One-Pot Synthesis of N-Fused Benzimidazo-ß-carbolines through Sequential Propargylation/aza-Cycloisomerization Approach.

The first sequential acid-catalyzed propargylation/base-mediated aza-cycloisomerization between indolyl-benzimidazoles and propargylic alcohols is described. This protocol enables the one-pot construction of N-fused benzimidazo-ß-carbolines in good yields. The synthetic utility of this approach is demonstrated by the assembly of an aza-helicene and also by a gram-scale reaction.

Domino alkyne insertion/aldol reaction/aromatization of 2-alkynyl indole-3-carbaldehyde with 1,3-diketones: entry to 2-indolyl phenols.

A novel one-pot base-promoted insertion of indolyl 2-alkynes into a C-C single bond of 1,3-diketones, followed by intramolecular aldol reaction and dehydrative aromatization is described. This reaction cascade leads to the construction of 2-indolyl phenols involving the formation of the C1-C2 and C3-C4 bonds of phenols resulting from the formal insertion process with a good substrate scope. Further, these bifunctional compounds were used in a novel arylative annulation in the presence of Grignard reagents to provide chromeno-indole frameworks.

Fluorinated Benzofuran and Dihydrobenzofuran as Anti-Inflammatory and Potential Anticancer Agents.

Benzofuran and 2,3-dihydrobenzofuran scaffolds are heterocycles of high value in medicinal chemistry and drug synthesis. Targeting inflammation in cancer associated with chronic inflammation is a promising therapy. In the present study, we investigated the anti-inflammatory effects of fluorinated benzofuran and dihydrobenzofuran derivatives in macrophages and in the air pouch model of inflammation, as well as their anticancer effects in the human colorectal adenocarcinoma cell line HCT116. Six of the nine compounds suppressed lipopolysaccharide-stimulated inflammation by inhibiting the expression of cyclooxygenase-2 and nitric oxide synthase 2 and decreased the secretion of the tested inflammatory mediators. Their IC50 values ranged from 1.2 to 9.04 µM for interleukin-6; from 1.5 to 19.3 µM for Chemokine (C-C) Ligand 2; from 2.4 to 5.2 µM for nitric oxide; and from 1.1 to 20.5 µM for prostaglandin E2. Three novel synthesized benzofuran compounds significantly inhibited cyclooxygenase activity. Most of these compounds showed anti-inflammatory effects in the zymosan-induced air pouch model. Because inflammation may lead to tumorigenesis, we tested the effects of these compounds on the proliferation and apoptosis of HCT116. Two compounds with difluorine, bromine, and ester or carboxylic acid groups inhibited the proliferation by approximately 70%. Inhibition of the expression of the antiapoptotic protein Bcl-2 and concentration-dependent cleavage of PARP-1, as well as DNA fragmentation by approximately 80%, were described. Analysis of the structure-activity relationship suggested that the biological effects of benzofuran derivatives are enhanced in the presence of fluorine, bromine, hydroxyl, and/or carboxyl groups. In conclusion, the designed fluorinated benzofuran and dihydrobenzofuran derivatives are efficient anti-inflammatory agents, with a promising anticancer effect and a combinatory treatment in inflammation and tumorigenesis in cancer microenvironments.

Discovery of potent dual ligands for dopamine D4 and σ1 receptors.

During our work on exploration of molecules with some piperidine-triazole scaffolds, we realized that our compounds display chemical similarity with some σ, as well as dopaminergic receptor ligands. Here we show that this series of molecules has indeed strong affinity both for σ1 and dopamine D4 receptors. Moreover, they appear selective towards σ2, dopamine paralogues D1, D2, D3 and D5 receptors and hERG channel. Extensive molecular dynamics with our lead compound AVRM-13 were carried out on σ1, supporting agonist activity of the ligand. Unexpectedly, several observations suggested the existence of a cation binding domain, a probable regulatory site for calcium.

Structure Activity Relationship Studies around DB18, a Potent and Selective Inhibitor of CLK Kinases.

Three series of our lead CLK1 inhibitor DB18 have been designed, synthetized and tested against CLKs and DYRK1A kinases. Their cytotoxicity was subsequently measured on seven representative cancer cell lines. Guided by docking experiments, we focused on the less constrained part of the scaffold, and showed that drastically different substituents can be tolerated here. This work ended with the discovery of another promising derivative 12g, with IC50 = 0.004 µM in the inhibition of HsCLK1 and IC50 = 3.94 µM for the inhibition of HsDYRK1A. The SAR results are discussed in the light of extensive molecular modeling analyses. Finally, a kinome scan (463 human kinases) confirmed the outstanding selectivity of our lead compound DB18, suggesting that this scaffold is of prominent interest for selective CLK inhibitors. Altogether, these results pave the way for the development of inhibitors with novel selectivities in this family of kinases.

Synthesis and biological studies of new piperidino-1,2,3-triazole hybrids with 3-aryl isoxazole side chains.

