Synthesis and cytotoxic evaluation of heterocyclic compounds by vinylic substitution of ketene dithioacetals.

N-heterocyclic compounds are important molecular scaffolds in the search for new drugs, since most drugs contain heterocyclic moieties in their molecular structure, and some of these classes of heterocycles are able to provide ligands for two or more biological targets. Ketene dithioacetals are important building blocks in organic synthesis and are widely used in the synthesis of N-heterocyclic compounds. In this work, we used double vinylic substitution reactions on ketene dithioacetals to synthesize a small library of heterocyclic derivatives and evaluated their cytotoxic activity in breast and ovarian cancer cells, identifying two benzoxazoles with good potency and selectivity. In silico predictions indicate that the two most active derivatives exhibit physicochemical properties within the range of drug-like compounds and showed potential to interact with HDAC8 and ERK1 cancer-related targets.

Novel trifluoromethyl ketone derivatives as oral cPLA2/COX-2 dual inhibitors for resolution of inflammation in rheumatoid arthritis.

Thirty-five trifluoromethyl hydrazones and seventeen trifluoromethyl oxime esters were designed and synthesized via molecular hybridization. All the target compounds were initially screened for in vitro anti-inflammatory activity by assessing their inhibitory effect on NO release in LPS-stimulated RAW264.7 cells, and the optimal compound was finally identified as 2-(3-Methoxyphenyl)-N'-((6Z,9Z,12Z,15Z)-1,1,1-trifluorohenicosa-6,9,12,15-tetraen-2-ylidene)acetohydrazide (F26, IC50 = 4.55 ± 0.92 µM) with no cytotoxicity. Moreover, F26 potently reduced the production of PGE2 in LPS-stimulated RAW264.7 cells compared to indomethacin. The interaction of F26 with COX-2 and cPLA2 was directly verified by the CETSA technique. F26 was found to modulate the phosphorylation levels of p38 MAPK and NF-κB p65, as well as the protein expression of IκB, cPLA2, COX-2, and iNOS in LPS-stimulated rat peritoneal macrophages. Additionally, F26 was observed to prevent the nuclear translocation of NF-κB p65 in LPS-stimulated rat peritoneal macrophages by immunofluorescence localization. Therefore, the aforementioned in vitro experiments demonstrated that F26 blocked the p38 MAPK and NF-κB pathways by binding to COX-2 and cPLA2. In the adjuvant-induced arthritis model, F26 demonstrated a significant effect in preventing arthritis symptoms and inflammatory status in rats, exerting an immunomodulatory role by regulating the homeostasis between Th17 and Treg through inhibition of the p38 MAPK/cPLA2/COX-2/PGE2 and NF-κB pathways. Encouragingly, F26 caused less acute ulcerogenicity in rats at a dose of 50 mg/kg compared to indomethacin. Overall, F26 is a promising candidate worthy of further investigation for treating inflammation and associated pain with lesser gastrointestinal irritation, as well as other symptoms in which cPLA2 and COX-2 are implicated in the pathophysiology.

Design, Synthesis, and Biological Activity of Novel Triketone-Containing Phenoxy Nicotinyl Inhibitors of HPPD.

4-Hydroxyphenylpyruvate dioxygenase (HPPD) is a crucial target enzyme in albino herbicides. The inhibition of HPPD activity interferes with the synthesis of carotenoids, blocking photosynthesis and resulting in bleaching and necrosis. To develop herbicides with excellent activity, a series of 3-hydroxy-2-(6-substituted phenoxynicotinoyl)-2-cyclohexen-1-one derivatives were designed via active substructure combination. The title compounds were characterized via infrared spectroscopy, 1H and 13C nuclear magnetic resonance spectroscopies, and high-resolution mass spectrometry. The structure of compound III-17 was confirmed via single-crystal X-ray diffraction. Preliminary tests demonstrated that some compounds had good herbicidal activity. Crop safety tests revealed that compound III-29 was safer than the commercial herbicide mesotrione in wheat and peanuts. Moreover, the compound exhibited the highest inhibitory activity against Arabidopsis thaliana HPPD (AtHPPD), with a half-maximal inhibitory concentration of 0.19 µM, demonstrating superior activity compared with mesotrione (0.28 µM) in vitro. A three-dimensional quantitative structure-activity relationship study revealed that the introduction of smaller groups to the 5-position of cyclohexanedione and negative charges to the 3-position of the benzene ring enhanced the herbicidal activity. A molecular structure comparison demonstrated that compound III-29 was beneficial to plant absorption and conduction. Molecular docking and molecular dynamics simulations further verified the stability of the complex formed by compound III-29 and AtHPPD. Thus, this study may provide insights into the development of green and efficient herbicides.

