Discovery and Mechanistic Studies of Dual-Target Hits for Carbonic Anhydrase IX and VEGFR-2 as Potential Agents for Solid Tumors: X-ray, In Vitro, In Vivo, and In Silico Investigations of Coumarin-Based Thiazoles.

A dual-targeting approach is predicted to yield better cancer therapy outcomes. Consequently, a series of coumarin-based thiazoles (5a-h, 6, and 7a-e) were designed and constructed as potential carbonic anhydrase (CA) and VEGFR-2 suppressors. The inhibitory actions of the target compounds were assessed against CA isoforms IX and VEGFR-2. The assay results showed that coumarin-based thiazoles 5a, 5d, and 5e can effectively inhibit both targets. 5a, 5d, and 5e cytotoxic effects were tested on pancreatic, breast, and prostate cancer cells (PANC1, MCF7, and PC3). Further mechanistic investigation disclosed the ability of 5e to interrupt the PANC1 cell progression in the S stage by triggering the apoptotic cascade, as seen by increased levels of caspases 3, 9, and BAX, alongside the Bcl-2 decline. Moreover, the in vivo efficacy of compound 5e as an antitumor agent was evaluated. Also, molecular docking and dynamics displayed distinctive interactions between 5e and CA IX and VEGFR-2 binding pockets.

Conversion of raltegravir carrying a 1,3,4-oxadiazole ring to a hydrolysis product upon pH changes decreases its antiviral activity.

Raltegravir (RAL), a human immunodeficiency virus (HIV)-1 integrase inhibitor, has been administered as part of antiretroviral therapy. Studies in patients with HIV-1 have shown high variability in the pharmacokinetics of RAL, and in healthy volunteers, coadministration of proton-pump inhibitors has been shown to increase the plasma RAL concentrations. Here, we found that RAL containing a 1,3,4-oxadiazole ring is converted to a hydrolysis product (H-RAL) with a cleaved 1,3,4-oxadiazole ring at pH 1.0 and 13.0 conditions in vitro, thereby reducing the anti-HIV activity of the drug. The inclusion of cyclodextrins (beta-cyclodextrin [ßCD], random methyl-ßCD [RAM-ßCD], and hydroxypropyl-ßCD [HP-ßCD]) can protect RAL from pH-induced changes. The conversion of RAL to H-RAL was detected by using various mass spectrometry analyses. The chromatogram of H-RAL increased in a time-dependent manner similar to another 1,3,4-oxadiazole-containing drug, zibotentan, using high-performance liquid chromatography. Oral bioavailability and target protein interactions of H-RAL were predicted to be lower than those of RAL. Moreover, H-RAL exhibited significantly reduced anti-HIV-1 activity, whereas combinations with ßCD, RAM-ßCD, and HP-ßCD attenuated this effect in cell-based assays. These findings suggest that ßCDs can potentially protect against the conversion of RAL to H-RAL under acidic conditions in the stomach, thereby preserving the anti-HIV-1 effect of RAL. Although clinical trials are needed for evaluation, we anticipate that protective devices such as ßCDs may improve the pharmacokinetics of RAL, leading to better treatment outcomes, including reduced dosing, long-term anti-HIV-1 activity, and deeper HIV-1 suppression.

Lithium Binaphtholate-Catalyzed Asymmetric Michael Reaction of Acrylamides.

Chiral lithium binaphtholates prepared from the corresponding binaphthols and lithium tert-butoxide effectively catalyze the asymmetric Michael additions of ketones to poorly reactive acrylamides. The lithium binaphtholate catalyst mediates ketone deprotonation and enantioselective carbon-carbon bond formation to the acrylamide to deliver the Michael adduct in good yield and enantioselectivity. A small excess of lithium tert-butoxide relative to the binaphthol successfully enolizes the ketone in the initial stage of the reaction to promote the Michael reaction. Computational analysis of the transition state suggested that the 3- and 3'-phenyl groups of the binaphtholate catalyst regulate the orientation of the lithium enolate and the subsequent approach of the acrylamide, leading to superior enantioselectivity.

Recruitment of hexahydroquinoline as anticancer scaffold targeting inhibition of wild and mutants EGFR (EGFRWT, EGFRT790M, and EGFRL858R).

