Patricia Melnyk

Parallel synthesis of polysubstituted tetrahydroquinolines

Abstract A three-component cycloaddition was used to prepare a library of polysubtituted tetrahydroquinolines. Reaction conditions were optimised and a large range of anilines, aldehydes and alkenes were tested.

Combinatorial chemistry : a rational approach to chemical diversity

Summary Although knowledge-based de novo design of high affinity ligands for receptors or enzymes appears to be the most rational approach to the discovery of new pharmacologically active substances, high throughput random screening of compounds with no known structural similarity to the natural ligand has proved to be a highly efficient method. In order to increase the number of new molecules, methods of combinatorial synthesis have been considerably developed in recent years. In this review we will examine some of the main strategies for generating large arrays of diverse molecular entities, the screening of such libraries, the methods used to identify an active compound, and the chemical technologies used in the development of this very promising source of new drugs.

Replacement of the 4'-hydroxy group of amodiaquine and amopyroquine by aromatic and aliphatic substituents: synthesis and antimalarial activity.

4′‐Substituted analogues of amodiaquine and amopyroquine were synthesized using Csp2–Csp2 and Csp2–Csp3 Suzuki–Miyaura cross‐coupling reactions as the key step. The new derivatives were found to be active against both chloroquine (CQ)‐sensitive and CQ‐resistant strains of P.u2005falciparum, with IC50 values in the range of 7–200u2005nM; one compound showed inu2005vivo activity.

Synthesis and antimalarial activity of carbamate and amide derivatives of 4-anilinoquinoline

A series of 4-anilinoquinolines bearing an amino side chain linked to the aromatic ring with a carbamate or an amide bond were synthesized and evaluated for their antimalarial activity and their cytotoxicity upon MRC-5 cells. Among the 17 compounds, a majority was found to be active in the low nanomolar range against both chloroquine-sensitive and -resistant strains of Plasmodium falciparum in vitro with relative low cytotoxicity. Two compounds were then tested on mice infected by Plasmodium berghei and were found to exhibit reasonable in vivo activity.

Tau pathology modulates Pin1 post-translational modifications and may be relevant as biomarker

A prerequisite to dephosphorylation at Ser-Pro or Thr-Pro motifs is the isomerization of the imidic peptide bond preceding the proline. The peptidyl-prolyl cis/trans isomerase named Pin1 catalyzes this mechanism. Through isomerization, Pin1 regulates the function of a growing number of targets including the microtubule-associated tau protein and is supposed to be deregulated Alzheimers disease (AD). Using proteomics, we showed that Pin1 is posttranslationally modified on more than 5 residues, comprising phosphorylation, N-acetylation, and oxidation. Although Pin1 expression remained constant, Pin1 posttranslational two-dimensional pattern was modified by tau overexpression in a tau-inducible neuroblastoma cell line, in our THY-Tau22 mouse model of tauopathy as well as in AD. Interestingly, in all of these systems, Pin1 modifications were very similar. In AD brain tissue when compared with control, Pin1 is hyperphosphorylated at serine 16 and found in the most insoluble hyperphosphorylated tau fraction of AD brain tissue. Furthermore, in all tau pathology conditions, acetylation of Pin1 may also contribute to the differences observed. In conclusion, Pin1 displays several posttranslational modifications, which are specific in tauopathies and may be useful as biomarker.

Non-Photoinduced Biological Properties of Verteporfin

BACKGROUNDnVerteporfin is a porphyrinic photosensitizer clinically used for the photodynamic treatment of age-related macular degeneration. It has been identified almost simultaneously as a YAP/TEAD and an autophagosome inhibitor. Over the last few years, YAP (TAZ), the downstream effectors of the Hippo pathway, have emerged as promising anticancer targets, as shown by several experimental lines of evidence, showing the overproduction of YAP in several cancers. However, YAP was also found to be closely connected to autophagy, mitochondria and reactive oxygen/nitrogen species. We herein, review the recent studies where VP was used without photoactivation as a YAP/TEAD inhibitor or protein oligomerization promoter, focusing on its effects on the YAP/TEAD gene targets and other biomarkers related to autophagy.nnnRESULTSnSince the identification of VP as YAP/TEAD inhibitor, several in vitro and in vivo studies have revealed the new potential of this molecule in different cancers, where YAP is overexpressed. However, detailed structural information about its interaction with YAP is still lacking. Concomitantly, VP was identified as autophagosome inhibitor by promoting oligomerization of p62. Moreover, VP proves to be tumor-selective proteotoxic (by oligomerization of p62, STAT3) in colorectal cancer. Knowledge on the biological properties of the only YAP inhibitor available to date is vital for its pharmacological use on cellular and animal models.nnnCONCLUSIONnVP is a multi-target drug interacting with several proteins implicated in major cellular processes. Although this does not impact its clinical use, VP does not seem to be the ideal drug for pharmacological inhibitions of YAP/TEAD.

Improved Syntheses of 2-Bromonicotinaldehyde and Acid

Abstract Synthetically useful 2-bromonicotinaldehyde and 2-bromonicotinic acid can be conveniently prepared in high yield from the directed ortho metalation of 2-bromopyridine.

Hit identification of novel heparanase inhibitors by structure- and ligand-based approaches

Heparanase is a key enzyme involved in the dissemination of metastatic cancer cells. In this study a combination of in silico techniques and experimental methods was used to identify new potential inhibitors against this target. A 3D model of heparanase was built from sequence homology and applied to the virtual screening of a library composed of 27 known heparanase inhibitors and a commercial collection of drugs and drug-like compounds. The docking results from this campaign were combined with those obtained from a pharmacophore model recently published based in the same set of chemicals. Compounds were then ranked according to their theoretical binding affinity, and the top-rated commercial drugs were selected for further experimental evaluation. Biophysical methods (NMR and SPR) were applied to assess experimentally the interaction of the selected compounds with heparanase. The binding site was evaluated via competition experiments, using a known inhibitor of heparanase. Three of the selected drugs were found to bind to the active site of the protein and their KD values were determined. Among them, the antimalarial drug amodiaquine presented affinity towards the protein in the low-micromolar range, and was singled out for a SAR study based on its chemical scaffold. A subset of fourteen 4-arylaminoquinolines from a global set of 249 analogues of amodiaquine was selected based on the application of in silico models, a QSAR solubility prediction model and a chemical diversity analysis. Some of these compounds displayed binding affinities in the micromolar range.

Minimal chemical modification of reductive end of dextran to produce an amphiphilic polysaccharide able to incorporate onto lipid nanocapsules.

In order to graft an amphiphilic polysaccharide to lipid nanocapsules, we present here a new method of dextran lipidation. The lipidation strategy is based on the formation of an oxime linkage between the amphiphilic hydroxylamine C16E20ONH2 and the reductive end of a 40 kDa dextran. This chemoselective reaction allows us to control the lipidation site and the number of lipid introduced on the dextran molecule. This new amphiphilic dextran was used to coat the surface of lipid nanocapsules. The coating efficiency was followed by dynamic light scattering and the presence of the polysaccharide was confirmed by (1)H NMR and observed by electronic microscopy.

Improved synthesis of pyridazinediones under microwave irradiation

Abstract Pyridazinediones have been synthesized with good to excellent yields under microwave irradiation. The results were compared with traditional stirring.