Carlo Scolastico

conformational preferences of peptides containing reverse-turn mimetic bicyclic lactams: inverse γ-turns versus type-ii′ β-turns — insights into β-hairpin stability.

The solid-phase synthesis and characterization of a series of peptides (3–9), containing reverse-turn mimetic bicyclic lactams (1a, 1b), was reported in the preceding paper. The bicyclic lactams (1a, 1b) possess high structural similarity to the two central residues of a β-turn. The conformational preferences of the constrained peptides have been investigated by NMR spectroscopy and IR spectroscopy. Our experimental results have been complemented by computer modelling studies and show that the constrained peptides (3–9) form an inverse γ-turn or a type-II′ β-turn through intramolecular hydrogen bonding, depending on the nature of the reverse-turn mimic. In N-acetylated tetrapeptide mimics incorporating the two different bicyclic lactams (a series and b series), H5 is available for either a γ-turn (7-membered ring with the carbonyl group of the bicyclic lactam) or a β-turn (10-membered ring with the carbonyl group of residue 2), as shown in Figures 7 and 9. The a series incorporating the (5,7)-bicyclic lactam predominantly induces the γ-turn conformation, while the b series incorporating the (5,6)-bicyclic lactam can promote either a γ-turn or a β-turn conformation, with the β-turn usually being preferred and with varying degrees of β-hairpin formation.

Stereoselective synthesis of statin analogues.

Abstract Statin analogues can be synthesized stereoselectively (diastereomeric ratios up to 4:1) starting from malic acid. The key step involves an unprecedented cis-selective allylation of an α-alkoxy N-acyliminium ion.

Enantioselective mukaiyama-michael reactions of 2-carbomethoxy cyclopentenone catalyzed by chiral bis(Oxazoline)-Cu(II) complexes

Abstract The conjugate addition of propionate silylketene acelal 1 to 2-carbomethoxy cyclopentenone is promoted by bis(oxazoline)-Cu(II) complexes with high diastereoselectivity and good enantiomeric excesses. The absolute configuration of the product can be controlled by varying the copper counterion. A catalytic version of the reaction was developed, which gave ketoacid 5a in 72% d.e. and 63% e.e.

Cyclic RGD functionalized gold nanoparticles for tumor targeting.

Integrin α(v)β(3) is an adhesion molecule involved in physiological and pathological angiogenesis as well as tumor invasion and metastasis. Therefore, it is considered an important target for molecular imaging and delivery of therapeutics for cancer, and there is a strong interest in developing novel agents interacting with this protein. Nevertheless, the interaction of individual ligands is often still weak for efficient tumor targeting, and many research groups have synthesized multivalent displays in order to overcome this problem. Gold nanoparticles can be considered a smart platform for polyvalent presentation on account of their globular shape, tunable size, facile surface chemistry, and biocompatibility. Moreover, their unique physical properties render gold nanoparticles ideal candidates for tumor diagnosis and therapy. Here, we report the synthesis and characterization of gold nanoparticles functionalized with cRGD integrin ligand and their employment for targeting human cancer cells expressing α(v)β(3) integrin.

Lewis acid mediated aldol condensations using thioester silyl ketene acetals

Abstract BF3-OEt2 mediated thioester silylketene acetal additions to aldehydes are stereoconvergent and give high anti-syn ratios and good chemical yields. An acyclic transition state model was hypothesized in order to account for the observed selectivity. Theoretical methods (MNDO) were used to evaluate the ground-state conformations of thioester silylketene acetals and to model the acyclic transition states. Lewis acid mediated additions of thioester silylketene acetals to 2-phenylpropion-aldehyde (BF3-OEt2), O-benzyl lactic aldehyde (SnCl4), 2,3-0,O-dibenzyl glyceraldehyde (SnCl4), and 3-benzyloxy-2-methylpropionaldehyde (TiCl4) were found to be highly diastereoface selective so that three contiguous stereocenters could be established. With α-, β- , or α,β-alkoxy aldehydes, relative stereoselection (chelation) effectively controls internal stereolection. The ground state conformations of the chiral aldehydes were studied using molecular mechanics (MM2).

Novel SMAC-mimetics synergistically stimulate melanoma cell death in combination with TRAIL and Bortezomib

