Antioxidant and antiproliferative activity of glycosides obtained by biotransformation of xanthohumol

The biotransformation of xanthohumol (1), a prenylated chalcone isolated from hops by selected fungi, was investigated. Microbial regioselective glycosylation at the C-4′ position led to xanthohumol 4′-O-β-d-glucopyranoside (2) and xanthohumol 4′-O-β-d-(4′′′-O-methyl)-glucopyranoside (3). The subsequent cyclization of 2 resulted in isoxanthohumol 7-O-β-glucopyranoside (4). The structures of the products were identified based on spectroscopic methods. The biological activity of isolated metabolites has been evaluated. Compared to xanthohumol (1), metabolite 2 is a better 2,2′-diphenyl-1-picrylhydrazyl (DPPH) radical scavenger, while 2 and 3 have stronger antiproliferative activity against the human HT-29 colon cancer cell line.     

Antioxidant and radical scavenging properties of curcumin

Curcumin (diferuoyl methane) is a phenolic compound and a major component of Curcuma longa L. In the present paper, we determined the antioxidant activity of curcumin by employing various in vitro antioxidant assays such as 1,1-diphenyl-2-picryl-hydrazyl free radical (DPPH*) scavenging, 2,2'-azino-bis(3-ethylbenzthiazoline-6-sulfonic acid) (ABTS) radical scavenging activity, N,N-dimethyl-p-phenylenediamine dihydrochloride (DMPD) radical scavenging activity, total antioxidant activity determination by ferric thiocyanate, total reducing ability determination by the Fe(3+)-Fe(2+) transformation method, superoxide anion radical scavenging by the riboflavin/methionine/illuminate system, hydrogen peroxide scavenging and ferrous ions (Fe(2+)) chelating activities. Curcumin inhibited 97.3% lipid peroxidation of linoleic acid emulsion at 15 microg/mL concentration (20 mM). On the other hand, butylated hydroxyanisole (BHA, 123 mM), butylated hydroxytoluene (BHT, 102 mM), alpha-tocopherol (51 mM) and trolox (90 mM) as standard antioxidants indicated inhibition of 95.4, 99.7, 84.6 and 95.6% on peroxidation of linoleic acid emulsion at 45 microg/mL concentration, respectively. In addition, curcumin had an effective DPPH* scavenging, ABTS*(+) scavenging, DMPD*(+) scavenging, superoxide anion radical scavenging, hydrogen peroxide scavenging, ferric ions (Fe(3+)) reducing power and ferrous ions (Fe(2+)) chelating activities. Also, BHA, BHT, alpha-tocopherol and trolox, were used as the reference antioxidant and radical scavenger compounds. According to the present study, curcumin can be used in the pharmacological and food industry because of these properties.     

Antituberculous activity of some aryl semicarbazone derivatives

During the course of our work on the synthesis and screening of new drugs for tuberculosis, we have identified N1-(4-acetamido phenyl)-N4-(2-nitro benzylidene) semicarbazone (1b), which inhibited in vitro Mycobacterium tuberculosis H(37)Rv; 100% inhibition at 1.56 microg/mL. This paper is first of its kind in which aryl semicarbazones are reported to possess antimycobacterials potency greater than p-aminosalicylic acid, ethionamide, ethambutol, ciprofloxacin and kanamycin.     

Antioxidant and antiproliferative activities of hydroxyl-substituted Schiff bases

Eight hydroxyl-substituted Schiff bases with the different number and position of hydroxyl group on the two asymmetric aromatic rings (A and B rings) were prepared by the reaction between the corresponding aromatic aldehyde and aniline. Their antioxidant effects against the stable galvinoxyl radical (GO) in ethyl acetate and methanol, and 2,2′-azobis(2-amidinopropane hydrochloride) (AAPH)-induced DNA strand breakage, and their antiproliferative effects on human hepatoma HepG2 cells, were investigated. Structure–activity relationship analysis demonstrates that o-dihydroxyl groups on the aromatic A ring and 4-hydroxyl group attached to the aromatic B ring contribute critically to the antioxidant and antiproliferative activities.     

Synthesis and antiproliferative activity of alkylphosphocholines

Alkylphosphocholines (APC) with one or more methylene groups in the alkyl chain replaced by oxygen atoms or carbonyl groups, or both have been assembled modularly using omega-diols as central building blocks. Out of 25 new compounds of this kind, 11 were evaluated for their antiproliferative activity on four cell lines and compared with miltefosine to evaluate their hemolytic activity (HA) and cytotoxicity on non-tumoral cells (MT2), used as markers of adverse effects. Compound 13 was more active on cancer cell lines than on non-tumoral cells and the data were similar for MTT and thymidine incorporation assays. It had less HA than miltefosine. Compound 13 could therefore be a candidate for the preparation of compounds with higher cytotoxicity on cancer cells and lower general toxicity.     

