Synthesis and Chemoinformatic Analysis of Fluorinated Piperidines as 3D Fragments for Fragment-Based Drug Discovery.

The concise synthesis of a small library of fluorinated piperidines from readily available dihydropyridinone derivatives has been described. The effect of the fluorination on different positions has then been evaluated by chemoinformatic tools. In particular, the compounds' pKa's have been calculated, revealing that the fluorine atoms notably lowered their basicity, which is correlated to the affinity for hERG channels resulting in cardiac toxicity. The "lead-likeness" and three-dimensionality have also been evaluated to assess their ability as useful fragments for drug design. A random screening on a panel of representative proteolytic enzymes was then carried out and revealed that one scaffold is recognized by the catalytic pocket of 3CLPro (main protease of SARS-CoV-2 coronavirus).

Accessing spiropiperidines from dihydropyridones through tandem triflation-allylation and ring-closing metathesis (RCM).

A novel approach to build 2-spiropiperidine moieties starting from dihydropyridones was developed. The triflic anhydride-promoted conjugate addition of allyltributylstannane onto dihydropyridones allowed for the formation of gem bis-alkenyl intermediates that were converted to the corresponding spirocarbocycles with excellent yields via ring closing metathesis. The vinyl triflate group generated on these 2-spiro-dihydropyridine intermediates could be successfully used as a chemical expansion vector for further transformations namely Pd-catalyzed cross-coupling reactions.

Structure simplification of the Securinine skeleton reveals the importance of BCD ring system for the cytotoxic activity on HCT116 and HL60 cell lines.

Function-oriented molecular editing of the polycyclic scaffold of securinine led to the preparation of a library of simplified analogs that have been evaluated for their cytotoxicity potential against HCT116 and HL60 human cell lines. Chemical diversity at the C14 position (securinine numbering) was generated through the site-selective γ-iodination followed by Pd-catalyzed Sonogashira and Suzuki-Miyaura reactions. To explain the selectivity in the iodination step, a reaction mechanism has been proposed. Surprisingly, the piperidine ring (ring A) of the securinine skeleton has been found to be irrelevant for the cytotoxic activity. Based on this finding, the pharmacophoric core of securinine could be simplified to the key BCD motif. The nature of the substituent at the nitrogen can vary from a methyl or an isobutyl group to a benzyl or a carbamate moiety. Interestingly, the N-benzyl substituted simplified analog exhibited the same cytotoxic activity as the parent compound securinine. This functional group tolerance paves the way for the installation of reactive handles for the synthesis of molecular probes for target identification.

Gold-Catalyzed Synthesis of Substituted 3-Trifluoromethylpyrroles from Mesylated Amino Trifluoromethylpropargylic Alcohols.

A series of substituted 3-trifluoromethylpyrroles was obtained from trifluoromethylamino-ynol derivatives via a gold-catalyzed cyclization. Using fluorinated starting materials, after mesylation, allowed for the desired compounds to be obtained in good yields under mild conditions.

Integrating targeted gene expression and a skin model system to identify functional inhibitors of the UV activated p38 MAP kinase.

The stress-activated p38α MAP Kinase is an integral and critical component of the UV-induced inflammatory response. Despite the advances in recent years in the development of p38 kinase inhibitors, validation of these compounds in the diseased models remains limited. Based on the pharmacological profile of p38α inhibitor lead compound, SB203580, we synthesized a series of pyrrole-derivatives. Using UV-irradiated human skin punch-biopsies and cell cultures, we identified and validated the inhibitory activity of the derivatives by quantitatively measuring their effect on the expression of p38α target genes using real-time PCR. This approach not only identified pyrrole-2 as a unique derivative of this series that specifically inhibited the UV-activated p38α kinase, but also documented the skin permeation, bioavailability and reversible properties of this derivative in a 3D structure. The successful skin permeation of pyrrole-2 and its impact on AREG, COX-2 and MMP-9 gene expression demonstrates its potential use in modulating inflammatory processes in the skin. This study underscored the importance of using adapted biological models to identify accurate bioactive compounds.

On the formation of a protic ionic liquid in nature.

