Synthesis of diosgenin prodrugs: anti-inflammatory and antiproliferative activity evaluation

Purpose : This study aimed to evaluate the possible cytotoxic activity of the essential oil of the Eugenia uniflora leaves on normal and tumoral human cells by colorimetric cell viability assay, based on the use of tetrazolium salt (XTT). Methods : To achieve the cytotoxicity it was used normal human lung fibroblast cell line GMO7492A and the evaluation of antiproliferative activity was performed on three tumor cell lines, as follows: human glioblastoma (MO59J), human cervical adenocarcinoma (HeLa) and human breast adenocarcinoma (MCF-7). For the determination of cytotoxic concentration to the normal line, 12 concentrations were evaluated being from 2.44 to 5000 µg/mL. In the evaluation of antiproliferative activity were tested 8 different concentrations of the extract (3.91 to 500 µg/mL). Results : The results in the normal line GM07492A showed that concentrations higher or equal to 39.1 µg/mL are significantly different of the negative control. In the evaluation of antiproliferative activity on tumor cell lines MO59J, HeLa and MCF-7 was observed that the concentration of 125 µg/mL showed a cytotoxic effect on these lines being significantly different from the negative control. The results from the evaluation of the antiproliferative activity in different tumor cell lines of E. uniflora oil was not selective for the tested cell types. Conclusion : E. uniflora oil did not show cytotoxic activity in concentrations lower than 39.1 µg/mL, however, the values found to IC 50 for tumor cells were superior, concluding that the oil has no selectivity for tumor cells tested.

Copper(I) is able to catalyze Huisgen 1,3-dipolar cycloaddition in a "click" fashion. This copper-catalyzed azide-alkyne cycloaddition (CuAAC) reaction presents excellent chemoselectivity and occurs over a wide-range of reaction conditions. It shows tolerance to variation in both pH and solvent polarity, thereby facilitating the ligation of peptides and proteins to produce peptidomimetics and synthetic proteins. In addition, the only product formed is a 1,4-disubstituted-1,2,3-triazole moiety, in many aspects resembling the natural peptide bond, including hydrogen-bonding capability, planarity, distance between the 1 and 4 substituents, and conformational restriction of the peptide backbone; thus the triazole-backbone-modified peptide, in which a triazole replaces the amide bond, may be anticipated to present a secondary structure similar to that of its natural counterpart. This Focus Review describes the scope and applications of copper(I)-catalyzed alkyne–azide cycloaddition in synthetic peptide/protein chemistry.

Despite advances for cancer treatment, it still remains a major worldwide public health problem. Compounds derived from natural sources are important alternatives to combat this mortal disease. Berberine is an isoquinoline alkaloid with a wide variety of pharmacological properties, including antiproliferative activity. Previously, we have found that fatty acids also show antiproliferative activity against cancer cell lines.. To combine berberine and fatty acids, or carboxylic acids, in order to improve their antiproliferative properties. We synthetized six new hybrid derivatives through a simple methylenedioxy group-cleavage method followed by the reaction with fatty acids, or carboxylic acids. The structure of the compounds was elucidated by IR, NMR and HRMS. The in vitro antiproliferative activity against four human cancer cell lines (HeLa, A-549, PC-3 and LS-180) and one normal cell line (ARPE-19), was evaluated by the MTT method. Chemical structures were drawn using SPARTAN '08 software and the conformational analysis was carried out with a molecular mechanic level of theory and the SYBIL force field. All molecular structures were subjected to geometrical optimization at the semi-empirical method PM3. Molecular descriptors were calculated using DRAGON 5.4 and SPARTAN ´08 programs. The geranic acid and berberine hybrid compound (6) improved the antiproliferative activity shown by natural berberine, even more than the 16- to 18-carbon atoms fatty acids. Compound 6 showed IC50 values of 2.40 ± 0.60, 1.5 ± 0.24, 5.85 ± 1.07 and 5.44 ± 0.24 μM, against HeLa, A-549, PC-3 and LS-180 human cancer cell lines, respectively. Using this information, we performed a quantitative structure-activity relationship (QSAR) of the hybrid molecules and found that the molecular descriptors associated with the antiproliferative activity are: hydrophobic constant associated with substituents (π(A) = 6.5), molecular volume descriptor (CPKvolume≈ 700 Å3), EHOMO, number of rotatable bonds (RBN) and number of 6-membered rings (nR06). The methylendioxy and methoxyl groups in berberine are important for the antiproliferative activity shown by its derivatives. Better results in antiproliferative activity were obtained in compound 6 with the prenyl moiety. The QSAR indicates that the molecular descriptors which associated positively with the antiproliferative activity are: hydrophobic constant associated with substituents (π(A) = 6.5), molecular volume descriptor (CPKvolume≈ 700 Å3) and EHOMO. This research gave the basis for the design and preparation of new, easily afforded molecules derived from berberine and carboxylic acids, with improved antiproliferative activity.