P(III)-Mediated Formal Reductive N-H Bond Insertion Reaction of Hydrazones to α-Keto Esters.

A diazo-, metal-, and base-free multi-substituted hydrazone synthesis via a formal reductive N-H bond insertion reactions of hydrazones to α-keto esters has been developed. The protocol features a broad substrate scope and good functional group tolerance, providing N-H bond insertion products in moderate to excellent yields. Moreover, P(III)-mediated N-H functionalization of pharmaceutical containing hydrazone moiety was also successfully achieved.

New enantioenriched ß-indolyl ketones as aromatase inhibitors: Unraveling heme-ligand interactions by MD simulation and MMPBSA analysis.

A series of enantioenriched ß-indolyl ketones as aromatase inhibitors (AI) is synthesized through the Michael-type Friedel-Crafts alkylation of indole. A highly efficient bifunctionalized amino catalyst is developed to access structurally diverse ß-indolyl ketones in high yields (up to 91%) and excellent enantioselectivity (enantiomeric ratio up to 98:2). All the synthesized compounds demonstrated promising aromatase inhibitory potential, where ortho-substituted analogs (3c and 3e) were found most active with IC50 values of 0.68 and 0.90 µM, respectively. Both of these compounds exhibited significant cytotoxicity (IC50 = 0.34 and 0.37 µM) against the MCF-7 breast cancer cell line in the (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide) assay. Molecular docking studies of the synthesized compounds demonstrate favorable binding interactions with the estrogens controlling CYP19A1 (3EQM) and metabolizing CYP3A4 (5VCC) enzymes. Molecular dynamic (MD) simulation analysis revealed the essentiality of heme-ligand interactions to build a stable protein-ligand complex. An average root mean square deviation of 0.35 nm observed during a 100-ns MD simulation and binding free energy in the range of -190 to -227 kJ/mol calculated by g_mmpbsa analysis authenticated the stability of the 3c-3EQM complex. ADMET and drug-likeness parameters supported the suitability of these indole derivatives as the drug lead to develop potent inhibitors for estrogen-dependent breast cancer.

Dual site reactivity of indole-3-Schiff bases with S/Se/Cl substituted ketenes for stereoselective C-4 substituted indole-ß-lactams, biological evaluations, magic chloro effect and molecular docking studies.

A convenient methodology for C-4 indole-ß-lactam hybrids with chloro, sulphur and seleno substitutions through dual site reactivity of indole-3-Schiff bases towards ketenes has been developed. The reaction proceeded in a stereospecific manner with the exclusive formation of trans-ß-lactams assigned with respect to C3-H and C4-H. The synthesized novel ß-lactams have been characterized with the help of elemental analysis (CHNS) and spectroscopic techniques viz.1H NMR, 13C NMR, DEPT 135, HSQC and IR. The trans configuration was further estabilished based on X-ray crystallographic data. Examination of antibacterial properties unveiled that only derivatives 5a and 5b, featuring chloro substitution, exhibited potent activities, underscoring the emergence of the recently coined term "magic chloro effect". Molecular docking analysis provided additional support for the observed in vitro antibacterial activities of compounds 5a-b.

The Kornblum DeLaMare rearrangement in natural product synthesis: 25 years of innovation.

Covering: 1998 up to the end of 2023Since its initial disclosure in 1951, the Kornblum DeLaMare rearrangement has proved an important synthetic transformation and has been widely adopted as a biomimetic step in natural product synthesis. Utilising the base catalysed decomposition of alkyl peroxides to yield a ketone and alcohol has found use in many syntheses as well as a key strategic step, including the unmasking of furans, as a biomimetic synthetic tool, and the use of the rearrangement to install oxygen enantioselectively. Since ca. 1998, its impact as a synthetic transformation has grown significantly, especially given the frequency of use in natural product syntheses, therefore this 25 year time period will be the focus of the review.

A unified strategy for the total syntheses of eribulin and a macrolactam analogue of halichondrin B.

A unified synthetic route for the total syntheses of eribulin and a macrolactam analog of halichondrin B is described. The key to the success of the current synthetic approach includes the employment of our reverse approach for the construction of cyclic ether structural motifs and a modified intramolecular cyclization reaction between alkyl iodide and aldehyde functionalities to establish the all-carbon macrocyclic framework of eribulin. These syntheses, together with our previous work on the total syntheses of halichondrin B and norhalichondrin B, demonstrate and validate the powerful reverse approach in the construction of cyclic ether structural motifs. On the other hand, the unified synthetic strategy for the synthesis of the related macrolactam analog provides inspiration and opportunities in the halichondrin field and related polycyclic ether areas.

