Continuous flow synthesis of lipophilic cations derived from benzoic acid as new cytotoxic chemical entities in human head and neck carcinoma cell lines.

Continuous flow chemistry was used for the synthesis of a series of delocalized lipophilic triphenylphosphonium cations (DLCs) linked by means of an ester functional group to several hydroxylated benzoic acid derivatives and evaluated in terms of both reaction time and selectivity. The synthesized compounds showed cytotoxic activity and selectivity in head and neck tumor cell lines. The mechanism of action of the molecules involved a mitochondrial uncoupling effect and a decrease in both intracellular ATP production and apoptosis induction.

A New Family of Jumonji C Domain-Containing KDM Inhibitors Inspired by Natural Product Purpurogallin.

Aberrant epigenetic modifications are involved in cancer development. Jumonji C domain-containing histone lysine demethylases (KDMs) are found mainly up-regulated in breast, prostate, and colon cancer. Currently, growing interest is focusing on the identification and development of new inhibitors able to block the activity of KDMs and thus reduce tumor progression.

Ligand Design for Modulation of RXR Functions.

Retinoid X receptors (RXRs) are promiscuous partners of heterodimeric associations with other members of the Nuclear Receptor (NR) superfamily. RXR ligands ("rexinoids") either transcriptionally activate the "permissive" subclass of heterodimers or synergize with partner ligands in the "nonpermissive" subclass of heterodimers. The rationale for rexinoid design with a wide structural diversity going from the structures of existing complexes with RXR determined by X-Ray, to natural products and other ligands discovered by high-throughput screening (HTS), mere serendipity, and rationally designed based on Molecular Modeling, will be described.

Sigmatropic Rearrangement of Vinyl Aziridines: Expedient Synthesis of Cyclic Sulfoximines from Chiral Sulfinimines.

A novel rearrangement of 2-vinyl aziridine 2-carboxylates to unusual chiral cyclic sulfoximines is described herein. The method allows the synthesis of substituted cyclic sulfoximines in high yields with complete stereocontrol, and tolerates a wide substrate scope. A one-pot process starting directly from sulfinimines provides access to complex chiral sulfoximines in only two steps from commercially available aldehydes.

Substitution Effects of Hypervalent Iodine(III) Reagents in the Diamination of Styrene.

The influence of electronic parameters on the reaction performance of hypervalent iodine(III) reagents in the vicinal diamination of styrene has been investigated. It demonstrates the influence of the relative electron density on the aryl substituent of the hypervalent iodine reagent. In these cases, compounds with donor substituents outperform the corresponding acceptor-substituted systems.

DFT Rationalization of the Diverse Outcomes of the Iodine(III)-Mediated Oxidative Amination of Alkenes.

A computational study of the mechanism for the iodine(III)-mediated oxidative amination of alkenes explains the experimentally observed substrate dependence on product distribution. Calculations with the M06 functional have been carried out on the reaction between PhI(N(SO2 Me)2 )2 and three different representative substrates: styrene, α-methylstyrene, and (E)-methylstilbene. All reactions start with electrophilic attack by a cationic PhI(N(SO2 Me)2 )(+) unit on the double bond, and formation of an intermediate with a single C-I bond and a planar sp(2) carbocationic center.

Machines vs Malaria: A Flow-Based Preparation of the Drug Candidate OZ439.

An efficient preparation of the antimalarial drug candidate OZ439, which was obtained by integrating a machine-assisted approach with batch processes, is reported. This approach allows a rapid and cost-effective production of the key intermediates that were readily elaborated into the target molecule.

Development of a flow method for the hydroboration/oxidation of olefins.

A method for the continuous preparation of alcohols by hydroboration/oxidation of olefins using flow techniques is described. The process allows the isolation of up to 120 mmol h(-1) of the desired alcohol in a very rapid manner with good functional group tolerance. The flow setup can be modified to perform a continuous extraction of the desired alcohol from the biphasic mixture produced by the reaction.

Isolation of stable non cyclic 1,2-disulfoxides. Revisiting the thermolysis of S-aryl sulfinimines.

The thermolysis of S-aryl sulfinimines is shown to generate 1,2-disulfoxides and disulfides via initial Cope elimination, dimerisation of the produced sulfenic acid to a thiosulfinate, and subsequent disproportionation of the thiosulfinate.

Hypervalent iodine mediated oxidative amination of allenes.

An oxidative amination of allenes using a single hypervalent iodine reagent is reported. The reaction proceeds very efficiently for monosubstituted allenes and leads to formation of the corresponding propargylic amines, either as the internal or as the terminal amine. The respective reaction outcome could be influenced in favor of the former product by addition of triphenylphosphine oxide to the iodine(III) reagent.

Indole synthesis based on a modified Koser reagent.

A new metal-free method for the rapid and productive preparation of indoles has been developed. This process is based on sterically congested hypervalent iodine compounds of the family of Koser reagents, and iodosobenzene in combination with 2,4,5-tris-isopropylbenzene sulfonic acid provides the highest yields and fastest reaction times. This reagent alone promotes the chemoselective oxidative cyclization of 2-amino styrenes to indoles in high yields under mild conditions.

Oxidative diamination promoted by dinuclear iodine(III) reagents.

New dinuclear iodine(III) reagents for the intermolecular diamination of alkenes are reported. These are accessible through protolytic aminolysis events, which generate defined imido-iodine(III) groups.

Metal-free iodine(III)-promoted direct intermolecular C-H amination reactions of acetylenes.

