Skeletally Diverse Small Molecules Using a Build/Couple/Pair Strategy

Intermolecular couplings of simple building blocks using catalytic, stereoselective cross-Mannich reactions followed by intramolecular functional group-pairing reactions of easily accessed variants of the Mannich products are explored as a route to skeletally diverse small molecules. The synthetic pathway yields products having 12 different skeletons using only three steps and has the potential to enable substantial stereochemical diversification in the future

Colorimetric tools for solid-phase organic synthesis

One of the unresolved problems of solid-phase organic synthesis (SPOS) is the availability of general and rapid methods to monitor the transformation of functional groups present in molecules supported on insoluble supports. Color tests, far from providing the ultimate solution, may help in detection (and sometimes in quantification) of different functional groups. In this short review, we have collected most of the methods available and applied in SPOS with an Experimental Section that describes the procedure we have successfully applied to bead analyses in our laboratories

Structural analysis of a simplified model reproducing SARS-CoV-2 S RBD/ACE2 binding site

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an RNA virus identified as the cause of the coronavirus outbreak in December 2019 (COVID-19). Like all the RNA viruses, SARS-CoV-2 constantly evolves through mutations in its genome, accumulating 1–2 nucleotide changes every month, giving the virus a selective advantage through enhanced transmissibility, greater pathogenicity, and the possibility of circumventing immunity previously acquired by an individual either by natural infection or by vaccination. Several SARS-CoV-2 variants of concern (VoC) have been identified, among which we find Alpha (Lineage B.1.1.7), Beta (Lineage B.1.351), and Gamma (Lineage P.1) variants. Most of the mutations occur in the spike (S) protein, a surface glycoprotein that plays a crucial role in viral infection; the S protein binds the host cell receptor, the angiotensin-converting enzyme of type 2 (ACE2) via the receptor binding domain (RBD) and catalyzes the fusion of the viral membrane with the host cell. In this work, we present the development of a simplified system that would afford to study the change in the SARS-CoV-2 S RBD/ACE2 binding related to the frequent mutations. In particular, we synthesized and studied the structure of short amino acid sequences, mimicking the two proteins’ critical portions. Variations in the residues were easily managed through the one-point alteration of the sequences. Nuclear magnetic resonance (NMR) and circular dichroism (CD) spectroscopies provide insights into ACE2 and SARS-CoV-2 S RBD structure with its related three variants (Alpha, Beta, and Gamma). Spectroscopy data supported by molecular dynamics lead to the description of an ACE2/RBD binding model in which the effect of a single amino acid mutation in changing the binding of S protein to the ACE2 receptor is predictable

Synthesis, structural aspects and cytotoxicity of the natural cyclopeptides yunnanins A, C and phakellistatins 1, 10

Yunnanins A and C, two cyclic heptapeptides occurring in the roots of Stellaria yunnanensis, and phakellistatins 1 and 10, a hepta- and an octacyclopeptide first isolated from marine sponges of the genus Phakellia, were efficiently synthesized using a combination of solid and solution-phase techniques. Structural analysis on the synthetic members of the yunnanin series showed that the synthetic sample of yunnanin A exhibited a configurational pattern at the Pro peptide linkages identical to the natural product (trans-Pro3, trans-Pro5), while yunnanin C was obtained as a complex mixture of geometric/conformational isomers; the major isomer (trans-Pro3) was indistinguishable from the natural cyclopeptide and co-occurred along with lower amounts of a mixture (1:1 ratio) of two different rotamers, both displaying cis geometry at the Pro3 linkage. In the phakellistatin series, the synthetic phakellistatin 1 (determined as cis-Pro1, cis-Pro3, cis-Pro5) was identical to the natural one, while two different isomeric products of phakellistatin 10 could be obtained: a major one (trans-Pro1, trans-Pro4, trans-Pro6) showing spectral properties superimposable with the natural metabolite, and a minor geometric isomer of the natural cyclopeptide. Interestingly, the synthetic cyclopeptides, although found to be chemically identical with their natural counterparts, did not display the same biological properties (in vitro cytotoxicity against a panel of cancer cell lines), leaving presently open the question whether or not the potent bioactivity reported in the literature should really be attributed to these natural cyclic peptides. q 2003 Elsevier Ltd. All rights reserved