Synthesis and antiproliferative activity of retroetoposide

Retro-4'-demethyl-4-epipodophyllotoxin 6 was synthesized in eight steps and 10% overall yield from 4'-demethyl-4-epipodophyllotoxin 12. Subsequent coupling of 22 with 1-O-trimethylsilyl-4,6-O-ethylidene-beta-D-glucoside 26 afforded retroetoposide 5 which is 10-fold less cytotoxic than etoposide against L1210 cell line.     

Antioxidant activity,phytochemical composition of Andricus tomentosus and its antiproliferative effect on Mia-Paca2 cell line

Molecular Biology Reports - Plant derived products are widely used in cancer treatment. Gall species has been preferred for treatment various diseases in folk medicine, but there are few studies on...     

The antimicrobial activity of lapachol and its thiosemicarbazone and semicarbazone derivatives

Lapachol was chemically modified to obtain its thiosemicarbazone and semicarbazone derivatives. These compounds were tested for antimicrobial activity against several bacteria and fungi by the broth microdilution method. The thiosemicarbazone and semicarbazone derivatives of lapachol exhibited antimicrobial activity against the bacteria Enterococcus faecalis and Staphylococcus aureus with minimal inhibitory concentrations (MICs) of 0.05 and 0.10 µmol/mL, respectively. The thiosemicarbazone and semicarbazone derivatives were also active against the pathogenic yeast Cryptococcus gattii (MICs of 0.10 and 0.20 µmol/mL, respectively). In addition, the lapachol thiosemicarbazone derivative was active against 11 clinical isolates of Paracoccidioides brasiliensis, with MICs ranging from 0.01-0.10 µmol/mL. The lapachol-derived thiosemicarbazone was not cytotoxic to normal cells at the concentrations that were active against fungi and bacteria. We synthesised, for the first time, thiosemicarbazone and semicarbazone derivatives of lapachol. The MICs for the lapachol-derived thiosemicarbazone against S. aureus, E. faecalis, C. gattii and several isolates of P. brasiliensis indicated that this compound has the potential to be developed into novel drugs to treat infections caused these microbes.     

Antioxidant,antiproliferative, and apoptotic activity of thymoquinone against benzo(a)pyrene-induced experimental lung cancer

Several studies have suggested that increased consumption of phytochemicals is a comparatively easy and practical strategy to significantly decrease the incidence of cancer. In the present study, we have reported the protective effect of a natural compound, thymoquinone (TQ) against benzo(a)pyrene (B(a)P)-induced lung carcinogenesis in Swiss albino mice. B(a)P (50 mg/kg body weight) was administered twice weekly for four successive weeks and left until 20 weeks to induce lung cancer in mice. TQ (20 mg/kg body weight) was given orally as a pretreatment and posttreatment drug to determine its chemopreventive and therapeutic effects. B(a)P-induced lung cancer-bearing animals displayed cachexia-like symptoms along with an abnormal increase in lung weight and the activities of marker enzymes adenosine deaminase, aryl hydrocarbon hydroxylase, gamma-glutamyl transpeptidase, 5′-nucleotidase and lactate dehydrogenase; tumor marker carcinoembryonic antigen levels. Furthermore, B(a)P-induced animals showed elevated levels of lipid peroxides with subsequent depletion in the antioxidant status and histological aberrations. These anomalies were accompanied by increased expressions of proliferating cell nuclear antigen and cyclin D1 in the lung sections derived from B(a)P-induced animals. On TQ treatment, all the above alterations were returned to near normalcy. Furthermore, TQ administration in B(a)P-induced animals downregulated phosphatidylinositol 3-kinase/protein kinase B signaling pathway and induced apoptosis as evidenced by a decrease in cytochrome c, proapoptotic Bax, caspase-3, and p53 with a parallel increase in antiapoptotic Bcl-2. Our present results demonstrate the potential effectiveness of TQ as an antioxidant, antiproliferative, and apoptotic agent against B(a)P-induced experimental lung tumorigenesis.     

Antioxidant properties of dehydrozingerone and curcumin in rat brain homogenates

The present study investigates the inhibition of lipid peroxidation by dehydrozingerone and curcumin in rat brain homogenates. Both the test compounds inhibited the formation of conjugated dienes and spontaneous lipid peroxidation. These compounds also inhibited lipid peroxidation induced by ferrous ions, ferric-ascorbate and ferric-ADP-ascorbate. In all these cases, curcumin was more active than dehydrozingerone and dl--tocopherol.     