A direct metal-free amination of arylalkynes has been developed, which proceeds by reaction of the terminal alkyne with the hypervalent iodine reagent PhI(OAc)NTs(2) within a single-step operation. This unprecedented intermolecular C-H to C-N bond conversion provides rapid access to the important class of ynamides. In addition to the title reaction, the related transformation between alkylated alkynes and the iodine(III) reagent is also discussed.

Iodine(III)-mediated intermolecular allylic amination under metal-free conditions.

A new approach to direct intermolecular allylic amination has been developed using metal-free conditions at room temperature. The reaction employs a hypervalent iodine(III) reagent as an oxidant and bistosylimide as a nitrogen source. A series of different allylic aminations are presented with up to a 99% yield.

Iodine(III)-promoted intermolecular diamination of alkenes.

A rapid and productive vicinal diamination of alkenes takes place in the presence of a hypervalent iodine(III) reagent and bissulfonimides as nitrogen sources. A total of more than 60 examples are presented. The reaction is characterized by its robustness and its wide substrate scope: it proceeds selectively with both terminal and internal alkenes and tolerates a range of functional groups.

New anacardic acid-inspired benzamides: histone lysine acetyltransferase activators.

A series of N-(4-cyano-3-trifluoromethyl-phenyl)-2-ethoxy-6-alkyl (and alkenyl) benzamides related to the anacardic acid derivative CTPB have been prepared from 2,6-dihydroxybenzoic acid with a Suzuki coupling and addition of the anion of 4-cyano-3-trifluoromethylphenylamine to a benzodioxinone as the key steps. In U937 cells, these analogues, in particular 7 c, 7 d, 7 f and 7 j, induced cell-cycle arrest in the G1 phase, caused apoptosis in about 20 % of the cells, and increased the acetylation levels of H3. These activities correlate with the enzymatic activation of histone lysine acetyltransferases (KATs): CBP and PCAF.

Competing thermal electrocyclic ring-closure reactions of (2Z)-hexa-2,4,5-trienals and their Schiff bases. Structural, kinetic, and computational studies.

The electrocyclic ring closure reactions of (2Z)-hexa-2,4,5-trienals (vinylallenals) to alkylidene-2H-pyrans and of the corresponding Schiff base derivatives to alkylidenepyridines can be concurrent. Rates of vinylallenal cyclization and imine formation upon addition of n-butylamine determine the extent of the competition. The activation energies for the electrocyclization of a series of 6-substituted-(2Z)-4-tert-butyl-3-methylhexa-2,4,5-trienals 2 and trienimines 4 depend on the steric interactions between the substituents at C6 and the tert-butyl group at C4.

Synthesis and biological characterization of the histone deacetylase inhibitor largazole and C7- modified analogues.

Largazole 4a and analogues with modifications at the C7 position, as well as 2,4'-bithiazole 5a, have been synthesized using an acyclic cross-metathesis of the corresponding depsipeptide structures assembled by N-C6(O) or C15(O)-N lactam formation. Similar to the parent system 4a, the series of largazole depsipeptides 4b-d, but not 2,4'-bithiazole 5a, showed a marked inhibition of recombinant HDAC1 and selectivity over HDAC4, as well as strong pro-apoptotic effects on the NB4 leukemia cell line, but they failed to induce differentiation to mature granulocytes. Functional assays of the analogues correlated with the in vitro activities, as shown by increased H3 and alpha-tubulin acetylation levels and p21(WAF1/CIP1) up-regulation in NB4 cells.

Synthesis of benzamides related to anacardic acid and their histone acetyltransferase (HAT) inhibitory activities.

A group of benzamides related to anacardic acid amide CTPB with alkyl chains of defined length were prepared by a five-step sequence starting from 2,6-dihydroxybenzoic acid, and their activities were compared with those reported for the HAT inhibitor anacardic acid (AA). The subset of 4-cyano-3-trifluoromethylphenylbenzamides with shorter chains exhibited activities similar to that of AA, as they behaved as human p300 inhibitors, induced a decrease in histone acetylation levels in immortalized HEK cells, and counteracted the action of the HDAC inhibitor SAHA in MCF7 breast cancer cells. Moreover, an analogue with the shortest alkyl chain induced significant apoptosis at 50 microM in U937 leukemia cells.

Pseudopericyclic design drives antara-antara [1,5] methylene sigmatropic shifts from a stepwise to a concerted mechanism.

Antara-antara [1,5]-methylene sigmatropic shifts of propenylidene cyclopropane and its heteroanalogues are shown to proceed through concerted or stepwise mechanisms depending on a delicate balance that is directly related to the presence or absence of heteroatoms at the termini atoms of the rearrangement. Lowering of activation energies upon heteroatom replacement are more significant for the oxacyclopropane analogues 1D, 1E, and 1F but double heterosubstitution is still needed to achieve a pseudopericyclic reaction. In fact only after reaching a pseudopericyclic process the energy balance favors the concerted pathway.

2-Alkylidenesulfol-3-enes by (regio- and) stereoselective cheletropic addition of SO2 to (di)vinylallenes.

[reaction: see text] The cheletropic addition of SO(2) to divinylallenes is regioselective, taking place at the most substituted vinylallene and at the E unit if vinyl groups of opposite geometry are competing. Diastereofacial differentiation results from the approach of the reagent from the less-substituted direction of the allene and from the concomitant disrotatory movement of the termini of the vinylallene to afford the sterically more congested 2-alkylidenesulfol-3-ene isomer. DFT computations confirm the regio- and the stereoselectivity of these cheletropic additions.