The practical utility of ionic liquids (ILs) makes the absence (heretofore) of reported examples from nature quite puzzling, given the facility with which nature produces many other types of exotic but utilitarian substances. In that vein, we report here the identification and characterization of a naturally occurring protic IL. It can be formed during confrontations between the ants S. invicta and N. fulva. After being sprayed with alkaloid-based S. invicta venom, N. fulva detoxifies by grooming with its own venom, formic acid. The mixture is a viscous liquid manifestly different from either of the constituents. Further, we find that the change results as a consequence of formic acid protonation of the N centers of the S. invicta venom alkaloids. The resulting mixed-cation ammonium formate milieu has properties consistent with its classification as a protic IL.

Gold-mediated synthesis and functionalization of chiral halopyridones.

A rapid and efficient one-step halopyridone synthesis has been developed based on gold-catalyzed cyclization of ß-amino-ynone intermediates and halodeauration process.

Total synthesis of dendrobate alkaloid (+)-241D, isosolenopsin and isosolenopsin A: application of a gold-catalyzed cyclization.

A new approach to total syntheses of piperidine alkaloids (+)-241D, isosolenopsin and isosolenopsin A has been developed from D-alanine. The key step to access the chiral pyridinone intermediate was achieved via a gold mediated cyclization. Finally, various reduction conditions afforded the natural products in few steps and good overall yields.

Enantiospecific synthesis of pyridinones as versatile intermediates toward asymmetric piperidines.

The enantiospecific syntheses of pyridinones from amino acids via a gold-catalyzed strategy are reported. Excellent stereocontrol was observed during the cyclization. This approach provides a straightforward tool for further synthetic applications toward piperidines.

Targeting the polyamine transport system with benzazepine- and azepine-polyamine conjugates.

The polyamine transport system (PTS) whose activity is up-regulated in cancer cells is an attractive target for drug design. Two heterocyclic (azepine and benzazepine) systems were conjugated to various polyamine moieties through an amidine bound to afford 18 compounds which were evaluated for their affinity for the PTS and their ability to use the PTS for cell delivery. Structure-activity relationship studies and lead optimization afforded two attractive PTS targeting compounds. The azepine-spermidine conjugate 14 is a very selective substrate of the PTS that may serve as a vector for radioelements used for diagnoses or therapeutics in nuclear medicine. The nitrobenzazepine-spermine conjugate 28 is a very powerful PTS inhibitor with very low intrinsic cytotoxicity, able to prevent the growth of polyamine depleted cells in presence of exogenous polyamines.

Synthesis of substituted pyrrolin-4-ones from amino acids in mild conditions via a gold-catalyzed approach.

The gold-catalyzed cyclization of various alpha-amino-ynone derivatives gave the corresponding pyrrolin-4-ones in high yields. Moreover, the use of gold(III) oxide as catalyst allows a moderate to total stereocontrol during the cyclization. These pyrrolin-4-ones are highly useful intermediates for the synthesis of functionalized pyrrolidines and other natural products.

Effect of polyamine homologation on the transport and biological properties of heterocyclic amidines.

Five sets of heterocyclic derivatives of various sizes and complexities coupled by an amidine function to putrescine, spermidine, or spermine were prepared. They were essentially tested to determine the influence of the polyamine chain on their cellular transport. To comment on affinity and on selective transport via the polyamine transport system (PTS), K(i) values for polyamine uptake were determined in L1210 cells, and the cytotoxicity and accumulation of the conjugates were determined in CHO and polyamine transport-deficient mutant CHO-MG cells, as well as in L1210 and alpha-difluoromethylornithine- (DFMO-) treated L1210 cells. Unlike spermine, putrescine and spermidine were clearly identified as selective motifs that enable cellular entry via the PTS. However, this property was clearly limited by the size of substituents: these polyamines were able to ferry a dihydroquinoline system via the PTS but did not impart any selectivity to bulkier substituents.

Synthesis of a laterally branched polyamine from alpha-methylene-gamma-butyrolactone.

[reaction: see text] A polyamine derivative was prepared from alpha-methylene-gamma-butyrolactone. This method used Michael addition and lactone aminolysis followed by the nucleophilic substitution of the hydroxyl group by an azido group. The coupling of a lipophilic alkyne led to a polyamine that will be probed as a gene transfer agent.

Parallel supported synthesis of polyamine-imidazole conjugates.

[reaction: see text] A small collection of nine polyamine-imidazole conjugates, potentially acting as RNases A mimics, has been synthesized on SynPhase lanterns using amino alcohols and diamines as building blocks. Couplings were performed via S(N)2 alkylation of methanesulfonates with amines. The final introduction of N-4-nitrobenzyloxycarbonyldiamines allowed easy purification of the cleaved compounds.