Apicidine, nuovi peptidi ciclici inibitori dell'istone deacetilasi (HDAC). Sintesi dei residui derivati dall'acido 2-amino 8-oxodecanoico (AODA)

Le Apicidine, una famiglia di tetrapeptidi ciclici di origine fungina, hanno mostrato una elevatissima attività  come inibitori reversibili di HDAC. Con l'obiettivo di sintetizzare le Apicidine e preparare analoghi semplificati che mantengano l'attività di inibitori di HDAC, abbiamo progettato una sintesi generale e multivariabile di derivati dell'acido 2-ammino-8-oxodecanoico

Synthesis of kainoids via a highly stereoselective hydroformylation of kainic acid.

An efficient prepn. of a series of secondary amines, structurally related to the kainic acid scaffold, is described.  Naturally occurring (-)-α-kainic acid was hydroformylated with complete terminal selectivity and high stereoselectivity.  The stereochem. of the product was investigated through the ROESY and HETLOC spectra of the corresponding 2,4-dinitrophenylhydrazone, showing the presence of a single diastereoisomer with rotamers related to the presence of the Boc group.  The aldehyde was used as a platform to prep. amines by reductive amination in ionic liqs

N-thioalkylcarbazoles derivatives as new antiproliferative agents: synthesis, characterisation and molecular mechanism evaluation

Synthetic or natural carbazole derivatives constitute an interesting class of heterocycles, which showed several pharmaceutical properties and occupied a promising place as antitumour tools in preclinical studies. They target several cellular key-points, e.g. DNA and Topoisomerases I and II. The most studied representative, i.e. Ellipticine, was introduced in the treatment of metastatic breast cancer. However, because of the onset of dramatic side effects, its use was almost dismissed. Many efforts were made in order to design and synthesise new carbazole derivatives with good activity and reduced side effects. The major goal of the present study was to synthesise a series of new N-thioalkylcarbazole derivatives with anti-proliferative effects. Two compounds, 5a and 5c, possess an interesting anti-proliferative activity against breast and uterine cancer cell lines without affecting non-tumoural cell lines viability. The most active compound (5c) induces cancer cells death triggering the intrinsic apoptotic pathway by inhibition of Topoisomerase II

Synthesis of Heterocycles via Microwave-Assisted Cycloadditions and Cyclocondensations

Controlled microwave heating has found many important applications in the synthesis of heterocycles. Almost all kinds of heterocycles have been prepared (or their preparation attempted) with the aid of microwaves. Many examples of cyclocondensations, reactions where two or more functional groups combine with the loss of another small molecule (usually water), have been described. Moreover, microwave irradiation successfully induces cycloaddition reactions, especially in the cases where high temperatures are required. This review collects the most representative examples of the application of microwaves to these two kinds of transformations. Except for a few examples, all the reactions selected have been carried out under controlled microwave irradiation using dedicated instruments

A simple procedure for the transformation of L- Glutamic acid into the corresponding g-aldehyde

2-Dibenzylamino-5-oxopentanoic acid benzyl ester has been obtained in good yields by complete benzylation of L-glutamic acid in NaOH and Na2CO3, selective redn. of the γ-ester into alc. with DIBAL and further transformation into aldehyde using Swern oxidn.  The overall three-step procedure from Glu gave aldehyde in good yield

Ionic Liquid as a Suitable Phase for Multistep Parallel Synthesis of an Array of Isoxazolines

3(Equation presented) A parallel array of isoxazoline diamides was prepared using an ionic liquid [bmim][BF4] as the phase where a three-step procedure (Schotten-Baumann, 1,3-dipolar cycloaddition, ester amidation with Me3Al) was carried out. At the end, selective extraction of the final products with diethyl ether allowed simple isolation of the 16 components of the array (Syncore technology).nonenoneRODRIQUEZ M; A. SEGA; TADDEI MRodriquez, M; Sega, Alessandro; Taddei, Maurizi