Hexahydroquinoline (HHQ) scaffold was constructed and recruited for development of new series of anticancer agents. Thirty-two new compounds were synthesised where x-ray crystallography was performed to confirm enantiomerism. Thirteen compounds showed moderate to good activity against NCI 60 cancer cell lines, with GI % mean up to 74% for 10c. Expending erlotinib as a reference drug, target compounds were verified for their inhibiting activities against EGFRWT, EGFRT790M, and EGFRL858R where compound 10d was the best inhibitor with IC50 = 0.097, 0.280, and 0.051 µM, respectively, compared to erlotinib (IC50 = 0.082 µM, 0.342 µM, and 0.055 µM, respectively). Safety profile was validated using normal human lung (IMR-90) cells. 10c and 10d disrupted cell cycle at pre-G1 and G2/M phases in lung cancer, HOP-92, and cell line. Molecular docking study was achieved to understand the potential binding interactions and affinities in the active sites of three versions of EGFRs.

New 32 hexahydroquinoline (HHQ) analogues 6a­i, 8a­m, 10a­d, and 12a­f having the same features of EGFR inhibitors were synthesised in racemic mixtures.The antiproliferative activities were assessed towards 60 cancer cell lines which were efficiently inhibited by compound 10c.Compound 10d remarkably inhibited EGFR^WT, EGFR^T790M, and EGFR^L858R.Cell cycle analysis and Annexin V-based flow cytometry in the HOP-92 lung cancer cells were performed.The safety profile of compounds 10c and 10d was validated using normal human lung (IMR-90) cells.Molecular docking studies revealed that the S-isomers exhibited higher affinity than R-isomers to active sites.

Synthesis of Selenoesters via Aldol Condensation and/or Conjugate Reduction and Their Antiviral Activities.

A variety of unsaturated selenoesters (including phenolic ones) were produced in good to high yields and with high E/Z ratios using TiCl4-promoted aldol condensation between Se-phenyl selenoacetate and their respective aldehydes without aqueous workup. A representative phenolic unsaturated selenoester was applied to acylation of tyrosine methyl ester without protection of the phenolic hydroxy groups to furnish the corresponding amino acid conjugate. The conjugate reduction of the unsaturated selenoesters including phenolic ones and selenocoumarin with HSiEt3 was catalyzed by B(C6F5)3 to afford the corresponding saturated selenoesters in good to high yields. This method was also applicable to the reduction of a saturated selenoester to the corresponding O-silyl hemiselenoacetal in a high yield. Moreover, most acyclic unsaturated selenoesters were found to show good multiple antiviral activities against HIV-1, HBV, and SARS-CoV-2.

Synthesis, crystallographic, DNA binding, and molecular docking/dynamic studies of a privileged chalcone-sulfonamide hybrid scaffold as a promising anticancer agent.

In the present study, a drug-like molecular hybrid structure between chalcone and sulfonamide moieties was synthesized and characterized. The structural peculiarities of the synthesized hybrid were further verified by means of single crystal X-ray crystallography. Furthermore, its biological activity as an anticancer agent was evaluated. The synthesized model of chalcone-sulfonamide hybrid 3 was found to have potent anticancer properties against the studied cancer cell lines. Hence, the in vitro binding interaction of hybrid 3 with Calf thymus DNA (CT-DNA) was studied at a simulated physiological pH to confirm its anticancer activity for the first time. This was investigated by applying different spectroscopic techniques, ionic strength measurements, viscosity measurements, thermodynamics, molecular dynamic simulation and molecular docking studies. The obtained results showed a clear binding interaction between hybrid 3 and CT-DNA with a moderate affinity via a minor groove binding mechanism. The binding constant (Kb) at 298 K calculated from the Benesi-Hildebrand equation was found to be 3.49 × 104 M-1. The entropy and enthalpy changes (ΔS0 and ΔH0) were 204.65 J mol-1 K-1 and 35.08 KJ mol-1, respectively, indicating that hydrophobic interactions constituted the major binding forces. The results obtained from molecular docking and dynamic simulation studies confirmed the minor groove binding interaction and the stability of the formed complex. This study can contribute to further understanding of the molecular mechanism of hybrid 3 as a potential antitumor agent and can also guide future clinical and pharmacological studies for rational drug design with enhanced or more selective activity and greater efficacy.[Figure: see text]Communicated by Ramaswamy H. Sarma.

Aromatic-Turmerone Analogs Protect Dopaminergic Neurons in Midbrain Slice Cultures through Their Neuroprotective Activities.

