Synthesis of new simplified hemiasterlin derivatives with α,β-unsaturated carbonyl moiety

In this Letter, we report a convenient and efficient method for the synthesis of new simplified derivatives of hemiasterlin in which the α,α-dimethylbenzylic moiety A is replaced by α,β-unsaturated aryl groups as Michael acceptor. Most of these derivatives have a strong cytotoxic activity on three human tumor cell lines (KB, Hep-G₂ and MCF₇). Analogs 17b and 17f showed a high cytotoxicity against KB and Hep-G₂ cancer cell lines comparable to paclitaxel and ellipticine.     

Enzymes catalysing conjugations of glutathione with αβ-unsaturated carbonyl compounds

1. Heat-inactivation experiments, ammonium sulphate-fractionation studies, enzyme-inhibition studies with S-(alphabeta-diethoxycarbonylethyl)glutathione, and evidence from the distribution of activities in rat liver, in rat kidney and in the livers of other animals, indicate that reactions of glutathione with (i) trans-benzylideneacetone, (ii) cyclohex-2-en-1-one, (iii) trans-cinnamaldehyde, (iv) diethyl maleate, (v) diethyl fumarate and (vi) 2,3-dimethyl-4-(2-methylenebutyryl)phenoxyacetic acid are catalysed by different enzymes. 2. Evidence is presented that the enzymes catalysing the reactions of glutathione with substrates (i)-(iv) are different from glutathione S-alkyltransferase, S-aryltransferase and S-epoxidetransferase. 3. The name ;glutathione S-alkenetransferases' is proposed for enzymes catalysing reactions of glutathione with alphabeta-unsaturated compounds. 4. The Arrenhius plot for the enzyme-catalysed reaction of diethyl maleate with glutathione is discontinuous, with lower energy of activation at 38 degrees .     

Synthesis and biological evaluation of α,β-unsaturated lactones as potent immunosuppressive agents

Compounds having α,β-unsaturated lactones display a variety of biological activities. Many research groups have tested both natural and unnatural α,β-unsaturated lactones for as-yet undiscovered biological properties. We synthesized α,β-unsaturated lactones with various substituents at the δ-position and studied their immunosuppressive effects, that is, the inhibition of Interleukin-2 (IL-2) production. Among the compounds synthesized, the benzofuran-substituted α,β-unsaturated lactone 4h showed the best inhibitory activity toward IL-2 production in Jurkat e6-1 T lymphocytes (IC(50)=66.9 nM) without cytotoxicity at 10 μM. The results indicated that 4h may be useful as a potent immunosuppressive agent, as well as in IL-2-related studies.     

Pharmacological evaluation and docking studies of α,β-unsaturated carbonyl based synthetic compounds as inhibitors of secretory phospholipase A2, cyclooxygenases,lipoxygenase and proinflammatory cytokines

Arachidonic acid and its metabolites have generated high level of interest among researchers due to their vital role in inflammation. The inhibition of enzymes involved in arachidonic acid metabolism has been considered as synergistic anti-inflammatory effect. A series of novel α,β-unsaturated carbonyl based compounds were synthesized and evaluated for their inhibitory activity on secretory phospholipase A₂ (sPLA₂), cyclooxygenases (COX), soybean lipoxygenase (LOX) in addition to proinflammatory cytokines comprising IL-6 and TNF-α. Six α,β-unsaturated carbonyl based compounds (2, 3, 4, 12, 13 and 14) exhibited strong inhibition of sPLA₂ activity, with IC₅₀ values in the range of 2.19–8.76 μM. Nine compounds 1–4 and 10–14 displayed inhibition of COX-1 with IC₅₀ values ranging from 0.37 to 1.77 μM (lower than that of reference compound), whereas compounds 2, 10, 13 and 14 strongly inhibited the COX-2. The compounds 10–14 exhibited strong inhibitory activity against LOX enzyme. All compounds were evaluated for the inhibitory activities against LPS-induced TNF-α and IL-6 release in the macrophages. On the basis of screening results, five active compounds 3, 4, 12, 13 and 14 were found strong inhibitors of TNF-α and IL-6 release in a dose-dependent manner. Molecular docking experiments were performed to clarify the molecular aspects of the observed COX and LOX inhibitory activities of the investigated compounds. Present findings increases the possibility that these α,β-unsaturated carbonyl based compounds might serve as beneficial starting point for the design and development of improved anti-inflammatory agents.     

