Daniela Perrone

Porphyrins in 1,3-dipolar cycloaddition reactions with sugar nitrones. Synthesis of glycoconjugated isoxazolidine-fused chlorins and bacteriochlorins

Glycoconjugated isoxazolidine-fused chlorins and bacteriochlorins were prepared in moderate to good yields by 1,3-dipolar cycloaddition reactions of meso-tetrakis(pentafluorophenyl)porphyrin with glycosyl nitrones.

Totally chemical synthesis of azasugars via thiazole intermediates. Stereodivergent routes to (-)-nojirimycin, (-)-mannojirimycin and their 3-deoxy derivatives from serine☆

Abstract The synthesis of the (-)-antipodes of the natural products nojirimycin (+)-1 and mannojirimycin (+)-2 has been carried out by stereocontrolled reduction of the thiazole ketone 7 as a common key intermediate. This ketone was in turn obtained from the L-serine derived aldehyde 3 by two convergent routes involving carbonylolefination and dihydroxylation processes. Moreover, 3-deoxy derivatives of (-)-1 and (-)-2 have been prepared from 3 and the lithium enolate of 2-acetylthiazole followed by stereocontrolled reduction of the resultant aldol.

A convergent synthesis of the renin inhibitor SPP-100 using a nitrone intermediate

Abstract The total synthesis of SPP-100 and its C-5 epimer involves the construction of the β-amino alcohol segment via addition of the Grignard reagent derived from 3-aryl-2-isopropyl-1-chloropropane to the nitrone functional group installed at C-4 of the pseudoephedrine spiroanellated γ-butyrolactone derivative.

A convenient synthesis of iminosugar-C-glycosides via organometallic addition to N-benzyl-N-glycosylhydroxylamines

N-Benzyl-N-glycosylhydroxylamines were prepared in very good yield via condensation of furanoses and pyranoses with N-benzylhydroxylamine at 110°C for 30 min under solvent-free conditions. These anomeric sugar-hydroxylamines exist in equilibrium with the open-chain nitrone form. In fact upon treatment with various organometallic reagents, the corresponding adducts were obtained with good to high diastereoselectivity. These adducts were converted into iminosugar-C-glycosides by reductive dehydroxylation and intramolecular cyclization.

Mcl-1 involvement in mitochondrial dynamics is associated with apoptotic cell death

Mcl-1 protein affects mitochondrial calcium homeostasis to modulate apoptosis. Mcl-1 is involved in mitochondrial fusion and fission in a Drp1-dependent manner By using splicing-switching antisense oligonucleotides, it is possible to increase the synthesis of the Mcl-1 proapoptotic isoform, increasing the sensitivity of cancer cells to apoptotic stimuli.

New entry to pyrrolidine homoazasugars: conversion of d-arabinose into 2,5-anhydro-2,5-imino-d-glucitol via aminohomologation

Abstract The title homoazasugar, also referred as (2 R ,5 S )-bis(hydroxymethyl)-(3 R ,4 R )-dihydroxypyrrolidine, has been synthesized by addition of 2-lithiothiazole to the 2,3,5-tri- O -benzyl- d -arabinofuranose-derived nitronehydroxylamine mixture followed by reductive N -dehydroxylation and conversion of the thiazole ring into the hydroxymethyl group.

Dystrophin restoration in skeletal, heart and skin arrector pili smooth muscle of mdx mice by ZM2 NP-AON complexes

