2,4-Diketo esters: Crucial intermediates for drug discovery.

Convenient structures such as 2,4-diketo esters have been widely used as an effective pattern in medicinal chemistry and pharmacology for drug discovery. 2,4-Diketonate is a common scaffold that can be found in many biologically active and naturally occurring compounds. Also, many 2,4-diketo ester derivatives have been prepared due to their suitable synthesis. These synthetic drugs and natural products have shown numerous interesting biological properties with clinical potential as a cure for the broad specter of diseases. This review aims to highlight the important evidence of 2,4-diketo esters as a privileged scaffold in medicinal chemistry and pharmacology. Herein, numerous aspects of 2,4-diketo esters will be summarized, including synthesis and isolation of their derivatives, development of novel synthetic methodologies, the evaluation of their biological properties as well as the mechanisms of action of the diketo ester derivates. This paperwork is expected to be a comprehensive, trustworthy, and critical review of the 2,4-diketo ester intermediate to the chemistry community.

Synthesis, characterization, anticancer evaluation and mechanisms of cytotoxic activity of novel 3-hydroxy-3-pyrrolin-2-ones bearing thenoyl fragment: DNA, BSA interactions and molecular docking study.

In order to make a progress in discovering a new agents for chemotherapy with improved properties and bearing in mind the fact that substituted 3-hydroxy-3-pyrrolin-2-ones belong to a class of biologically active compounds, series of novel 1,5-diaryl-4-(2-thienylcarbonyl)-3-hydroxy-3-pyrrolin-2-ones were synthesized and characterized by spectral (UV-Vis, IR, NMR, ESI-MS), X-ray and elemental analysis. All compounds were examined for their cytotoxic effect on human cancer cell lines HeLa and MDA-MB 231 and normal fibroblasts (MRC-5). Four compounds, 3-hydroxy-1-(p-tolyl)-4-(2-thienylcarbonyl)-5-(4-chlorophenyl)-2,5-dihydro-1H-pyrrol-2-one (D10), 3-hydroxy-1-(3-nitrophenyl)-4-(2-thienylcarbonyl)-5-(4-(benzyloxy)phenyl)-2,5-dihydro-1H-pyrrol-2-one (D13), 3-hydroxy-1-(4-nitrophenyl)-4-(2-thienylcarbonyl)-5-(4-(benzyloxy)phenyl)-2,5-dihydro-1H-pyrrol-2-one (D14), and 3-hydroxy-1-(4-chlorophenyl)-4-(2-thienylcarbonyl)-5-(4-(benzyloxy)phenyl)-2,5-dihydro-1H-pyrrol-2-one (D15), that showed the highest cytotoxicity against malignant cells and the best selectivity towards normal cells were selected for further experiments. Results obtained by investigating mechanisms of cytotoxic activity suggest that selected 3-hydroxy-3-pyrrolin-2-one derivatives in HeLa cells induce apoptosis that is associated with S phase arrest (D13, D15, and D10) or unrelated to cell cycle distribution (D14). Additionally, to better understand their suitability for potential use as anticancer medicaments we studied the interactions between biomacromolecules (DNA or BSA) and D13 and D15. The results indicated that D13 and D15 have great affinity to displace EB from the EB-DNA complex through intercalation [Ksv = (3.7 ±â€¯0.1) and (3.4 ±â€¯0.1) × 103 M-1, respectively], an intercalative mode also confirmed through viscosity measurements. Ka values, obtained as result of fluorescence titration of BSA with D13 and D15 [Ka = (4.2 ±â€¯0.2) and (2.6 ±â€¯0.2) × 105 M, respectively], support the fact that a significant amount of the tested compounds could be transported and distributed through the cells. In addition, by DNA and BSA molecular docking study for D13, D14 and D15 is determined and predicted the binding mode and the interaction region.

Discovery of the Biginelli hybrids as novel caspase-9 activators in apoptotic machines: Lipophilicity, molecular docking study, influence on angiogenesis gene and miR-21 expression levels.

In order to investigate potential therapeutically agents, novel products of Biginelli reaction (4a-l) were synthesized and exposed to cytotoxic and caspase activities, angiogenesis, cell cycle distribution, gene and microRNA expression levels, lipophilicity assessment and docking study. Among the twelve novel compounds (4a-l) evaluated for the cytotoxic activity, five of them (4c, 4d, 4f, 4k and 4l) that showed excellent activity on the tested cell lines (HeLa, LS174 and A549) were selected for further evaluation. Interestingly, compound 4f has up to three times higher selectivity index (SI) towards cancer cells than cisplatin (on HeLa, LS174 and A549 SI = 18.2, 13.5 and 11.2, respectively). The obtained results from cell cycle distribution and caspase activity indicate that tested compounds (4c, 4d, 4f, 4k and 4l) promoted caspase-9 activation, implicated in the intrinsic pathway of apoptosis. Lipophilicity of 4a-l was determinate by using reversed-phase high-performance liquid chromatography.