Parkinson's disease (PD) is a neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra. The inflammatory activation of microglia participates in dopaminergic neurodegeneration in PD. Therefore, chemicals that inhibit microglial activation are considered to have therapeutic potential for PD. Aromatic (ar)-turmerone is a main component of turmeric oil extracted from Curcuma longa and has anti-inflammatory activity in cultured microglia. The aims of the present study are (1) to investigate whether naturally occurring S-enantiomer of ar-turmerone (S-Tur) protects dopaminergic neurons in midbrain slice cultures and (2) to examine ar-turmerone analogs that have higher activities than S-Tur in inhibiting microglial activation and protecting dopaminergic neurons. R-enantiomer (R-Tur) and two analogs showed slightly higher anti-inflammatory effects in microglial BV2 cells. S- and R-Tur and these two analogs reversed dopaminergic neurodegeneration triggered by microglial activation in midbrain slice cultures. Unexpectedly, this neuroprotection was independent of the inhibition of microglial activation. Additionally, two analogs more potently inhibited dopaminergic neurodegeneration triggered by a neurotoxin, 1-methyl-4-phenylpyridinium, than S-Tur. Taken together, we identified two ar-turmerone analogs that directly and potently protected dopaminergic neurons. An investigation using dopaminergic neuronal precursor cells suggested the possible involvement of nuclear factor erythroid 2-related factor 2 in this neuroprotection.

O-Monoacyltartaric Acid/(Thio)urea Cooperative Organocatalysis for Enantioselective Conjugate Addition of Boronic Acid.

(Thio)urea cocatalyst accelerates O-monoacyltartaric acid (MAT)-catalyzed enantioselective conjugate addition of boronic acid to unsaturated ketone. Kinetic studies of this reaction revealed first-order dependence of each substrate and catalyst and second-order dependence of (thio)urea, leading to reduction of the catalyst loading and development of more active and enantioselective MAT monoaryl ester catalyst.

Lewis Base-Catalyzed Enantioselective Conjugate Reduction of ß,ß-Disubstituted α,ß-Unsaturated Ketones with Trichlorosilane: E/Z-Isomerization, Regioselectivity, and Synthetic Applications.

The chiral bisphosphine dioxide-catalyzed asymmetric conjugate reduction of acyclic ß,ß-disubstituted α,ß-unsaturated ketones with trichlorosilane affords saturated ketones having a stereogenic carbon center at the carbonyl ß-position with high enantioselectivities. Because the E/Z-isomerizations of enone substrates occur concomitantly, reduction products with the same absolute configurations are obtained from either (E)- or (Z)-enones. Conjugate reduction is accelerated in the presence of an electron-rich aryl group at the ß-position of the enone owing to its carbocation-stabilizing ability. Computational studies were also conducted in order to elucidate the origin of the observed enantioselectivity. The regio- and enantioselective reductions of dienones were realized and applied to the syntheses of ar-turmerone, turmeronol A, mutisianthol, and jungianol, which are optically active sesquiterpenes.

Selective Monoacylation of Diols and Asymmetric Desymmetrization of Dialkyl meso-Tartrates Using 2-Pyridyl Esters as Acylating Agents and Metal Carboxylates as Catalysts.

With 2-pyridyl benzoates as acylating agents and Zn(OAc)2 as a catalyst, 1,2-diols, 1,3-diols, and catechol were selectively monoacylated. Furthermore, the highly enantioselective desymmetrization of meso-tartrates was achieved for the first time, utilizing 2-pyridyl esters and NiBr2/AgOPiv/Ph-BOX in CH3CN or CuCl2/AgOPiv/Ph-BOX in EtOAc catalyst systems (up to 96% ee). The latter catalyst system was also effective for the kinetic resolution of dibenzyl dl-tartrate.

Catalytic Enantioselective Aldol Reactions of Unprotected Carboxylic Acids under Phosphine Oxide Catalysis.

The first catalytic enantioselective aldol reaction of various unprotected carboxylic acids is described. In the presence of a chiral bis(phosphine oxide) as a Lewis base catalyst, carboxylic acids were activated with silicon tetrachloride to form the corresponding bis(trichlorosilyl)enediolates in situ, which subsequently underwent an aldol reaction with an aldehyde or a ketone to produce ß-hydroxycarboxylic acids in high enantioselectivities of up to 92 % ee.

Asymmetric Aldol/Vinylogous Aldol/Cyclization Reaction Using Phosphine Oxide Catalysts.

Chiral phosphine oxide sequentially activates silicon tetrachloride and trichlorosilyl enol ethers to facilitate asymmetric aldol/vinylogous aldol reaction of 4-methoxy-3-penten-2-one and conjugated aldehydes in a highly enantioselective fashion, and the subsequent cyclization produced optically active 2,6-disubstituted 2,3-dihydro-4-pyranones bearing stereogenic centers at a remote position in a single operation.