Ethacrynic acid analogues lacking the α,β-unsaturated carbonyl unit—Potential anti-metastatic drugs

A series of ethacrynic acid analogues, lacking the α,β-unsaturated carbonyl unit, was synthesized and subsequently evaluated for their ability to inhibit the migration of human breast cancer cells, MCF-7/AZ. Several of the analogues were already active in the low micromolar range, whereas ethacrynic acid itself shows no potential to inhibit the migration of these cancer cells. Preliminary studies show that the presence of one or more methoxy groups at the phenyl ring of ethacrynic acid is important in order for the ethacrynic acid analogues to demonstrate an inhibitory effect on the migration.     

Reversible addition of thiols to steroid α,β-unsaturated carbonyl groups: Possible role in steroid-protein interactions

The equilibrium constant (M^?1) for addition of 2-mercaptoethanol at 25°C was found to be 7 × 10³ with 2-cyclohexenone, to be near 2 with 3-methyl-2-cyclohexenone, 19-norprogesterone, and 19-nortestosterone, and to be in the range of 0.01–0.03 with progesterone and testosterone. The results demonstrate that thiol addition to steroid α,β-unsaturated carbonyl groups is sufficiently favorable to be of potential importance in steroid-protein interactions.     

Synthesis,antimycobacterial and cytotoxic activity of α,β-unsaturated amides and 2,4-disubstituted oxazoline derivatives

The synthesis of six α,β,-unsaturated amides and six 2,4-disubstituted oxazolines derivatives and their evaluation against two Mycobacterium tuberculosis strains (sensitive H37Rv and a resistant clinical isolate) is reported. 2,4-Disubstituted oxazolines (S)-3b,d,e were the most active in the sensitive strain with a MIC of 14.2, 13.6 and 10.8 μM, respectively, and the compounds (S)-3d,f were the most active against resistant strain with a MIC of 6.8 and 7.4 μM. The ex-vivo evaluation of hepatotoxicity on precision-cut rat liver slices was also tested for the α,β-unsaturated amides (S)-2b and (S)-2d,f and for the oxazolines (S)-3b and (S)-3d,f at different concentrations (5, 15 and 30 μg/mL). The results indicate that these compounds possess promising antimycobacterial activity and at the same time are not hepatotoxic. These findings open the possibility for development of new drugs against tuberculosis.     

Mutagen production by chlorination of methylated α,β-unsaturated ketones

Mesityl oxide and isophorone, two β-methylated-α,β-unsaturated industrial solvent ketones, were found to be converted to mutagens by aqueous chlorination under conditions of pH and reactant concentration that may be relevant to waste water and drinking water chlorination. Chlorination of millimolar concentrations of isophorone generated mutagens at a pH as low as 8.5, while mutagens were formed from submillimolar concentrations of mesityl oxide at pH 8.5, or millimolar concentrations at pH 7.5. It is suggested that mutagen formation can occur via a haloform reaction at such low pH levels because of extended resonance stabilization of an intermediate carbanion.     

Synthesis of prebiotic molecules — Role of some carbonyl compounds in prebiotic chemistry

Methyleneaminoacetonitrile(MAAN) resulting from the interaction of formaldehyde, ammonia and hydrogen cyanide on hydrolysis under mildly alkaline conditions gives a number of amino acids and peptides. Various aldehydes react with glycine to give corresponding hydroxyalkyl amino acids, which on reduction with formic acid are converted to reduced amino acids. Formaldehyde reacts with uracil to give 5-hydroxymethyl uracil which on reduction with formic acid yields thymine. Pyrrole formed by heating serine reacts with aldehydes to form porphyrins. Clays do not seem to influence most of these reactions, except the uracil-formaldehyde — formic acid reaction which results in enhanced yield of thymine.     

Biological evaluation of synthetic α,β-unsaturated carbonyl based cyclohexanone derivatives as neuroprotective novel inhibitors of acetylcholinesterase,butyrylcholinesterase and amyloid-β aggregation