Potentially viable therapeutic approaches for Duchenne muscular dystrophy (DMD) are now within reach. Indeed, clinical trials are currently under way. Two crucial aspects still need to be addressed: maximizing therapeutic efficacy and identifying appropriate and sensible outcome measures. Nevertheless, the end point of these trials remains painful muscle biopsy to show and quantify protein restoration in treated boys. In this study we show that PMMA/N-isopropil-acrylamide+ (NIPAM) nanoparticles (ZM2) bind and convey antisense oligoribonucleotides (AONs) very efficiently. Systemic injection of the ZM2–AON complex restored dystrophin protein synthesis in both skeletal and cardiac muscles of mdx mice, allowing protein localization in up to 40% of muscle fibers. The mdx exon 23 skipping level was up to 20%, as measured by the RealTime assay, and dystrophin restoration was confirmed by both reverse transcription-PCR and western blotting. Furthermore, we verified that dystrophin restoration also occurs in the smooth muscle cells of the dorsal skin arrector pili, an easily accessible histological structure, in ZM2–AON-treated mdx mice, with respect to untreated animals. This finding reveals arrector pili smooth muscle to be an appealing biomarker candidate and a novel low-invasive treatment end point. Furthermore, this marker would also be suitable for subsequent monitoring of the therapeutic effects in DMD patients. In addition, we demonstrate herein the expression of other sarcolemma proteins such as α-, β-, γ- and δ-sarcoglycans in the human skin arrector pili smooth muscle, thereby showing the potential of this muscle as a biomarker for other muscular dystrophies currently or soon to be the object of clinical trials.

Brain uptake of a Zidovudine prodrug after nasal administration of solid lipid microparticles.

Our previous results demonstrated that a prodrug obtained by the conjugation of the antiretroviral drug zidovudine (AZT) with ursodeoxycholic acid (UDCA) represents a potential carrier for AZT in the central nervous system, thus possibly increasing AZT efficiency as an anti-HIV drug. Based on these results and in order to enhance AZT brain targeting, the present study focuses on solid lipid microparticles (SLMs) as a carrier system for the nasal administration of UDCA-AZT prodrug. SLMs were produced by the hot emulsion technique, using tristearin and stearic acid as lipidic carriers, whose mean diameters were 16 and 7 μm, respectively. SLMs were of spherical shape, and their prodrug loading was 0.57 ± 0.03% (w/w, tristearin based) and 1.84 ± 0.02% (w/w, stearic acid based). The tristearin SLMs were able to control the prodrug release, whereas the stearic acid SLMs induced a significant increase of the dissolution rate of the free prodrug. The free prodrug was rapidly hydrolyzed in rat liver homogenates with a half-life of 2.7 ± 0.14 min (process completed within 30 min). The tristearin SLMs markedly enhanced the stability of the prodrug (75% of the prodrug still present after 30 min), whereas the stabilization effect of the stearic acid SLMs was lower (14% of the prodrug still present after 30 min). No AZT and UDCA-AZT were detected in the rat cerebrospinal fluid (CSF) after an intravenous prodrug administration (200 μg). Conversely, the nasal administration of stearic acid based SLMs induced the uptake of the prodrug in the CSF, demonstrating the existence of a direct nose-CNS pathway. In the presence of chitosan, the CSF prodrug uptake increased six times, up to 1.5 μg/mL within 150 min after nasal administration. The loaded SLMs appear therefore as a promising nasal formulation for selective zidovudine brain uptake.

O-Silyl triflate-promoted addition of diethyl phosphite to chiral aldonitrones. A rapid access to complex α-amino phosphonates and their N-hydroxy derivatives

Abstract The addition reaction of diethyl phosphite to O -silylated N -benzyl nitrones derived from chiral α-alkoxy and N- Boc α-amino aldehydes has been studied as a stereoselective carbon phosphorus bond forming process for the synthesis of polyhydroxylated α-amino and α,β-diamino phosphonates. Key intermediates are the corresponding N -hydroxy α-amino phosphonates.

Homologation of L-phenylalanine to ketomethylene and hydroxyethylene dipeptide isosteres via 2-thiazolyl amino ketone intermediate

Abstract A highly efficient route is presented for the synthesis of N-protected isosteric dipeptides Pheψ[COCH 2 ]Gly and Pheψ[CH(OH)CH 2 ]Phe from L -phenylalanine through 2-thiazolyl α-amino ketone and δ-amino-γ-hydroxy-(E)-α,β-enoate derivatives as key intermediates.