Apoptotic mechanism in human brain microvascular endothelial cells triggered by 4'-iodo-α-pyrrolidinononanophenone: Contribution of decrease in antioxidant properties.

In this study, we newly synthesized four α-pyrrolidinononanophenone (α-PNP) derivatives [4'-halogenated derivatives and α-pyrrolidinodecanophenone (α-PDP)], and then performed the structure-cytotoxicity relationship analyses. The results showed the rank order for the cytotoxic effects, α-PNP < α-PDP < 4'-fluoro-α-PNP < 4'-chrolo-α-PNP < 4'-bromo-α-PNP < 4'-iodo-α-PNP (I-α-PNP), and suggest that cytotoxicities of 4'-halogenated derivatives were more intensive than that of elongation of the hydrocarbon chain (α-PDP). We also surveyed the apoptotic mechanism of I-α-PNP in brain microvascular endothelial (HBME) cells that are utilized as the in vitro model of the blood-brain barrier. HBME cell treatment with I-α-PNP facilitated the apoptotic events (caspase-3 activation, externalization of phosphatidylserine, and DNA fragmentation), which were almost completely abolished by pretreating with antioxidants. In addition, the immunofluorescent staining revealed the enhanced production of hydroxyl radical in mitochondria by the I-α-PNP treatment, inferring that the I-α-PNP treatment triggers the apoptotic mechanism dependent on the enhanced ROS production in mitochondria. The treatment with I-α-PNP increased the production of cytotoxic aldehyde 4-hydroxy-2-nonenal and decreased the amount of reduced glutathione. Additionally, the treatment decreased the 26S proteasome-based proteolytic activities and aggresome formation. These results suggest that decrease in the antioxidant properties is also ascribable to HBME cell apoptosis elicited by I-α-PNP.

Visible-Light-Induced C4-Selective Functionalization of Pyridinium Salts with Cyclopropanols.

The site-selective C-H functionalization of heteroarenes is of considerable importance for streamlining the rapid modification of bioactive molecules. Herein, we report a general strategy for visible-light-induced ß-carbonyl alkylation at the C4 position of pyridines with high site selectivity using various cyclopropanols and N-amidopyridinium salts. In this process, hydrogen-atom transfer between the generated sulfonamidyl radicals and O-H bonds of cyclopropanols generates ß-carbonyl radicals, providing efficient access to synthetically valuable ß-pyridylated (aryl)ketones, aldehydes, and esters with broad functional-group tolerance. In addition, the mild method serves as an effective tool for the site-selective late-stage functionalization of complex and medicinally relevant molecules.

Ruthenium-on-Carbon-Catalyzed Facile Solvent-Free Oxidation of Alcohols: Efficient Progress under Solid-Solid (Liquid)-Gas Conditions.

A protocol for the ruthenium-on-carbon (Ru/C)-catalyzed solvent-free oxidation of alcohols, which proceeds efficiently under solid-solid (liquid)-gas conditions, was developed. Various primary and secondary alcohols were transformed to corresponding aldehydes and ketones in moderate to excellent isolated yields by simply stirring in the presence of 10% Ru/C under air or oxygen conditions. The solvent-free oxidation reactions proceeded efficiently regardless of the solid or liquid state of the substrates and reagents and could be applied to gram-scale synthesis without loss of the reaction efficiency. Furthermore, the catalytic activity of Ru/C was maintained after five reuse cycles.

Bile-Acid-Appended Triazolyl Aryl Ketones: Design, Synthesis, In Vitro Anticancer Activity and Pharmacokinetics in Rats.

A library of bile-acid-appended triazolyl aryl ketones was synthesized and characterized by detailed spectroscopic techniques such as 1H and 13C NMR, HRMS and HPLC. All the synthesized conjugates were evaluated for their cytotoxicity at 10 µM against MCF-7 (human breast adenocarcinoma) and 4T1 (mouse mammary carcinoma) cells. In vitro cytotoxicity studies on the synthesized conjugates against MCF-7 and 4T1 cells indicated one of the conjugate 6cf to be most active against both cancer cell lines, with IC50 values of 5.71 µM and 8.71 µM, respectively, as compared to the reference drug docetaxel, possessing IC50 values of 9.46 µM and 13.85 µM, respectively. Interestingly, another compound 6af (IC50 = 2.61 µM) was found to possess pronounced anticancer activity as compared to the reference drug docetaxel (IC50 = 9.46 µM) against MCF-7. In addition, the potent compounds (6cf and 6af) were found to be non-toxic to normal human embryonic kidney cell line (HEK 293), as evident from their cell viability of greater than 86%. Compound 6cf induces higher apoptosis in comparison to 6af (46.09% vs. 33.89%) in MCF-7 cells, while similar apoptotic potential was observed for 6cf and 6af in 4T1 cells. The pharmacokinetics of 6cf in Wistar rats showed an MRT of 8.47 h with a half-life of 5.63 h. Clearly, these results suggest 6cf to be a potential candidate for the development of anticancer agents.