A small library of new piperidine-triazole hybrids with 3-aryl isoxazole side chains has been designed and synthesized. Their cytotoxicity against a panel of seven cancer cell lines has been established. For the most promising compound, an IC50 value of 3.8 µM on PUMA/Bcl-xL interaction in live cancer cells was established through BRET analysis. A rationale was proposed for these results through complete molecular modelling studies.

Structural revision of the Mcl-1 inhibitor MIM1: synthesis and biological studies on ovarian cancer cells with evaluation of designed analogues.

In the area of cancer research, the development of new and potent inhibitors of anti-apoptotic proteins is a very active and promising topic. The small molecule MIM1 has been reported earlier as one of the first selective inhibitors of the anti-apoptotic protein Mcl-1. In the present paper, we first revised the structure of this molecule based on extensive physicochemical analyses. Then we designed and synthesized a focused library of analogues for the corrected structure of MIM1. Next, these molecules were subjected to a panel of in cellulo biological studies, allowing the identification of dual Bcl-xL/Mcl-1 inhibitors, as well as selective Mcl-1 inhibitors. These results have been complemented by fluorescence polarization assays with the Mcl-1 protein. Preliminary structure-activity relationships were discussed and extensive molecular modelling studies allowed us to propose a rationale for the biological activity of this series of new inhibitors, in particular for the selectivity of inhibition of Mcl-1 versus Bcl-xL.

Discovery of DB18, a potent inhibitor of CLK kinases with a high selectivity against DYRK1A kinase.

We describe in this paper the synthesis of a novel series of anilino-2-quinazoline derivatives. These compounds have been screened against a panel of eight mammalian kinases and in parallel they were tested for cytotoxicity on a representative panel of seven cancer cell lines. One of them (DB18) has been found to be a very potent inhibitor of human "CDC2-like kinases" CLK1, CLK2 and CLK4, with IC50 values in the 10-30 nM range. Interestingly, this molecule is inactive at 100 µM on the closely related "dual-specificity tyrosine-regulated kinase 1A" (DYRK1A). Extensive molecular simulation studies have been performed on the relevant kinases to explain the strong affinity of this molecule on CLKs, as well as its selectivity against DYRK1A.

Metal-free propargylation/aza-annulation approach to substituted ß-carbolines and evaluation of their photophysical properties.

An efficient acid-catalyzed propargylation/aza-annulation sequence was developed under metal-free reaction conditions, thus leading to a one-pot synthesis of a variety of substituted ß-carbolines starting from propargylic alcohols and indole 2-carbonyls. This versatile strategy was further extended to the synthesis of 5-azaindoles and 5-azabenzothiazoles. Optical properties suggested that manipulation of electron donor and acceptor moieties on ß-carbolines has an impact on their ground and excited state electronic behavior. This leads to blue or green emission and should facilitate the development of organic light emitting diodes (OLEDs). Electrochemical and stability studies revealed that 4a-6 shows ease of redox activity and photostability during illumination.

Strategies towards the synthesis of anti-tuberculosis drugs.

Antituberculosis drugs have captured the attention of the scientific community due to the emergence of drug resistance. Hence, the development of new analogs and new drugs which can treat drug-resistant tuberculosis is required. In this report, we reviewed the strategies towards the synthesis of antituberculosis drugs. These strategies include semisynthetic approaches, resolution based strategies, microbial transformations, solid phase synthesis, and asymmetric synthesis. As stereochemistry is an important hallmark of many drugs, the strategies based on asymmetric synthesis are described in detail. The emphasis on semisynthetic approaches is given for aminoglycoside antibiotics.

Synthesis and biological evaluation of longanlactone analogues as neurotrophic agents.

Longanlactone analogues were synthesized using a route featuring Friedel-Crafts acylation, Sonogashira coupling and 1,3-dipolar cycloaddition reactions. Structure-activity relationships were investigated for neurotrophic activity. Compound 6 was found to have the most potent neurotrophic activity among all the synthesized analogues in Neuro2a cells as evidenced by a battery of in vitro/cell based assays for assessment of neurogenic and potential neurotrophic activity including neurite outgrowth assay and real time PCR for popular markers of augmented neurotrophic activity. Compound 6 might serve as a template for further development of highly effective neurotrophic molecules.

Preparation of imidazo[1,2-a]-N-heterocyclic derivatives with gem-difluorinated side chains.

Using an aerobic oxidative coupling, different new imidazo[1,2-a]-N-heterocycles with gem-difluroroalkyl side chains have been prepared in fair yields by the reaction of gem-difluoroenones with aminopyridines, -pyrimidines and -pyridazines. Condensed heterocycles of this type play an important role as key core structures of various bioactive compounds. Further, starting with a chloroimidazopyridazine derivative, Pd-catalyzed coupling reactions as well as nucleophilic substitutions have been performed successfully in order to increase the molecular diversity.

α-Hydroxyallylsilanes as propionaldehyde enolate equivalents and their use toward iterative aldol reactions.

Smooth and efficient reaction conditions have been found for the transformation of protected ß-hydroxyacylsilanes into the corresponding aldehydes. This opens a new route to iterative aldol reactions, and it has been used for the synthesis of fragments of several bioactive natural products.