Stereoselective Synthesis of Nitrogen-Containing Compounds from Enamines.

The domino reaction of enamines, electrophiles (N-sulfonylimines, N-tosylisocyanate, or diethyl azodicarboxylate), and trichlorosilane provided trans-amines (trans/cis = > 99:1 to 96:4). Meanwhile, the sequential imino ene-type reaction of enamines and electrophiles/NaBH3CN reduction afforded cis-amines (trans/cis = 1:>99 to 15:85). The reversal of selectivity is discussed on the basis of diastereofacial selection of the plausible iminium ion intermediates. For the domino reaction of cyclic enamines and cyclic imines, high enantioselectivity (er = 95.7:4.3 to 99.9:0.1) was achieved by utilizing chiral Lewis base catalysts.

Sequential Catalysis of Phosphine Oxide for Stereoselective Synthesis of Stereopentads.

An efficient method for accessing enantiomerically pure stereopentads via a catalytic asymmetric sequential aldol reaction has been developed for the first time. The enantioselective sequential aldol reaction produces a wide range of chiral stereopentad precursors in good yields with excellent enantioselectivities. The key to success is the use of the sequential catalytic system involving a chiral phosphine oxide catalyst and trichlorosilyl triflate.

Stereoselective Synthesis of Highly Functionalized 2,3-Dihydro-4-pyranones Using Phosphine Oxide as Catalyst.

2,3-Dihydro-4-pyranones were synthesized stereoselectively using a chiral phosphine oxide as the catalyst. The phosphine oxide sequentially activated silicon tetrachloride and promoted the double aldol reaction of 4-methoxy-3-buten-2-one with aldehydes. Subsequent stereoselective cyclization afforded the corresponding highly functionalized 2,3-dihydro-4-pyranones bearing three contiguous chiral centers in good yields and with high diastereo- and enantioselectivities.

Concise Asymmetric Construction of C2 -symmetric 1,9-Diarylnonanoids Using a Hypervalent Silicon Complex: Total Synthesis of (-)-Ericanone.

By using a phosphine oxide-catalyzed enantioselective double aldol reaction, we achieved the concise construction of C2 -symmetric 1,9-diarylnonanoids, enabling the synthesis of (-)-ericanone from p-hydroxybenzaldehyde in 6 steps with 65 % overall yield. The enantioselective double aldol reaction is useful for establishing C2 -symmetric 1,9-diaryl-3,7-dihydroxy-5-nonanones with a single operation. Furthermore, the use of o-nosyl-protected p-hydroxybenzaldehyde and a 4,4'-disubstituted BINAP dioxide catalyst dramatically improved the reactivity and selectivity in the double aldol reaction, enabling the total synthesis of (-)-ericanone with high yield and with excellent enantiopurity.

One-Pot Synthesis of ß,ß-Disubstituted α,ß-Unsaturated Carbonyl Compounds.

TiCl4-promoted aldol reaction of ketones as aldol acceptors followed by elimination of the titanoxy group from the Ti-aldolates affords ß,ß-disubstituted α,ß-unsaturated carbonyl compounds in a one-pot procedure. The use of additives, such as DMF, N,N,N',N'-tetramethylethylenediamine, and pyridine, in the elimination step was found to be important.

O-Monoacyltartaric acid catalyzed enantioselective conjugate addition of a boronic acid to dienones: application to the synthesis of optically active cyclopentenones.

Enantioselective conjugate addition of styrylboronic acid to dienones was effectively catalyzed by an O-monoacyltartaric acid to afford monostyrylated products with good enantioselectivity. The RCM of the monostyrylated products using the Hoveyda-Grubbs II catalyst afforded optically active cyclopentenones, including a synthetic intermediate of the antitumor agent TEI-9826. The study shows that a diene additive such as 1,6-heptadiene or diallyl ether was essential for the RCM.

Phosphine oxide-catalyzed enantioselective intramolecular aldol reaction via regioselective enolization of unsymmetrical diketones with tetrachlorosilane.

The phosphine oxide-catalyzed asymmetric intramolecular aldol reactions of diketones were investigated. The combination of tetrachlorosilane and a chiral phosphine oxide catalyst promoted the acetyl-selective enolization of diketones, and the subsequent intramolecular aldol reaction occurred in an enantioselective manner. The introduction of two trimethylsilyl groups at the 4- and 4'-positions in BINAP dioxide catalyst improved the enantioselectivity. This reaction provides an effective synthetic method to access ß-tertiary-hydroxy cyclohexanones in high yields and with high enantioselectivity.