Bromomethylbenzoates are suitable initiators for the polymerization of 2-oxazolines. They provide high end-group fidelity and enable access to heterotelechelic polyoxazolines and block copolymers with methyl ester or carboxylic acid end groups.

Literature data show that butyric acid derivatives bear a dose-dependent differentiative anti-proliferative activity on cancer cell lines and that apoptosis induction may play a major role. Although it was recently shown that solid lipid nanospheres (SLNs) are a suitable tool for several in vivo drug administration routes, there is little available information on melanoma cell lines. This study was aimed at evaluating the anti-proliferative and apoptotic in vitro effects of cholesteryl butyrate (chol-but) SLNs on melanoma cells. Increasing concentrations of chol-but SLNs were used to test two melanoma cell lines. Both cell lines were treated with Na-butyrate (Na-but) and chol-but SLNs for viability. Those tested with chol-but SLNs were more effective than Na-butirate (3 to 72 h). The apoptotic effects of chol-but SLNs were evaluated between 3 and 72 h by annexin-V (ANX-V)/propidium iodide (PI) staining and the antiproliferative effect by PI staining. Apoptosis anti-proliferative-regulatory proteins as bcl-2, Fas/APO1 (CD95) and PCNA (PC10) were also investigated. Flow cytometric analyses evidenced a G(0/1)-S transition block and a 'sub-G(0/1)' apoptotic peak from 0.5 to 1.0 mM butyric acid. In ANX-V/PI flow cytometric staining, a dose- and time-dependent increase in the apoptotic cell percentage (ANX-V+) coupled with a down-regulation of PC10 and bcl-2 and a parallel up-regulation of Fas/APO1 (CD95) were found in both lines started after 3 to 24 h of chol-but SLNs treatment. Results show that chol-but SLNs exerts a dose/time-dependent effect in melanoma cell apoptosis induction between 3 and 24 h and a dose but not time-dependent effect after 24 h of treatment.

PAMAM dendron-grafted poly(vinyl alcohol) via click reaction

The therapeutic potential of the somatostatin analogue RC-160 having antiproliferative activity, is limited by its short serum half life. To overcome this limitation, fatty acids namely butanoic acid and myristic acid were conjugated to the N-terminal residue of RC-160. The lipophilized derivatives of RC-160 were synthesized, purified by reverse phase HPLC and characterized by ES-mass spectroscopy. The antiproliferative activity of lipophilized derivatives of RC-160 on the growth of MIA-PaCa2 (human pancreatic carcinoma), DU145 (human prostate carcinoma), ECV304 (human umbilical chord endothelioma), as well as their antiangiogenic activity was evaluated in vitro. The relative stability of myristoyl-RC-160 towards degradation by proteases and serum was also determined. Myristoyl-RC-160 exhibited significantly higher antiproliferative efficacy than RC-160, on the above cell lines (P<0.01). Receptor binding assays, demonstrated that the affinity of RC-160 towards somatostatin receptors remains unaltered by myristoylation. Unlike RC-160, the myristoylated derivative was found to have significantly greater resistance to protease and serum degradation (P<0.01). Myristoyl-RC-160 exhibited significantly greater antiproliferative activity on ECV304, than RC-160 (P<0.01). Myristoyl RC-160 could also inhibit capillary tube formation more efficiently than RC-160 in a dose dependent manner, suggesting that it possessed enhanced antiangiogenic activity in vitro (P<0.001). Lipophilization of RC-160 with long chain fatty acids like myristic acid endows it with improved antiproliferative and antiangiogenic activity, stability and therapeutic index. British Journal of Pharmacology (2000) 109, 101 - 109