Biological evaluation of selected 3,4-dihydro-2(1H)-quinoxalinones and 3,4-dihydro-1,4-benzoxazin-2-ones: Molecular docking study.

In order to investigate new potential therapeutically active agents, we investigated the biological properties of two small libraries of quinoxalinones and 1,4-benzoxazin-2-ones. The results obtained showed that compounds 5, 9-11 have good cytotoxic activity against HeLa cells where the lowest IC50 value (10.46 ± 0.82 µM/mL) was measured for compound 10. Additionally, the most active compounds (5, 9-11) showed much better selectivity for MRC-5 cells (up to 17.4) compared to cisplatin. In vitro evaluation of the inhibition of the enzyme α-glucosidase showed that compounds 10 and 11 exert significant inhibition of the enzyme at 52.54 ± 0.09 and 40.09 ± 0.49 µM, respectively. Competitive experiments with ethidium bromide (EB) indicated that all tested compounds have affinity to displace EB from the EB-DNA complex through intercalation, suggesting good competition with EB (Ksv = (3.1 ± 0.2), (5.1 ± 0.1), (5.6 ± 0.2), and (6.3 ± 0.2) × 103 M-1 ). A molecular docking study was also performed to better understand the binding modes and to conclude the structure-activity relationships of the synthesized compounds.

Vanillic aldehydes for the one-pot synthesis of novel 2-oxo-1,2,3,4-tetrahydropyrimidines.

A small library of novel 2-oxo-1,2,3,4-tetrahydropyrimidines was synthesized via a one-pot multicomponent Biginelli reaction. Copper complex [Formula: see text] which was used for the first time as a homogeneous and heterogeneous catalyst, makes this a facile and efficient reaction at room temperature. All the obtained products fall out of the solution in pure form and are easily isolated via filtration in good-to-excellent yields. The molecular structure of one of the products, ethyl 6-methyl-2-oxo-4-(4[Formula: see text]-isopropoxy-3[Formula: see text]-methoxyphenyl) - 1,2,3,4 - tetrahydropyrimidine-5- carboxylate, has been determined by X-ray crystallography. All non-hydrogen atoms in the heterocyclic, six-membered ring are determined to be approximately coplanar.

Antioxidative and antiproliferative evaluation of 2-(phenylselenomethyl)tetrahydrofuran and 2-(phenylselenomethyl)tetrahydropyran.

PURPOSE: To determine the antioxidant and antiproliferative influence of 2-(phenylselenomethyl)tetrahydrofuran (1a) and 2-(phenylselenomethyl)tetrahydropyran (2a) on colon cancer cell line HCT-116 and breast cancer cell line MDA-MB-231. METHODS: Cell viability was monitored in a dose-dependent manner using MTT assay. The concentration of superoxide anion radical (O2 •(-)) was determined spectrophotometrically. Spectrophotometric determination of nitrites (NO2 -) was performed by using the Griess method. Determination of total glutathione (GSH) was also performed spectrophotometrically. RESULTS: HCT-116 cell line was more sensitive to the effects of the investigated substances than MDA-MB-231 cell line. Also, it was noticed that 1a produced greater effect compared to 2a. Moreover, both investigated compounds decreased to a certain degree the oxidative stress by decreasing the O2•(-) and thus the peroxynitrite concentration. At the same time, 1a and 2a acted more efficiently in promoting the endogenous antioxidative capacities (increased GSH concentration) providing better self-defence capabilities for cells. CONCLUSION: Our findings showed that the investigated selenium compounds play an important role in reducing the levels of reactive oxygen species (ROS); therefore, we believe that, as antioxidants, they could prevent the processes arising as a consequence of oxidative stress, including cancer.

Kinetic and mechanistic studies of base-catalyzed phenylselenoetherification of (Z)- and (E)-hex-4-en-1-ols.