A series of new α,β-unsaturated carbonyl-based cyclohexanone derivatives was synthesized by simple condensation method and all compounds were characterized by using various spectroscopic techniques. New compounds were evaluated for their effects on acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). These compounds were also screened for in vitro cytotoxicity and for inhibitory activity for self-induced Aβ_1–42 aggregation. The effect of these compounds against amyloid β-induced cytotoxicity was also investigated. The findings of in vitro experiment revealed that most of these compounds exhibited potent inhibitory activity against AChE and self-induced Aβ_1–42 aggregation. The compound 3o exhibited best AChE (IC₅₀ = 0.037 μM) inhibitory potential. Furthermore, compound 3o disassembled the Aβ fibrils produced by self-induced Aβ aggregation by 76.6%. Compounds containing N-methyl-4-piperidone linker, showed high acetylcholinesterase and self-induced Aβ aggregation inhibitory activities as compared to reference drug donepezil. The pre-treatment of cells with synthetic compounds protected them against Aβ-induced cell death by up to 92%. Collectively, these findings suggest that some compounds from this series have potential to be promising multifunctional agents for AD treatment and our study suggest the cyclohexanone derivatives as promising new inhibitors for AChE and BuChE, potentially useful to treat neurodegenerative diseases.     

Inhibitory effects of ethacrynic acid analogues lacking the α,β-unsaturated carbonyl unit and para-acylated phenols on human cancer cells

A series of ethacrynic acid analogues, lacking the α,β-unsaturated carbonyl unit, was synthesized and subsequently evaluated for their ability to inhibit the migration of human breast cancer cells, Hs578Ts(i)8 as well as of human prostate cancer cells, C4-2B. These cell lines provide a good model system to study migration and invasion, since they represent metastatic cancer. Our studies show that ethacrynic acid analogues with methyl substituents at the aromatic ring demonstrate no inhibitory effect on the migration of both cancer cell lines, whereas a precursor in the synthesis of these ethacrynic acid analogues (II-1, a para-acylated m-cresol) is an excellent inhibitor of the migration of both cancer cell lines.     

Enhancement of mycobactericidal activity of glutaraldehyde with α,β-unsaturated and aromatic aldehydes

Summary Several ,-unsaturated and aromatic aldehydes were evaluated for antimicrobial activity usingMycobacterium bovis as the test strain. Activity of most of the compounds was determined in the presence and absence of 2% glutaraldehyde. Several compounds highly active against this organism, e.g. 2-pentenal, benzaldehyde, ando-phthalaldehyde showed rapid kill of >10⁵ CFU ml^–1 in 5 min. Activity of ,-unsaturated compounds substituted in the ₁ position showed increasing activity with increasing chain length. Of the aromatic aldehydes tested, benzaldehyde andp-dimethylamino benzaldehyde showed little activity alone, but when combined with 2% glutaraldehyde showed increased activity. Substituents added to the benzaldehyde ring (nitro, chloro, methyl, and methoxy) all detracted from the synergism, but still showed increased activity over the activity of 2% glutaraldehyde. The same affect was noted with disubstituted benzaldehyde compounds but not with substitutedo-phthaladehyde (2-formylformaldehyde).     

Reactivity of δ-substituted α,β-unsaturated cyclic lactones with antileishmanial activity

The present study examines a set of 43 compounds for their antileishmanial activities and cytotoxicities. Negative lowest unoccupied molecular orbitas and similar values for the electrophilic Fukui function condensed at the β-position for a subset of δ-substituted α,β-unsaturated cyclic lactones classify them as strong Michael acceptors. There was a well-defined trend of increasing antileishmanial activity with increasing cytotoxicity and large selectivity indices for the most active compounds. Softer compounds were more active than harder ones as observed from the experimental data and rationalised by calculated reactivity indices.     

Synthesis and in vitro evaluation of antimycobacterial and cytotoxic activity of new α,β-unsaturated amide,oxazoline and oxazole derivatives from l-serine

The synthesis of 19 compounds derived from l-serine and analogs of p-substituted cinnamic acid is reported. Oxazolines 9 and oxazoles 10 have high antitubercular activity with Minimum Inhibitory Concentration (MIC) of 0.7812–25.0 µg/mL (3.21–100.3 µM), against two strains of Mycobacterium tuberculosis sensitive to first-line drugs Isoniazid (INH), Rifampicin (RIF), Ethambutol (EMB), Pyrazinamide (PZE) (H37Rv) and a clinical isolate resistant to INH, RIF and EMB (G122). The cytotoxic evaluation shows that oxazoles have low activity, finding viability>96% against the VERO cell line. The results show these compounds could be considered as future alternatives for antitubercular treatment.     