A combination of in silico and SAR studies to identify binding hot spots of Bcl-xL inhibitors.

Inhibition of Bcl-2 family protein-protein interactions (PPI) is a very promising direction in cancer chemotherapy. Hence over the last decade, many medicinal chemistry studies endeavoured to discover drug candidates, and a wealth of chemical scaffolds with striking chemical diversity was reported as Bcl-xL inhibitors. This raises the question of whether all these molecules could occupy a unique binding site, or rather discrete pockets of the protein surface. To test if small and chemically diverse Bcl-xL inhibitors are likely to bind a single pocket, and to identify which pocket, we used a battery of computational and modeling approaches. We first checked that the large dataset of Bcl-xL inhibitors we built can actually fit to a universal pharmacophore. Then we defined the probable binding hot spots of interaction through comparison of crystal structures, as well as virtual fragment screening. Finally, new analogues of small polyphenol derivatives were synthesized to precisely probe a hydrogen bond suggested by docking experiments. Bcl-xL inhibition potency of these products confirmed the predicted binding mode. This combination of X-ray structure exploration, molecular modeling studies and medicinal chemistry supports that all these small Bcl-xL inhibitors occupy the same hot spot of interaction. The identification of this binding site should help the design and optimization of small PPI Bcl-xL inhibitors.

Tuning the reactivity of oxygen/sulfur by acidity of the catalyst in Prins cyclization: oxa- versus thia-selectivity.

An unprecedented oxa- versus thia-selectivity has been observed in Prins cyclization of 6-mercaptohex-3-en-1-ol with aldehydes. In the presence of a stoichiometric amount of strong Lewis or Brønsted acids, the reaction provides the hexahydro-2H-thieno[3,2-c]pyran skeleton predominantly via oxonium-Prins cyclization. In contrast, a catalytic amount of weak Lewis or Brønsted acids provides the hexahydro-2H-thiopyrano[4,3-b]furan preferentially through thionium-Prins cyclization.

Design, synthesis and biological evaluation of new inhibitors of Bax/Bcl-xL interaction in cancer cells.

We describe the synthesis of a series of new molecules containing phenol and triazoles moieties, compounds which have been evaluated for their ability to inhibit Bax/Bcl-xL interactions in cancer cells, by using BRET assays, and to induce cell death. Several derivatives exhibit a very promising activity, being more potent than the reference compounds acylpyrogallol A and ABT-737. These preliminary results demonstrate that derivatives of this family can be attractive to develop new molecules with potent anticancer activity.

Synergistic effects between Lewis and Brønsted acids: application to the Prins cyclization.

Brønsted and Lewis acids can catalyze the Prins cyclization, an efficient method for the synthesis of tetrahydropyrans from homoallylic alcohols and carbonyl compounds. Synergistic effects between weak Brønsted and Lewis acids in these reactions have been analyzed by density functional theory [M06-L/def2-QZVP/IEFPCM(CH2Cl2)//M06-L/6-311+G(2df,2p)]. In order to characterize the reactivities of the employed Lewis acids, methyl anion and hydroxide affinities were determined. On the basis of our calculations, we found that the coordination of Lewis acids to carboxylic and sulfonic acids results in a significant increase in the Brønsted acidities of the latter.

Synthesis of enones, pyrazolines and pyrrolines with gem-difluoroalkyl side chains.

Starting from easily accessible gem-difluoropropargylic derivatives, a DBU-mediated isomerisation affords enones in fair yields with a gem-difluoroalkyl chain. These derivatives were used to prepare pyrazolines and pyrrolines with the desired gem-difluoroalkyl side chain by cyclocondensations in good yields and with excellent stereoselectivity. A one-pot process was also successfully developed for these sequential reactions. By carrying out various types of Pd-catalyzed coupling reactions for compounds with a p-bromophenyl substituent a route to focused chemical libraries was demonstrated.

Acylsilane Directed Rh-Catalyzed Arene C-H Alkylation with Maleimides and Visible-Light-Induced Siloxycarbene-Amide Cyclization: [3 + 2] Carbo-Annulation in Ru Catalysis.

We herein demonstrate the acylsilane-directed Rh-catalyzed arene C-H bond alkylation with maleimides. The resulting derivatives were utilized in visible-light-induced intramolecular siloxycarbene-amide cyclization for the synthesis of new tricyclic γ-lactams. In parallel, we also harnessed the same acylsilane and maleimide units through [3 + 2] carbo-annulation by using Ru-catalysis. A wide range of maleimides and aroylsilanes were used to establish the broadness of these transformations.

Synthesis and neurite growth evaluation of new analogues of honokiol, a neolignan with potent neurotrophic activity.

A versatile synthetic route is reported towards the preparation of new analogues for potent neurotrophic agent biaryl-type lignan honokiol. A focused 24-membered library of derivatives containing five different groups at 5'-position of honokiol has been prepared in fair to good overall yields. Compared to the natural product, or to analogues with a short alkyl chain in this position, these new derivatives have lost most of the neurotrophic activity.