The mechanism of phenylselenoetherification of (Z)- and (E)-hex-4-en-1-ols using some bases (triethylamine, pyridine, quinoline, 2,2'-bipyridine) as catalysts and some solvents [tetrahydrofuran (THF) and CCl4] as reaction media was examined through studies of kinetics of the cyclization by UV-vis spectrophotometry. It was demonstrated that the intramolecular cyclization is facilitated in the presence of bases as a result of the hydrogen bond between the base and the alkenol's OH group. The rate constants in the base-catalyzed reactions are remarkably influenced by the bulkiness and basicity of the base used and the nature of the considered nitrogen donors. The obtained values for rate constants show that the reaction with triethylamine is the fastest one. THF with higher polarity and higher basic character is better as a solvent than CCl4. Quantum-chemical calculations [MP2(fc)/6-311+G**//B3LYP/6-311+G** + ZPE(B3LYP/6-311+G**] show that the cyclization of (Z)-hex-4-en-1-ol to a tetrahydrofuranoid five-membered ring is kinetically controlled, while the cyclization of (E)-hex-4-en-1-ol to the tetrahydropyranoid six-membered ring is thermodynamically controlled. This is in accordance with previous experimental findings.

Synthesis, Characterization, Antioxidant Activity of ß-diketonates, and Effects of Coordination to Copper(II) Ion on their Activity: DNA, BSA Interactions and Molecular Docking Study.

BACKGROUND: In order to make some progress in discovering the more effective way to eliminate ROS which cause the oxidative stress in organism in humans and bearing in mind the fact that ethyl-2-hydroxy-4-aryl(alkyl)-4-oxo-2-butenoates (ß-diketonates) belong to a class of biologically active compounds, series of ß-diketonates were synthesized, characterized, and tested to evaluate there antioxidant activity. Further, to investigate how coordination to copper(II) ion affects the activity of ß-diketonates, appropriate complexes were synthesized and characterized. METHODS: All complexes were characterized by UV-Vis, IR, and EPR spectroscopy, MS spectrometry, and elemental analysis. Fluorescence spectroscopic method was used for investigations of the interactions between biomacromolecules (DNA or BSA) and compound 2E. Viscosity measurements and molecular docking study were performed to confirm the mode of interactions between DNA and BSA and compound 2E. RESULTS: Scavenging activity on DPPH radical revealed that compounds 2A, 2B, and 2E possess largest free radical scavenging, comparable to standard while results of superoxide anion scavenging activities of tested samples showed that maximum scavenging activity (IC50=168.92 µg/mL) was found for 2E, very similar to standard ascorbic acid, followed by 2B and 2G. Results of the interactions between biomacromolecules and 2E indicated that 2E has the affinity to displace EB from the EB-DNA complex through intercalation [Ksv = (3.7 ± 0.1) × 103 M-1], while Ka value obtained via titration of BSA with 2E [Ka = (4.2 ± 0.2) × 105 M-1], support the fact that the significant amount of the drug could be transported and distributed through the cells. CONCLUSION: All ß-diketonates exhibited better scavenging activities than their corresponding copper complexes. Among all the tested compounds, 2E gave the highest reducing power, even higher than standard ascorbic acid, while reducing power for compounds 2A and 2B was also good but lower than standard. DNA and BSA binding study for 2E showed that this compound has the potential to be used as medicament.

Synthesis, Anticancer Evaluation and Synergistic Effects with cisplatin of Novel Palladium Complexes: DNA, BSA Interactions and Molecular Docking Study.

BACKGROUND: In order to discover new agents for chemotherapy with improved properties compared to the existing agents and bearing in mind the fact that some Pd complexes possess better antitumor activity and exhibit less kidney toxicity compared to cisplatin, a series of novel square-planar palladium(II) complexes [Pd (L)2] (3a-f) with O,O bidentate ligands [L = ethyl 2- hydroxy-alkyl(aryl)-4-oxo-2-butenoate] were synthesized. METHODS: All complexes were characterized by spectral (UV-Vis, IR, NMR, ESI-MS) and X-ray analysis and examined for their cytotoxic effect on human cancer cell lines HeLa and MDA-MB 231 and normal fibroblasts (MRC-5). Fluorescence spectroscopic method was used for investigations of the interactions between CT-DNA or bovine serum albumin (BSA) and complex 3c. Viscosity measurements and molecular docking study were performed to confirm the mode of interactions between DNA and BSA and complex 3c. RESULTS: Complexes that showed the best results, 3c, 3d, and 3e, were placed under further investigations. Selected complexes induced apoptosis and cell cycle arrest in HeLa and MDA-MB 231 cells. Low concentrations of 3c and 3e showed strong to moderate synergism with low concentrations of cisplatin. The interaction of 3d with cisplatin was antagonistic in all used concentrations, but low IC50 value indicates its usefulness as a single cytotoxic agent. It was also noted that the change of viscosity is more pronounced in DNA solution after addition of complex 3c. CONCLUSION: Obtained results indicate that the novel palladium(II) complexes have the potential to become candidates for treatment in anticancer therapy.