Optimized synthesis and antiproliferative activity of desTHPdactylolides

Dactylolide and certain analogues are attractive targets for study due to their structural resemblance to zampanolide, a very promising anticancer lead compound and a unique covalent-binding microtubule stabilizing agent. The primary goal of this project is identification and synthesis of simplified analogues of dactylolide that would be easier to prepare and could be investigated for antiproliferative activity in comparison with zampanolide. Extension of Almann’s concept of a simplified zampanolide analogue to dactylolide in the form of desTHPdactylolide was attractive not only for reasons of synthetic simplification but also for the prospect that analogues of dactylolide could be prepared in both (17S) and (17R) configurations. Since Altmann’s overall yield for the six-step procedure leading to the C9–C18 fragment of desTHPdactylolide was only 8.7%, a study focused on optimized synthesis and antiproliferative evaluation of each enantiomer of desTHPdactylolide was initiated using Altmann’s route as a framework. To this end, two optimized approaches to this fragment C9–C18 were successfully developed by us using allyl iodide or allyl tosylate as the starting material for a critical Williamson ether synthesis. Both (17S) and (17R) desTHPdactylolides were readily synthesized in our laboratory using optimized methods in yields of 37–43%. Antiproliferative activity of the pair of enantiomeric desTHPdactylolides, together with their analogues, was evaluated in three docetaxel-sensitive and two docetaxel-resistant prostate cancer cell models using a WST-1 cell proliferation assay. Surprisingly, (17R) desTHPdactylolide was identified as the eutomer in the prostate cancer cell models. It was found that (17S) and (17R) desTHPdactylolide exhibit equivalent antiproliferative potency towards both docetaxel-sensitive (PC-3 and DU145) and docetaxel-resistant prostate cancer cell lines (PC-3/DTX and DU145/DTX).     

Anticancer and antiproliferative activity of natural brassinosteroids

Brassinosteroids (BRs) are steroid plant hormones that are essential for many plant growth and developmental processes, including cell expansion, vascular differentiation and stress responses. Up to now the inhibitory effects of BRs on cell division of mammalian cells are unknown. To determine basic anticancer structure-activity relationships of natural BRs on human cells, several normal and cancer cell lines have been used. Several of the tested BRs were found to have high cytotoxic activity. Therefore, in our next series of experiments, we tested the effects of the most promising and readily available BR analogues with interesting anticancer properties, 28-homocastasterone (1) and 24-epibrassinolide (2), on the viability, proliferation, and cycling of hormone-sensitive/insensitive (MCF-7/MDA-MB-468) breast and (LNCaP/DU-145) prostate cancer cell lines to determine whether the discovered cytotoxic activity of BRs could be, at least partially, related to brassinosteroid-nuclear receptor interactions. Both BRs inhibited cell growth in a dose-dependent manner in the cancer cell lines. Flow cytometry analysis showed that BR treatment arrested MCF-7, MDA-MB-468 and LNCaP cells in G(1) phase of the cell cycle and induced apoptosis in MDA-MB-468, LNCaP, and slightly in the DU-145 cells. Our results provide the first evidence that natural BRs can inhibit the growth, at micromolar concentrations, of several human cancer cell lines without affecting the growth of normal cells. Therefore, these plant hormones are promising leads for potential anticancer drugs.     

Synthesis and antiproliferative activity of some steroidal lactams

Using cholesterol as starting material, a series of 6-substituted-3-aza-A-homo-3-oxycholestanes and 6-substituted-4-aza-A-homo-3-oxycholestanes were synthesized by the oxidation, reduction, oximation, Beckman rearrangement and condensation reaction. These synthesized compounds displayed a distinct cytotoxicity against MGC 7901, HeLa and SMMC 7404 cancer cells. Our results revealed that the structures of functional groups at position-6 on the steroidal ring are crucial for the IC₅₀ value of antiproliferative activities of these compounds and the cytotoxic activity against MGC 7901 and SMMC 7404 cells was not significantly different between 4-N-lactams and 3-N-lactams when its 6-substituted group was a carbonyl or a hydroximino, but all 3-N-lactams showed a higher cytotoxicity against HeLa cells than 4-N-lactams. In particular, compounds 6, 8, 9 (IC₅₀6: 6.5 μmol/L; 8: 7.7 μmol/L; 9: 5.6 μmol/L) were even more cytotoxic than cisplatin to HeLa cells (positive contrast, 10.1 μmol/L). The information obtained from the studies may be useful for the design of novel chemotherapeutic drugs.     