Synthesis and Characterisation of Novel Tricyclic and Tetracyclic Furoindoles: Biological Evaluation as SAHA Enhancer against Neuroblastoma and Breast Cancer Cells.

The dihydropyranoindole structures were previously identified as promising scaffolds for improving the anti-cancer activity of histone deacetylase inhibitors. This work describes the synthesis of related furoindoles and their ability to synergize with suberoylanilide hydroxamic acid (SAHA) against neuroblastoma and breast cancer cells. The nucleophilic substitution of hydroxyindole methyl esters with α-haloketones yielded the corresponding arylether ketones, which were subsequently cyclized to tricyclic and tetracyclic furoindoles. The furoindoles showed promising individual cytotoxic efficiency against breast cancer cells, as well as decent SAHA enhancement against cancer cells in select cases. Interestingly, the best IC50 value was obtained with the non-cyclized intermediate.

A diketopyrrolopyrrole-based ratiometric fluorescent probe for endogenous leucine aminopeptidase detecting and imaging with specific phototoxicity in tumor cells.

Leucine aminopeptidase (LAP) is a vital proteolytic enzyme, and its overexpression is often associated with many physiological diseases, such as liver dysfunction and breast cancer. Therefore, the accurate measurement of LAP concentrations in cells is critical for the diagnosis and prevention of related diseases. Herein, a new ratiometric fluorescent probe, DPP-Leu, based on diketopyrrolopyrrole (DPP) was designed and synthesized for LAP detection based on the specific enzymatic cleavage of the N-terminal leucine residue. The fluorescence intensity ratio of DPP-Leu (I548/I651) showed a remarkable change in the presence of LAP, with a limit of detection of 0.011 U L-1, and DPP-Leu was successfully applied to detect LAP in fetal bovine serum (FBS) and artificial urine. Cell imaging experiments revealed that DPP-Leu could target mitochondria and distinguish tumor cells with high LAP content from normal cells. Importantly, benefiting from the structural transformation of DPP-Leu to the photosensitizer 4 under LAP catalysis, the probe could kill tumor cells under light irradiation without damaging normal cells.

Characterization of an aromatic trifluoromethyl ketone as a new warhead for covalently reversible kinase inhibitor design.

An aromatic trifluoromethyl ketone moiety was characterized as a new warhead for covalently reversible kinase inhibitor design to target the non-catalytic cysteine residue. Potent and selective covalently reversible inhibitors of FGFR4 kinase were successfully designed and synthesized by utilizing this new warhead. The binding mode of a representative inhibitor was fully characterized by using multiple technologies including MALDI-TOF mass spectrometry, dialysis assay and X-ray crystallographic studies etc. This functional group was also successfully applied to discovery of a new JAK3 inhibitor, suggesting its potential application in designing other kinase inhibitors.

New ß-ketophosphonates for the synthesis of prostaglandin analogues. 1. Phosphonates with a bicyclo[3.3.0]octene scaffold spaced by a methylene group from the ß-ketone.

The synthesis of ß-ketophosphonates, linked by a methylene group to a bicyclo[3.3.0]octene fragment, was performed by the reaction of dimethyl methanephosphonate with the ester group of two intermediates with this scaffold. Starting from a diol, protected with good leaving groups (mesyl and tosyl), we performed a sequence of reactions with good yields: the carbon chain lengthening by reaction with KCN, the hydrolysis of the nitrile groups to carboxyl, the esterification of carboxyl to ester and finally the phosphonate synthesis, which gave one bis-ß-ketophosphonate and two mono ß-ketophosphonates. The new ß-ketophosphonates are key intermediates for obtaining new prostaglandin analogues with a bicyclo[3.3.0]octene fragment in the ω-side chain. The bicyclo[3.3.0]octane scaffold, found in natural products and in anticancer compounds, are expected to keep their activity in PG analogs; the bulky scaffold, separated by a methylene group from the C-15 carbon atom, is expected to diminish the inactivation of the PG analog by enzyme oxidation of 15α-OH oxidation to 15-Keto via PGDH pathway.

Platanic Acid-Aryl Enones as Potential Anticancer Compounds: Synthesis and Biological Profiling against Breast, Prostate and Lung Cancer Cell Lines.