The influence of cobalt(II) and tin(II) chloride on regioselectivity and kinetics of phenylselenocyclization of 6-methyl-hept-5-en-2-ol.

The reaction of the Δ4-alkenols with PhSeX can follow three possible reaction pathways: two pathways lead to the formation of two regioisomeric cyclic ether products through the process of intramolecular cyclization, while the third represents the addition of the reagent to the double bond of an alkenol. As there are relatively few literature data on the kinetics of these reactions, we have chosen 6-methyl-hept-5-en-2-ol as a substrate of interest in order to obtain valuable results that will enable better understanding of the mechanism of phenylselenoetherification reactions. 6-Methyl-hept-5-en-2-ol is a particularly interesting model-substrate due to its substitution pattern of functional groups involved in the cyclization process. In this research, through synthetic and kinetic studies, we aimed to resolve key questions concerning the influence on kinetics, chemo- and regioselectivity of the reagent's counter ion, steric hindrances in substrate functional groups and the presence of additives.

Effects of cisplatin and other Pt(II) complexes on spontaneous motility of isolated human oviduct.

The toxicity of platinum(II) ion could be significantly modified by coordination with some organic compounds. In our study, the cytotoxicity and the influence of platinum(II) complexes, such as cisplatin, cis-[PtCl(2)(NH(3))(2)], [PtCl(2)(SMC)] and [PtCl(2)(DMSO)(2)] (where SMC is S-methyl-l-cysteine and DMSO is dimethyl sulphoxide) on spontaneous motility of isolated human fallopian tubes were investigated. Cisplatin showed potent pro-apoptotic effects on peripheral blood mononuclear cells (PBMC). However, peripheral blood mononuclear cells were substantially less sensitive to [PtCl(2)(SMC)] and [PtCl(2)(DMSO)], and these compounds showed no toxic effect on PBMC in all concentrations examined. Cisplatin showed concentration-dependent inhibition of spontaneous contractions of the isolated ampulla. (EC(50)=1.14+/-0.03 x 10(-6)M/l, r=0.714, p<0.05) while [PtCl(2)(SMC)] and [PtCl(2)(DMSO)(2)] did not affect spontaneous contractions of isolated fallopian tube ampulla.

Evaluation of antimicrobial activity and retention behavior of newly synthesized vanilidene derivatives of Meldrum's acids using QSRR approach.

Increased antimicrobial resistance together with the lack of new antimicrobial drugs suggest on an urgent need for new therapeutics in this field. Vanilidene derivatives of Meldrum's acid present one of the possible approaches. In this work lipophilicity of 13 vanilidene derivatives of Meldrum's acid as well as their predicted antimicrobial activity towards several characteristic species has been evaluated. 10 vanilidene derivatives have been previously synthesized and 3 new compounds are synthetized afterwards following the same procedure. These selected 13 candidates were examined using thin layer chromatography in two different solvent systems. Gained retention parameters were a starting point for further Quantitative Structure Property Relationships (QSRR) studies in which minimum inhibitory concentration (MIC) for Candida albicans, Trichoderma viride, Penicillium italicum, Fuscarium oxysporum, Pseudomonas aeruginosa and Escherichia coli were determined. Statistically significant QSRR models were established and clustering of the compounds was performed with the help of principal component analysis (PCA) and hierarchical cluster analysis (HCA). Absorption, Distribution, Metabolism, and Excretion (ADME) properties of investigated molecules were subjected to sum of ranking differences (SRD) analysis in order to explore their pharmacokinetic properties. SRD analysis was also performed for the ranking of the established QSRR models. It was shown that compounds 6, 8 and 9 possess a significant antimicrobial activity, satisfied ADME properties and these candidates should be further optimized in order to utilize unexplored potential of Meldrum's acid in synthesis of novel antifungal compounds.

Synthesis, characterization, biological activity, DNA and BSA binding study: novel copper(ii) complexes with 2-hydroxy-4-aryl-4-oxo-2-butenoate.