Background:XIAP (X-linked inhibitor of apoptosis protein) is an anti-apoptotic protein exerting its activity by binding and suppressing caspases. As XIAP is overexpressed in several tumours, in which it apparently contributes to chemoresistance, and because its activity in vivo is antagonised by second mitochondria-derived activator of caspase (SMAC)/direct inhibitor of apoptosis-binding protein with low pI, small molecules mimicking SMAC (so called SMAC-mimetics) can potentially overcome tumour resistance by promoting apoptosis.Methods:Three homodimeric compounds were synthesised tethering a monomeric SMAC-mimetic with different linkers and their affinity binding for the baculoviral inhibitor repeats domains of XIAP measured by fluorescent polarisation assay. The apoptotic activity of these molecules, alone or in combination with tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) and/or Bortezomib, was tested in melanoma cell lines by MTT viability assays and western blot analysis of activated caspases.Results:We show that in melanoma cell lines, which are typically resistant to chemotherapeutic agents, XIAP knock-down sensitises cells to TRAIL treatment in vitro, also favouring the accumulation of cleaved caspase-8. We also describe a new series of 4-substituted azabicyclo[5.3.0]alkane monomeric and dimeric SMAC-mimetics that target various members of the IAP family and powerfully synergise at submicromolar concentrations with TRAIL in inducing cell death. Finally, we show that the simultaneous administration of newly developed SMAC-mimetics with Bortezomib potently triggers apoptosis in a melanoma cell line resistant to the combined effect of SMAC-mimetics and TRAIL.Conclusion:Hence, the newly developed SMAC-mimetics effectively synergise with TRAIL and Bortezomib in inducing cell death. These findings warrant further preclinical studies in vivo to verify the anticancer effectiveness of the combination of these agents.

Isolation and structure determination of a new antifungal α-hydroxymethyl-α-amino acid

Abstract A new α-hydroxymethyl-α-amino acid, thermozymocidin showing antifungal activity, has been isolated from a thermophilic mold. Physical and chemical evidence suggest structure 1.

Asymmetric synthesis of functionalized α -amino-β-hydroxy acids via chiral norephedrine-derived oxazolidines

Abstract Both anti and syn enantiomerically pure functionalized α -amino-β-hydroxy acids and derivatives were synthesized starting from norephedrine-derived oxazolidine (1). The key-steps of the synthesis were the nucleophilic epoxidation of (1) and the nucleophilic opening of epoxy acid (3) with ammonia, both reactions proved regio- and diastereospecific. High yield preparation of the target anti aldehyde (9) was accomplished using standard procedures. The complementary syn aldehyde (23) was obtained via alkaline isomerization of the cis oxazolidinone (13) to the trans one. The aldehyde function of (9) and (23) provides a useful handle for manipulation to more complex structures, allowing potential access to a range of optically pure α -amino-β-hydroxy acids. The formal total synthesis of the monocyclic β-lactam antibiotic “carumonam” was accomplished using the present methodology.

Designing Smac-mimetics as antagonists of XIAP, cIAP1, and cIAP2.

Inhibitor of apoptosis proteins (IAPs) such as XIAP, cIAP1, and cIAP2 are upregulated in many cancer cells. Several compounds targeting IAPs and inducing cell death in cancer cells have been developed. Some of these are synthesized mimicking the N-terminal tetrapeptide sequence of Smac/DIABLO, the natural endogenous IAPs inhibitor. Starting from such conceptual design, we generated a library of 4-substituted azabicyclo[5.3.0]alkane Smac-mimetics. Here we report the crystal structure of the BIR3 domain from XIAP in complex with Smac037, a compound designed according to structural principles emerging from our previously analyzed XIAP BIR3/Smac-mimetic complexes. In parallel, we present an in silico docking analysis of three Smac-mimetics to the BIR3 domain of cIAP1, providing general considerations for the development of high affinity lead compounds targeting three members of the IAP family.

Biological and molecular properties of a new αvβ3/αvβ5 integrin antagonist

The aim of the present study was to identify specific αvβ3/αvβ5 integrin antagonists active on tumor-induced angiogenesis. To this purpose, in vitro integrin-binding assays were used to screen a library of conformationally constrained bicyclic lactam Arg-Gly-Asp–containing pseudopeptides. The results identified ST1646 as a high-affinity specific ligand for αvβ3 and αvβ5 integrins with negligible interacting with α5β1 integrin. In all the assays, ST1646 was equipotent to or more potent than the well-characterized integrin antagonists c(RGDfV) and cyclo(Arg-Gly-Asp-d-Phe-[NMe]Val) (EMD121974). In the chorioallantoic membrane assay, topical administration of ST1646 was able to prevent the angiogenic responses elicited by recombinant fibroblast growth factor-2 or vascular endothelial growth factor. In addition, systemic administration of ST1646 in mice exerted a significant antiangiogenic activity on neovascularization triggered by mammary carcinoma MDA-MB435 cells implanted s.c. in a dorsal air sac via a (Millipore Filter Corporation, Bedford, MA) chamber. Moreover, ST1646 delivery via an osmotic pump inhibited the growth and vascularization of tumor xenografts originating from the injection of αvβ3/αvβ5-expressing human ovarian carcinoma cells in nude mice. In agreement with the biochemical and pharmacologic studies, Monte Carlo/Stochastic Dynamics simulation showed that the bicyclic scaffold in ST1646 forced the compound to assume a preferred conformation superimposable to the X-ray conformation of αvβ3-bound EMD121974. Accordingly, computer-docking studies indicated that the ST1646-αvβ3 integrin complex maintains the ligand-receptor distances and interactions observed in the crystalline EMD121974-αvβ3 integrin complex. Taken together, these observations indicate that ST1646 represents a dual αvβ3/αvβ5 integrin antagonist with interesting biochemical and biological features to be tested in cancer therapy.