A series of rationally designed platanic acid-based compounds derived from naturally occurring betulinic acid were synthesized through a sequence of Lemieux-Johnson oxidation and Aldol condensation reaction. All the compounds were screened for cytotoxicity against a panel of human cancer and normal cell lines using MTT assay. From the biological data, it was observed that some of these semi-synthetic congeners exhibited potent biological profiles compared to platanic acid. One of the compounds with the p-tolyl substitution was found to be most active in this study, and its cytotoxicity against two of the cell lines, MDA-MB 231 and A-549 were in tune with the standard compound, 5-fluorouracil.

α- and ß-Functionalized Ketones from 1,3-Dienes and Aldehydes: Control of Regio- and Enantioselectivity in Hydroacylation of 1,3-Dienes.

Ketones are among the most widely used intermediates in organic synthesis, and their synthesis from inexpensive feedstocks could be quite impactful. Regio- and enantioselective hydroacylation reactions of dienes provide facile entry into useful ketone-bearing chiral motifs with an additional latent functionality (alkene) suitable for further elaboration. Three classes of dienes, 2- or 4-monosubstituted and 2,4-disubstituted 1,3-dienes, undergo cobalt(I)-catalyzed regio- and enantioselective hydroacylation, giving products with high enantiomeric ratios (er). These reactions are highly dependent on the ligands, and we have identified the most useful ligands and reaction conditions for each class of dienes. 2-Substituted and 2,4-disubstituted dienes predominantly undergo 1,2-addition, whereas 4-substituted terminal dienes give highly enantioselective 4,1- or 4,3-hydroacylation depending on the aldehyde, aliphatic aldehydes giving 4,1-addition and aromatic aldehydes giving 4,3-addition. Included among the substrates are feedstock dienes, isoprene (US$1.4/kg) and myrcene (US$129/kg), and several common aldehydes. We propose an oxidative dimerization mechanism that involves a Co(I)/Co(III) redox cycle that appears to be initiated by a cationic Co(I) intermediate. Studies of reactions using isolated neutral and cationic Co(I) complexes confirm the critical role of the cationic intermediates in these reactions. Enantioselective 1,2-hydroacylation of 2-trimethylsiloxy-1,3-diene reveals a hitherto undisclosed route to chiral siloxy-protected aldols. Finally, facile syntheses of the anti-inflammatory drug (S)-Flobufen (2 steps, 92% yield, >99:1 er) and the food additive (S)-Dihydrotagetone (1 step, 83% yield; 96:4 er) from isoprene illustrate the power of this method for the preparation of commercially relevant compounds.

Asymmetric Catalytic Epoxidation of Terminal Enones for the Synthesis of Triazole Antifungal Agents.

An enantioselective epoxidation of α-substituted vinyl ketones was realized to construct the key epoxide intermediates for the synthesis of various triazole antifungal agents. The reaction proceeded efficiently in high yields with good enantioselectivities by employing a chiral N,N'-dioxide/ScIII complex as the chiral catalyst and 35% aq. H2O2 as the oxidant. It enabled the facile transformation for optically active isavuconazole, efinaconazole, and other potential antifungal agents.

Synthesis and Biological Evaluation of New N-Acyl-α-amino Ketones and 1,3-Oxazoles Derivatives.

In order to develop novel bioactive substances with potent activities, some new valine-derived compounds incorporating a 4-(phenylsulfonyl)phenyl fragment, namely, acyclic precursors from N-acyl-α-amino acids and N-acyl-α-amino ketones classes, and heterocycles from the large family of 1,3-oxazole-based compounds, were synthesized. The structures of the new compounds were established using elemental analysis and spectral (UV-Vis, FT-IR, MS, NMR) data, and their purity was checked by reversed-phase HPLC. The newly synthesized compounds were evaluated for their antimicrobial and antibiofilm activities, for toxicity on D. magna, and by in silico studies regarding their potential mechanism of action and toxicity. The 2-aza-3-isopropyl-1-[4-(phenylsulfonyl)phenyl]-1,4-butanedione 4b bearing a p-tolyl group in 4-position exhibited the best antibacterial activity against the planktonic growth of both Gram-positive and Gram-negative strains, while the N-acyl-α-amino acid 2 and 1,3-oxazol-5(4H)-one 3 inhibited the Enterococcus faecium biofilms. Despite not all newly synthesized compounds showing significant biological activity, the general scaffold allows several future optimizations for obtaining better novel antimicrobial agents by the introduction of various substituents on the phenyl moiety at position 5 of the 1,3-oxazole nucleus.