Discovery of sertraline and its derivatives able to combat drug-resistant gastric cancer cell via inducing apoptosis.

Resistance phenomena during chemotherapy of tumor has been severely hampering the applications of chemotherapeutics. Due to advantage of drug repurposing, discovery of new chemosensitizers based on approved drugs is an effect strategy to find new candidates. Herein, we found antidepressant drug - sertraline, could sensitize drug-resistant gastric cancer cell (SGC-7901/DDP) with the IC50 value of 18.73 µM. To understand the structure-activity relationship and improve the activity, 30 derivatives were synthesized and evaluated. The IC50 value of the best compound was improved to 5.2 µM. Moreover, we found apoptosis induction and cell cycle arrest was the reason for the cell death of the drug-resistant cells after treatment of sertraline and derivatives, and PI3K/Akt/mTOR pathway was involved.

Nickel-Catalyzed α-Carbonylalkylarylation of Vinylarenes: Expedient Access to γ,γ-Diarylcarbonyl and Aryltetralone Derivatives.

We report a Ni-catalyzed regioselective α-carbonylalkylarylation of vinylarenes with α-halocarbonyl compounds and arylzinc reagents. The reaction works with primary, secondary, and tertiary α-halocarbonyl molecules, and electronically varied arylzinc reagents. The reaction generates γ,γ-diarylcarbonyl derivatives with α-secondary, tertiary, and quaternary carbon centers. The products can be readily converted to aryltetralones, including a precursor to Zoloft, an antidepressant drug.

Palladium-Catalyzed Dearomative syn-1,4-Carboamination with Grignard Reagents.

A protocol for palladium-catalyzed dearomative functionalization of simple, nonactivated arenes with Grignard reagents has been established. This one-pot method features a visible-light-mediated [4+2] cycloaddition between an arene and an arenophile, and subsequent palladium-catalyzed allylic substitution of the resulting cycloadduct with a Grignard reagent. A variety of arenes and Grignard reagents can participate in this process, forming carboaminated products with exclusive syn-1,4-selectivity. Moreover, the dearomatized products are amenable to further elaborations, providing functionalized alicyclic motifs and pharmacophores. For example, naphthalene was converted into sertraline, one of the most prescribed antidepressants, in only four operations. Finally, this process could also be conducted in an enantioselective fashion, as demonstrated with the desymmetrization of naphthalene.

Asymmetric allylation/ring closing metathesis: one-pot synthesis of benzo-fused cyclic homoallylic amines. Application to the formal synthesis of Sertraline derivatives.

A one-pot asymmetric allylation/ring closing metathesis (RCM) sequence for the synthesis of cyclic homoallylic amines has been developed. A library of six- and seven-membered benzo-fused products has been synthesized in good yields and complete diastereoselectivity. The new methodology has been applied to the formal syntheses of the antidepressant Sertraline and the epimeric Norsertraline. The methodology is amenable for the synthesis of analogs.

Stereoselective amination of chiral benzylic ethers using chlorosulfonyl isocyanate: total synthesis of (+)-sertraline.

The stereoselective amination of various chiral benzylic ethers using chlorosulfonyl isocyanate is developed, and the application of this method to the total synthesis of a potent antidepressant, (+)-sertraline, from readily available 1-naphthol is also described.

Enantioselective syntheses of (+)-sertraline and (+)-indatraline using lithiation/borylation-protodeboronation methodology.

The lithiation/borylation-protodeboronation of a homoallyl carbamate was applied to the synthesis of (+)-sertraline and (+)-indatraline. Due to the presence of the alkene, significant modifications of the methodology were required (use of 12-crown-4, TMSCl, H(2)O), or a solvent switch to CHCl(3), to achieve high yields and high selectivities.

Asymmetric synthesis of bicyclic diol derivatives through metal and enzyme catalysis: application to the formal synthesis of sertraline.

Enzyme- and ruthenium-catalyzed dynamic kinetic asymmetric transformation (DYKAT) of bicyclic diols to their diacetates was highly enantio- and diastereoselective to give the corresponding diacetates in high yield with high enantioselectivity (99.9 % ee). The enantiomerically pure diols are accessible by simple hydrolysis (NaOH, MeOH), but an alternative enzyme-catalyzed ester cleavage was also used to give the trans-diol (R,R)-1 b in extremely high diastereomeric purity (trans/cis=99.9:0.1, >99.9 % ee). It was demonstrated that the diols can be selectively oxidized to the ketoalcohols in a ruthenium-catalyzed Oppenauer-type reaction. A formal enantioselective synthesis of sertraline from a simple racemic cis/trans diol 1 b was demonstrated.