Synthesis and initial evaluation of novel,non-peptidic antagonists of the αv-integrins αvβ3 and αvβ5

The discovery, synthesis and preliminary SAR of a novel class of non-peptidic antagonists of the α_v-integrins α_vβ₃ and α_vβ₅ is described. High-throughput screening of an extensive series of ECLiPS? compound libraries led to the identification of compound 1 as a dual inhibitor of the α_v-integrins α_vβ₃ and α_vβ₅. Optimization of compound 1 involving, in part, introduction of two novel constraints led to the discovery of compounds 15a and 15b with reduced PSA and much improved potency for both the α_vβ₃ and α_vβ₅ integrins. Compounds 15a and 15b were shown to have promising activity in functional cellular assays and compound 15a also exhibited a promising Caco-2 permeability profile.     

Synthesis,antitumor activity evaluation of some new N-aroyl-α,β-unsaturated piperidones with fluorescence

Novel N-aroyl-α,β-unsaturated piperidones, series 1, series 2 and series 3 (featuring 2-bromo-4,5-dimethoxybenzylidene, 4-dimethylaminobenzylidene and 4-trifluoromethylbenzylidene, respectively), were synthesized as candidate cytotoxins. Most of the compounds displayed potent cytotoxicity against the human neoplastic cell lines SK-BR-3, PG-BE1, NCI-H460, MIA PaCa-2 and SW1990 in vitro, and approximately 64% of the IC₅₀ values were lower than 5?μM. Among those tested, compound 1b of series 1, 3a, 3d and 3e of series 3 proved to be the most active. Importantly, 1b displayed marked inhibitory effects on tumor growth in vivo and had no apparent toxicity to mice; this was evaluated by a nude mouse PG-BE1 xenograft model. In addition, the fluorescent properties of compounds series 1–3 were investigated. The interesting fluorescence exhibited by these compounds could be useful for their visualization in tumor cells, permitting further studies on these α,β-unsaturated piperidones as candidates for novel fluorescent antitumor agents.     

Synthesis, characterization and cytotoxic activity of palladium (II) dithiocarbamate complexes with α,ω-diamines

The polymeric [PdCl(dithiocarbamate)]_n complexes, in which the ligand ion is dimethyldithiocarbamate (DMDT), pyrrolidine dithiocarbamate (PyDT, (CH₂)₄NCS₂⁻) and sarcosine ethyl ester dithiocarbamate (ESDT, EtO₂CCH₂N(CH₃)CS₂⁻), have been reacted with chelating diamines, like ethylenediamine (en) or 1,3-diaminopropane (dap) and long chain diamines, like 1,4-diaminobutane (dab) or 1,7-diaminoheptane (dah). The reaction products depend on either diamine chain length or molar ratio. By operating at PdCl(dithiocarbamate)/diamine molar ratio 1:1 chelating diamines yielded the ionic [Pd(dithiocarbamate)(diamine)]Cl species (diamine = en or dap), whereas with long chain diamines species of the type [Pd(dithiocarbamate)(diamine)]_nCl_n (diamine = dab or dah) were obtained, in which each Pd(dithiocarbamate)⁺ unit binds to the NH₂ group of two different molecules, in a network of bridging diamines. At molar ratio 1:0.5, the long chain diamines yielded the binuclear [Pd₂Cl₂(dithiocarbamate)₂(diamine)] complexes (diamine = dab or dah), whereas exchange reactions take place generally in the presence of en or dap. The reaction trend is described on the basis of IR and proton NMR spectra. The new dithiocarbamate complexes were preliminarily tested for their cytotoxicity on human cancer cells.     

Synthesis and evaluation of novel α-heteroaryl-phenylpropanoic acid derivatives as PPARα/γ dual agonists

The synthesis of a new series of phenylpropanoic acid derivatives incorporating an heteroaryl group at the α-position and their evaluation for binding and activation of PPARα and PPARγ are presented in this report. Among the new compounds, (S)-3-{4-[3-(5-methyl-2-phenyl-oxazol-4-yl)-propyl]-phenyl}-2-1,2,3-triazol-2-yl-propionic acid (17j), was identified as a potent human PPARα/γ dual agonist (EC₅₀ = 0.013 and 0.061 μM, respectively) with demonstrated oral bioavailability in rat and dog. 17j was shown to decrease insulin levels, plasma glucose, and triglycerides in the ZDF female rat model. In the human apolipoprotein A-1/CETP transgenic mouse model 17j produced increases in hApoA1 and HDL-C and decreases in plasma triglycerides. The increased potency for binding and activation of both PPAR subtypes observed with 17j when compared to previous analogs in this series was explained based on results derived from crystallographic and modeling studies.