Amorphous solid dispersions are widely used to enhance the oral bioavailability of poorly water-soluble drugs. Polymeric additives are commonly used to delay crystallization of the drug from the supersaturated solutions formed upon ASD dissolution by influencing the nucleation and growth of crystals. However, there is limited evidence regarding the mechanisms by which polymers stabilize supersaturated drug solutions. The current study used experiments and computational modeling to explore polymer-drug interactions in aqueous solutions. Nucleation induction times for supersaturated solutions of nine drugs in the presence of five newly synthesized cellulose-based polymers were evaluated. The polymers had carboxylic acids substituents with additional variations in the side-chain structure: (1) one with a single side chain and a carboxylic acid termination, (2) three with a branched side chain terminated with a carboxylic and an alcohol group (varying the cellulose linkage and the length of the hydrocarbon side chain), and (3) one with a branched side chain with two carboxylic acid end groups. The polymers with a short side chain and one carboxylic acid were effective, whereas the polymers with the two carboxylic acids or a long hydrocarbon chain were less effective. Atomic force microscopy experiments, evaluating polymer adsorption onto amorphous drug films, indicated that the effective polymers were uniformly spread across the surface. These results were supported by molecular dynamics simulations of a polymer chain in the presence of a drug aggregate in an aqueous environment, whereby the effective materials had a higher probability of establishing close contacts and more negative estimated free energies of interaction. The insights provided by this study provide approaches to design highly effective polymers to improve oral drug delivery.

Antiproliferative and apoptotic activities of sequence-specific histone acetyltransferase inhibitors

BackgroundWithout doubt, natural products have been, and still are, the cornerstone of the health care armamentarium. Of all natural sources, the marine environment is clearly the last great frontier for pharmaceutical and medical research.MethodsThis work progresses in the direction of identifying component(s) from the Mediterranean sponge, Spongia officinalis with pharmacological activities. In the present study we investigated the efficacy of methanol extract and its semi-purified fractions (F2, F3) from Spongia officinalis for their in vivo anti-inflammatory activity using the carrageenan-induced paw edema in rats and their in vitro antiproliferative effects by their potential cytotoxic activity using the MTT colorimetric method and clonogenic inhibition against three human cancer cell lines (A549, lung cell carcinoma, HCT15, colon cell carcinoma and MCF7, breast adenocarcinoma).ResultsThe fractions F2 and F3 showed interesting anti-inflammatory and antiproliferative activities in a dose dependent manner.ConclusionsThe present study indicates that the methanolic extrac and its fractions from Spongia officinalis are a significant source of compounds with the antiproliferative and anti-inflammatory activities, and this may be useful for developing potential chemopreventive substances.

Ethanol, the major component of biofuel mixture, has significantly lower heat capacity compared to that of longer-chain alcohols such as butanol. As a result, oligomerization of ethanol has gained much attention. A three-step process that includes transition metal catalyzed C-alkylation was proposed for alcohol oligomerization. This cycle includes: (I) alcohol oxidation to the corresponding carboxylic acid, (II) dimerization via carboxylic acid terminals, and (III) further reduction of the oligomer to form the saturated alcohol. In this context, TEMPO has been vastly utilized for the electrochemical oxidation of alcohols. This process suffers from shortcomings such as limited turnover frequency of the reagent and small conversion yield of the synthesis. There have been some reports on the application of semiconductor electrodes for oxidizing certain types of alcohols. This approach, however, has shown some pitfalls such as high oxidation overpotential, low reaction yield, and low stability of the working electrode.The goal of this research is to fabricate a novel photoanode for oxidizing alcohols to their corresponding carboxylic acids. In this work, we aimed at fabricating an architecture shown in Fig. 1. To prepare such an electrode, a 10 nm layer of Ti was first deposited over fused silica substrate via thermal deposition method. Then, TiO2 with thickness of 500-µm was deposited with application of sol-gel technique, and finally WO3 was loaded onto the TiO2 with application of controlled-potential pulse deposition. Our experimental results have shown that this electrode have great stability toward photoelectron corrosion and the yield of conversion is the function of the deposited tungsten oxide. Figure 1