A serie of novel square pyramidal copper(ii) complexes [Cu(L)2H2O] (3a-d) with O,O-bidentate ligands [L = ethyl-2-hydroxy-4-aryl-4-oxo-2-butenoate; aryl = 3-methoxyphenyl-2a, (E)-2-phenylvinyl-2b, (E)-2-(4'-hydroxy-3'-methoxyphenyl)vinyl-2c, 3-nitrophenyl-2d, 2-thienyl-2e] were synthesized and characterized by spectral (UV-Vis, IR, ESI-MS and EPR), elemental and X-ray analysis. The antimicrobial activity was estimated by the determination of the minimal inhibitory concentration (MIC) using the broth microdilution method. The most active antibacterial compounds were 3c and 3d, while the best antifungal activity was showed by complexes 3b and 3e. The lowest MIC value (0.048 mg mL-1) was measured for 3c against Proteus mirabilis. The cytotoxic activity was tested using the MTT method on human epithelial carcinoma HeLa cells, human lung carcinoma A549 cells and human colon carcinoma LS174 cells. All complexes showed extremely better cytotoxic activity compared to cisplatin at all tested concentrations. Compound 3d expressed the best activity against all tested cell lines with IC50 values ranging from 7.45 to 7.91 µg mL-1. The type of cell death and the impact on the cell cycle for 3d and 3e were evaluated by flow cytometry. Both compounds induced apoptosis and S phase cell cycle arrest. The interactions between selected complexes (3d and 3e) and CT-DNA or bovine serum albumin (BSA) were investigated by the fluorescence spectroscopic method. Competitive experiments with ethidium bromide (EB) indicated that 3d and 3e have a propensity to displace EB from the EB-DNA complex through intercalation suggesting strong competition with EB [Ksv = (1.4 ± 0.2) and (2.9 ± 0.1) × 104 M-1, respectively]. Ksv values indicate that these complexes bind to DNA covalently and non-covalently. The achieved results in the fluorescence titration of BSA with 3d and 3e [Ka = (2.9 ± 0.2) × 106 and (2.5 ± 0.2) × 105 M, respectively] showed that the fluorescence quenching of BSA is a result of the formation of the 3d- and 3e-BSA complexes. The obtained Ka values are high enough to ensure that a significant amount of 3d and 3e gets transported and distributed through the cells.

Synthesis, crystal and solution structures and antimicrobial screening of palladium(II) complexes with 2-(phenylselanylmethyl)oxolane and 2-(phenylselanylmethyl)oxane as ligands.

Two novel Pd(II) complexes with 2-(phenylselanylmethyl)oxolane and 2-(phenylselanylmethyl)oxane as ligands were synthesized. The crystal and molecular structure of the complexes has been determined by single crystal X-ray diffraction. It turned out for both complexes that the two ligands are coordinated to Pd via Se atoms in a trans-fashion and the other two trans-positions are occupied by Cl ions. Detailed 1D- and 2D-NMR analyses revealed the existence of equilibrating trans-diastereomeric species differing in the configuration at four chiral centers (selenium and carbon) in the solution of the complexes. A computational study was also undertaken to assess the relative stabilities of the mentioned stereoisomeric species. The antimicrobial properties of the complexes were investigated against a series of human pathogenic bacterial and fungal strains. The complexes were shown to possess promising broad spectrum moderate antimicrobial activity that is more pronounced against fungal organisms. The noted activity could be completely attributed to the Pd(II) center, whereas the ligands probably mediate the transportation of a Pd(II) species across cell membranes.

Mechanistic investigation of the base-promoted cycloselenoetherification of pent-4-en-1-ol.

The mechanism of phenylselenoetherification of pent-4-en-1-ol using some bases (pyridine, triethylamine, quinoline, 2,2'-bipyridine) as catalyst was examined through studies of kinetics of the cyclization, by UV-VIS spectrophotometry. It was demonstrated that the intramolecular cyclization is facilitated in the presence of bases caused by the hydrogen bond between base and alkenol's OH-group. The obtained values for rate constants have shown that the reaction with triethylamine is the fastest one. Quantum chemical calculations (MP2(fc)/6-311+G**//B3LYP/6-311+G**) show, that the transition state of the cyclisation is S(N)2 like.

Studies of interactions between platinum(II) complexes and some biologically relevant molecules.

The reactions of Pt(II) complexes, cis-[Pt(NH3)2Cl2], [Pt(terpy)Cl]+, [Pt(terpy)(S-cys)]2+, and [Pt(terpy)(N7-guo)]2+, where terpy=2,2':6',2''-terpyridine, S-cys=L-cysteine, and N7-guo=guanosine, with some biologically relevant ligands such as guanosine-5'-monophosphate (5'-GMP), L-cysteine, glutathione (GSH) and some strong sulfur-containing nucleophiles such as diethyldithiocarbamate (dedtc), thiosulfate (sts), and thiourea (tu), were studied in aqueous 0.1 M Hepes at pH of 7.4 using UV-vis, stopped-flow spectrophotometry, and 1H NMR spectroscopy.