1), modulated p38 mitogen-activated protein kinase activation, sustained survival of serum-starved PC12 or RDG cells, and promoted their differentiation. However, the intensity of such responses was heterogenous, as the ability of maintaining survival was equally possessed by NGF and MT2, whereas the induction of differentiation was expressed at definitely lower levels by the mimetic. Analysis of TrkA autophosphorylation patterns induced by MT2 revealed a strong tyrosine (Tyr)490 and a limited Tyr785 and Tyr674/675 activation, findings coherent with the observed functional divarication. Consistently, in an NGF-deprived rat hippocampal neuronal model of Alzheimer Disease, MT2 could correct the biochemical abnormalities and sustain cell survival. Thus, NGF mimetics may reveal interesting investigational tools in neurobiology, as well as promising drug candidates.

Synthesis of a new enantiopure bicyclic γ/δ-amino acid (BTKa) derived from tartaric acid and α-amino acetophenone

Abstract The synthesis of a novel enantiopure γ/δ-amino acid having the 3-aza-6,8-dioxabicyclo[3.2.1]octane structure was realized by the combination of tartaric acid derivatives and α-amino acetophenone followed by a trans-acetalisation process. This amino acid, which has a rigid skeleton and carries substituents at the 3, 5 and 7 positions of the scaffold, could find different applications in organic and peptidomimetic synthesis. Two different synthetic strategies were studied, one of them allowing the multigram scale preparation of the amino acid.

Baker's yeast reduction of prochiral γ-nitroketones. II.1 straightforward enantioselective synthesis of 2,7-dimethyl-1,6-dioxaspiro[4.4]nonanes

Abstract The bakers yeast reduction of 5-nitro-2,8-nonanedione 2 afforded the corresponding (2 S ,8 S )-5-nitro-2,8-nonanediol 3 with complete diastereoselectivity and high enantioselectivity. The conversion of 3 into the thermodynamic (E,E) (Z,Z) (3:1) mixture of optically active (95% e.e.) 2,7-dimethyl-1,6-dioxaspiro[4.4]nonanes 5 was then achieved by spontaneous cyclization under the acidic conditions of the Nef reaction.

Introduction of the new dipeptide isostere 7-endo-BtA as reverse turn inducer in a Bowman-Birk proteinase inhibitor: synthesis and conformational analysis

Two dipeptide isosteres 7-exo-BTG (1) and 7-endo-BtA (2), belonging to the new class of gamma/delta-bicyclic amino acid BTAa, were inserted into an 11-residue peptide deriving from the Bowman Birk Inhibitor (BBI) class of serine protease inhibitors, and the conformational properties of these modified peptides have been studied by NMR and molecular modelling. The dipeptide isostere 7-endo-BtA [(1R,4S,5R,7R)-4-endo-methyl-6,8-dioxa-3-azabicyclo[3.2.1]octane-7-endo-carboxylic acid] (2), derived from L-alanine and meso tartaric acid, gave rise to the modified BBI peptide 5 whose structure was very similar to that of the original peptide 3, suggesting a possible reverse turn inducing property for this dipeptide isostere.

Stereoselective Meisenheimer rearrangement using BTAa's as chiral auxiliaries

Abstract The Meisenheimer rearrangement involves the [2,3]-sigmatropic rearrangement of allylic tertiary amine-N-oxides to O-allyl hydroxylamines. Various BTAas (bicycles derived from tartaric acid and α-amino acids) were employed as chiral auxiliaries in the Meisenheimer rearrangement of the N-oxides of N-allylamines obtained by the coupling of BTAas with cinnamyl bromide and (E)-2-methyl-2-pentenyl acetate. While the formation of the N-oxides was highly diastereoselective, the asymmetric induction in the rearrangement was generally low. However, the interaction between the 4-endo group on the BTAa and a 2′-substituent on the allylic moiety allowed a more efficient chirality transfer in the [2,3]-sigmatropic process, affording d.e. values as high as 65% in the best case. The cleavage of the NO bond in the rearrangement products was possible by using Mo(CO)6 with a good recovery of both alcohol and chiral auxiliary.

Baker's yeast reduction of prochiral γ-nitroketones: Enantioselective synthesis of (S)-4-nitroalcohols

Abstract The bakers yeast reduction of seven different prochiral nitroketones 1a-g occurred on the re face of the carbonyl group, thus affording the ( S )-nitroalcohols 2a-g , with different level of enantioselectivity (e.e. 15–99%). The best results (e.e. = 99%) were achieved when the substituent R is markedly different from the nitroalkyl group [e.g. 1a (R = Me) and 1e (R = o -MeO-C 6 H 4 )]. The e.e. and the configuration of the bioproducts were assigned by NMR study of the corresponding Mosher esters and in one case ( 2d ) by means of chemical correlation. The syntheses of optically active lactone 7 and pyrrolidine 11 starting from 2d are also described.

Synthesis of benzo[c]quinolizin-3-ones : Selective non-steroidal inhibitors of steroid 5α-reductase 1

A short and efficient synthesis of novel benzo[c]quinolizin-3-one derivatives is described. The synthesis is based on the tandem Mannich-Michael cyclization between 2-silyloxy-1,3-butadienes and a N-t-Boc iminium ion. The prepared derivatives are selective inhibitors of human steroid 5 alpha-reductase isoenzyme 1, thus having potential application as drugs for treatment of male pattern baldness and other DHT-dependent skin disorders.

Synthesis of Vinylogous Amides by Gold(I)-Catalyzed Cyclization of N-Boc-Protected 6-Alkynyl-3,4-dihydro-2H-pyridines

The gold(I)-catalyzed cyclization of N-Boc-protected 6-alkynyl-3,4-dihydro-2H-pyridines, prepared by the Sonogashira coupling of lactam-derived enol triflates or phosphates, provides vinylogous amides, which are useful intermediates in the synthesis of natural compounds. The Au(I)-catalyzed reaction is carried out with Ph3PAuOTf as a catalyst and proceeds via a 6-endo-dig cyclization to form a vinylgold species that after protodeauration generates a cyclic carbamate intermediate. This intermediate is in most cases not isolated, but the addition of a base to the reaction mixture rapidly and quantitatively delivers the target vinylogous amide. The first synthesis of a natural compound from Sonneratia hainanensis has been accomplished by this approach.

Stereochemical Assignment of Strigolactone Analogues Confirms Their Selective Biological Activity

Strigolactones (SLs) are new plant hormones with various developmental functions. They are also soil signaling chemicals that are required for establishing beneficial mycorrhizal plant/fungus symbiosis. In addition, SLs play an essential role in inducing seed germination in root-parasitic weeds, which are one of the seven most serious biological threats to food security. There are around 20 natural SLs that are produced by plants in very low quantities. Therefore, most of the knowledge on SL signal transduction and associated molecular events is based on the application of synthetic analogues. Stereochemistry plays a crucial role in the structure-activity relationship of SLs, as compounds with an unnatural D-ring configuration may induce biological effects that are unrelated to SLs. We have synthesized a series of strigolactone analogues, whose absolute configuration has been elucidated and related with their biological activity, thus confirming the high specificity of the response. Analogues bearing the R-configured butenolide moiety showed enhanced biological activity, which highlights the importance of this stereochemical motif.