Ethanol, the major component of biofuel mixture, has significantly lower heat capacity compared to that of longer-chain alcohols such as butanol. As a result, oligomerization of ethanol has gained much attention. This three-step process includes: (I) alcohol oxidation to the corresponding carboxylic acid, (II) dimerization via carboxylic acid terminals, and (III) further reduction of the oligomer to form the saturated alcohol.1 In this context, TEMPO has been vastly utilized for the electrochemical oxidation of alcohols, but this process suffers from shortcomings such as limited turnover frequency of the reagent and small conversion yield of the synthesis.2 There have been some reports on the application of semiconductor electrodes for oxidizing certain types of alcohols. This approach, however, has shown some pitfalls such as high oxidation overpotential, low reaction yield, and low stability of the working electrode.3 The goal of this research is to fabricate a novel photoanode for oxidizing alcohols to their corresponding carboxylic acids. In this work, we aimed at fabricating an ordered array of TiO2 nanopillars decorated with WO3 nanoparticles. To prepare such an electrode, silicon oxide nanospheres (SONS) were deposited onto a silicon wafer covered with a 5-nm layer of gold. Then, TiO2 was electrodeposited into the empty hexagonal spaces resulting from SONS forming a tight-packed structure. Subsequently, SONS were washed away and a layer of WO3 was electrodeposited. Our experimental results have shown a homogeneous deposition of the WO3 layer when 60-ms symmetrical pulse cycles of potential (-0.5 V vs. SCE) were applied for 50 min.

A series of pyrazolone compounds with different substitution patterns have been synthesized using microwave-assisted methods and evaluated their in vitro antiproliferative activity against human lung adenocarcinoma cell lines (A549 and NCI-H522). Among the tested compounds, the pyrazolone P7 exhibited high antiproliferative activity against both A549 and NCIH522 cancer cell lines while being 10 times less cytotoxic to non-cancerous cells. Moreover, our compounds P7 and P11 exhibited higher antiproliferative activity and selectivity against A549 and NCIH522 cells compared with the clinically approved drugs Afatinib and Gefitinib. The cell cycle analysis showed that the compound P7 and P11 arrests the cell cycle at G0/G1 phase, whereas the compounds P13 and P14 involved in G2/M phase arrest. The results from antiproliferative activity screening, cell cycle analysis, and kinase profiling indicate that the suitably substituted 1,3-diarylpyrazolones exhibit high antiproliferative activity against non-small cell lung cancer cells.

Development of bis(tridentate) ruthenium(II) complexes for various applications

The activity of three iron chelators, methyl [2'-(2-hydroxyphenyl)-2'-thiazoline-4'-carboxylate] (MTL); 2'-(2-hydroxyphenyl)-2'-thiazoline-4'-carboxylic acid (TFAL); and 2-hydroxyphenyl-imido-ethyl-ether (Imidate), regarding antiproliferative, cytocidal, and cell-cycle effects are reported and compared with hydroxyurea (HU). In vitro, against L1210 and P388 murine neoplasms, MTL and TFAL displayed substantially greater antiproliferative activity than HU, although Imidate displayed no appreciable activity. MTL also induced a statistically more complete G1/S cell-boundary block than did HU at equimolar concentrations (100 microM). The IC50 values produced by MTL and TFAL were low enough (less than or equal to 20 microM) to warrant further testing of these chelators as potential antineoplastic agents.