Palladium-catalyzed gamma-selective and stereospecific allyl-aryl coupling between acyclic allylic esters and arylboronic acids.

Reactions between acyclic (E)-allylic acetates and arylboronic acids in the presence of a palladium catalyst prepared from Pd(OAc)(2), phenanthroline (or bipyridine), and AgSbF(6) (1:1.2:1) proceeded with excellent gamma-selectivity to afford allyl-aryl coupling products with E-configuration. The reactions of alpha-chiral allylic acetates took place with excellent alpha-to-gamma chirality transfer with syn stereochemistry to give allylated arenes with a stereogenic center at the benzylic position. The reaction tolerated a broad range of functional groups in both the allylic acetates and the arylboronic acids. Furthermore, gamma-arylation of cinnamyl alcohol derivatives afforded gem-diarylalkane derivatives containing an unconjugated alkenic substituent. The synthetic utility of this method was demonstrated by its utilization in an efficient synthesis of (+)-sertraline, an antidepressant agent. The observed gamma-regioselectivity and E-1,3-syn stereochemistry were rationalized based on a Pd(II) mechanism involving transmetalation between a cationic mono(acyloxo)palladium(II) complex and arylboronic acid, and directed carbopalladation followed by syn-beta-acyloxy elimination. The results of stoichiometric reactions of palladium complexes related to possible intermediates were fully consistent with the proposed mechanism.

Spiro[4,4]-1,6-nonadiene-based phosphine-oxazoline ligands for iridium-catalyzed enantioselective hydrogenation of ketimines.

From imines to amines through catalysis by Ir(I) complexes of a new type of P,N ligand (see scheme): This reaction affords the corresponding optically active amines with up to 98 % ee and has also been used with perfect stereoselectivity in the asymmetric synthesis of sertraline (1), an important antidepressant chiral drug.

Asymmetric hydrogenation of a 4,4-diaryl-3-butenoate; a novel approach to sertraline.

The asymmetric hydrogenation of a selectively crystallised (E)-4,4-diaryl-3-butenoate with a rhodium-PhanePhos catalyst is described, providing an intermediate to the antidepressant sertraline.

The preparation and intra- and intermolecular addition reactions of acyclic N-acylimines: application to the synthesis of (+/-)-sertraline.

Intramolecular endo-cyclization reactions of N-acyliminium ions have seen wide application for the synthesis of heterocyclic compounds. The corresponding exocyclic variant, which would provide 1-aminotetralin derivatives, for example, has little precedent. We have discovered that acyclic N-acylcarbamates can be readily reduced to the corresponding N-acylhemiaminal derivatives in high yield using DIBAL as the reducing agent. These intermediates are remarkably stable and, if desired, can be purified and stored. The acyclic N-acylhemiaminals undergo both intra- and intermolecular nucleophilic addition reactions mediated by strong Lewis acids, such as TiCl(4). Diastereoselectivity, induced either by a substituent on the newly formed ring, or by utilizing a chiral ester on the carbamic acid, was disappointingly low. This methodology was successfully applied to the synthesis of the racemic form of the marketed antidepressant sertraline.

Efficient kinetic resolution in the asymmetric hydrosilylation of imines of 3-substituted indanones and 4-substituted tetralones.

Kinetic resolution of the N-methyl imines of 3-substituted indanones and 4-substituted tetralones could be accomplished by hydrosilylation with a chiral titanocene catalyst. N-Methyl imines of 4-substituted tetralones were resolved to yield, after hydrolysis of the unreacted starting materials, ketones with high ee's and the amine products with high diastereomeric and enantiomeric purity. The utility of this process was demonstrated in the synthesis of sertraline.

Efficient enantioselective synthesis of sertraline, a potent antidepressant, via a novel intramolecular nucleophilic addition to imine.

[formula: see text] An efficient enantioselective synthesis of sertraline, an antidepressant, utilizing anionic imine ring closure is described.