Antibacterial and antiproliferative activity of cationic fullerene derivatives

We examined the antibacterial and antiproliferative activities of alkylated C₆₀-bis(N,N-dimethylpyrrolidinium iodide) derivatives. The fullerene derivatives inhibited bacteria and cancer cell growth effectively. However, the fullerene derivatives with a long alkyl chain did not show antibacterial activity.     

Synthesis and antiproliferative activity of threo-5-fluoro-L-dihydroorotate

Fluorinated compounds play an important role in enzymology as well as clinical medicine. Based on the stereochemical preferences of dihydroorotate oxidase and enzymes that use fluoroaspartate, it was anticipated that threo-5-fluoro-L-dihydroorotate (t-FDHO) would have the properties of an antimetabolite. Thus, t-FDHO was synthesized via the reduction of 5-fluoroorotate using NADH and dihydroorotate dehydrogenase that was free of dihydroorotase. When the product was purified and studied by high field proton and carbon 13 NMR, the fluorine, the five carbons, and all the nonexchangeable protons were readily observed. Confirmation of threo configuration was obtained by examining the vicinal coupling constants between the substituents on carbon 5 and carbon 6 of the newly synthesized compound. Additionally, t-FDHO could be reoxidized to 5-fluoroorotate in the presence of dihydroorotate dehydrogenase and NAD+. Treatment of t-FDHO with dihydroorotase generated N-carbamyl-threo-3-fluoro-L-aspartate (CTF-ASP) which was also purified and characterized by NMR. The antiproliferative activity of t-FDHO was determined against a diploid human fibrosarcoma cell line (HT-1080). Fifty microM t-FDHO caused 50% inhibition of HT-1080 cell proliferation. During the 48-h toxicity study, extracellular t-FDHO underwent significant hydrolysis to CTF-ASP. Further extracellular degradation to fluoroaspartate was not seen. The antiproliferative activity of t-FDHO was not due to extracellular degradation since CTF-ASP itself was essentially nontoxic.     

Lipophilicity and antiproliferative activity profiling of 2-benzylidencycloalkanones

High performance liquid chromatographic (HPLC) method has been developed to separate the members of a library including 24 benzylidenecycloalkanone-type structures and to characterize their lipophilicity. The experimental lipophilicity data (k) of the compounds have been compared with their calculated lipophilicity parameters (CLOGP). In general, good correlations between the measured and calculated lipophilicities have been found and these results were in good accordance with our previously data obtained in case of structurally related molecular libraries. In addition, cytotoxicity screening has been performed to determine the antiproliferative activity of these compounds. Some of the investigated compounds possessed noticeable inhibitory potential. Based on the correlation between the antiproliferative activity and experimentally determined lipophilicity of the molecules investigated, limited structural demands to obtain more potent compounds can be exhibited to support the synthetic design.     

Synthesis and antiproliferative activity of some diaryldiazepines and diarylpyrimidines

Novel substituted 5,7-diaryl-2,3-dihydro-1,4-diazepines and 4,6-diaryl-2-aminopyrimidines were synthesized and tested for their antiproliferative activity. Title compounds were obtained by cyclocondensation of a substituted flavone with ethylenediamine and guanidine respectively. The cytotoxicity in vitro against various human leukemic cancer cell lines viz., Jurkat, HL60, MOLT3, NCEB-1, K562 was determined.     

Synthesis and antiproliferative activity of some diaryldiazepines and diarylpyrimidines

Novel substituted 5,7-diaryl-2,3-dihydro-1,4-diazepines and 4,6-diaryl-2-aminopyrimidines were synthesized and tested for their antiproliferative activity. Title compounds were obtained by cyclocondensation of a substituted flavone with ethylenediamine and guanidine respectively. The cytotoxicity in vitro against various human leukemic cancer cell lines viz., Jurkat, HL60, MOLT3, NCEB-1, K562 was determined.     

Cysteinyl-flavan-3-ol conjugates from grape procyanidins. Antioxidant and antiproliferative properties

New bio-based antioxidant compounds have been obtained by depolymerisation of grape polymeric flavanols in the presence of cysteine. Their preparation and purification, as well as their antiradical/antioxidant and antiproliferative properties are reported. 4beta-(S-cysteinyl)epicatechin 5, 4beta-(S-cysteinyl)catechin 6 and 4beta-(S-cysteinyl)epicatechin 3-O-gallate 7 were efficiently purified from the crude depolymerised mixture by cation-exchange chromatography and preparative reversed-phase chromatography. The new compounds were more efficient than the underivatised (-)-epicatechin 1 as scavengers of the 1,1-diphenyl-2-picrylhydrazyl free radical (DPPH) and weak growth inhibitors of human colon carcinoma HT29 cells. The order of antiradical and antiproliferative efficiency was 7 >5 approximately 6 >1, the same for both assays.