Cytotoxicity of the hinokitiol-related compounds, gamma-thujaplicin and beta-dolabrin

Gamma-thujaplicin and beta-dolabrin, the constituents of the wood of Thujopsis dolabrata Sieb. et Zucc. var. hondai showed strong in vitro cytotoxic effects against the human stomach cancer cell lines KATO-III and Ehrlich's ascites carcinoma. The cytotoxic effects of the two compounds against both tumor cell lines were clear when cell growth was measured by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method. Gamma-thujaplicin and beta-dolabrin at 0.32 microg/ml inhibited cell growth of human stomach cancer KATO-III by 85 and 67%, and Ehrlich's ascites carcinoma by 91 and 75%, respectively. There is no large difference in cytotoxicity between these compounds, but the activity of gamma-thujaplicin was slightly more potent than that of beta-dolabrin. On the other hand, hinokitiol acetate did not show a cytotoxic effect, suggesting that at least a part of the mechanism of the cytotoxic effect of hinokitiol-related compounds is due to metal chelation between the carbonyl group at C-1 and the hydroxyl group at C-2 in the tropolone skeleton of these molecules. The acute toxicities [50% lethal dose (LD50) value: intraperitoneal injection, Van der Waedem] of gamma-thujaplicin and beta-dolabrin in mice were 277 mg/kg and 232 mg/kg, respectively.     

Phytogrowth-Inhibitory activities of beta-dolabrin and gamma-thujaplicin, hinokitiol-related compounds and constituents of Thujopsis dolabrata Sieb. et Zucc. var hondai Makino

Beta-dolabrin and gamma-thujaplicin isolated from Thujopsis dolabrata Sieb. et Zucc. var hondai Makino, like hinokitiol, showed strong phytogrowth-inhibitory activities, and their growth-inhibitory activities were as high as that of sodium 2,4-dichlorophenoxyacetate used as a positive control. In particular, the phytogrowth-inhibitory activity of gamma-thujaplicin was strong and it completely inhibited the germination of this seed of Brassica campestris L. subsp. rapa Hook f. et Anders at the concentration of 30 ppm. Both compounds exhibited inhibitory activities on B. campestris L. subsp. rapa Hook f. et Anders and Sesamum indicum Linne, even at the low concentration of 10 ppm. At 7 d after treatment with beta-dolabrin and gamma-thujaplicin, the amount of chlorophyll in the cotyledons of B. campestris L. subsp. rapa Hook f. et Anders treated with both compounds was greatly decreased as compared with the control. The findings indicate that the phytogrowth-inhibitory action might be a common biological activity of hinokitiol-related compounds, suggesting that at least a part of their phytogrowth-inhibitory actions seems to be related to a decrease in chlorophyll content.     

Biological activity of 4-acetyltropolone,the minor component of Thujopsis dolabrata SIeb. et Zucc. hondai Mak

4-Acetyltropolone, a minor component of Thujopsis dolabrata SIEB. et Zucc. hondai MAKINO, showed antimicrobial activity against various microorganisms including wood-rotting fungi, a phytogrowth-inhibitory effect with chlorophyll biosynthesis inhibition, cytotoxic effect and inhibitory activity on metalloproteases. This compound had strong antifungal activity on Daedalea dickinsii IFO-4979 [minimum inhibitory concentration (MIC): 0.2 microg/ml] and Coriolus versicolor IFO-4940 (MIC: 0.39 microg/ml). Its cytotoxic effect at 20.0/microg/ml on human stomach cancer KATO-III and Ehrich's ascites carcinoma was stronger than those of podophyllotoxin, vincristine and vinblastine, the anticancer agents isolated from higher plants and used clinically. This compound also had potent antibacterial activity against Staphylococcus epidermidis IFO-12993, its MIC being 1.56 microg/ml. However, other biological activities of 4-acetyltropolone were lower than those of hinokitiol which is the main component of this plant, suggesting that the contribution of the acetyl group at C-4 to biological activity is smaller than that of the isopropyl group at that position. The acute toxicity of 4-acetyltropolone (LD50: 335.2 mg/kg) to mice was much lower than that of hinokitiol (LD50: 191 mg/kg).     

Antimicrobial activity and metalloprotease inhibition of hinokitiol-related compounds, the constituents of Thujopsis dolabrata S. and Z. hondai MAK.

Gamma-thujaplicin, beta-dolabrin and hinokitiol(beta-thujaplicin), hinokitiol-related compounds isolated from the wood of Thujopsis dolabrata S. and Z. hondai MAK have antimicrobial activity. In particular, strong antibacterial activity of hinokitiol and beta-dolabrin on Staphylococcus epidermidis IFO-12993 was found, with a minimum inhibitory concentration (MIC) of 0.2 microg/ml. This activity was higher than that of gentamicin, used as a positive control, and so the strong antibacterial activity of both compounds on this bacterium is of considerable interest. Of the three compounds, gamma-thujaplicin showed the strongest antifungal activity and its MIC was found to be around 1.5 microg/ml. The three compounds also inhibited metalloproteases. The inhibitory activity of hinokitiol on carboxypeptidase A was especially strong, its 50%-inhibitory concentration (IC50) being 2.76x10(-6) M. Considering that metalloproteases are involved in inflammation, the strong inhibitory activity of hinokitiol could be important. On the other hand, hinokitiol-acetate did not show any antimicrobial activity and metalloprotease inhibition, suggesting that at least part of the activity is due to metal chelation between the carbonyl group at C-1 and the hydroxyl group at C-2 in the tropolone skeleton.     

Biological activity of some aldose-containing compounds

Several aldose-containing compounds, including di-(β-D-glucopyranosyl)-bis-diphenylsilyl-2,2,4,4-tetraphenylcyclodisilazane, di-(β-D-glucopyranosyl)-bis-dimethylsily-2,2,4,4-tetramethylcyclodisilazane, 1-β-(2,3,4,6-tetra-O-acetyl)-D-glucopyranosyl-2-pyrrolidone, and-ε-caprolactam were synthesized and examined for biological activity. The synthesized compounds suppress the growth and development of phytopathogenic microbes. The influence of various fragments on the antibacterial activity of compounds is established. __________ Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 41, No. 3, pp. 1 4–15, March, 2007.     

Biological activity of 3-formylchromones and related compounds

Several 3-formylchromone derivatives were examined for their tumor cell-cytotoxic, anti-Helicobacter pylori, urease inhibitory and anti-HIV activity. Comparing their relative cytotoxicity against four human tumor cell lines and three normal human cells, tumor cell-specific cytotoxicity was detected in some 3-formylchromone derivatives. There was no clear-cut relationship between the cytotoxicity and the chemical structures of the compounds. 6,8-Dichloro-3-formylchromone (FC10) showed comparable anti-H. pylori activity with metronidazole and potent urease inhibition against jack bean urease. On the other hand, 6,8-dibromo-3-formylchromone (FC11) exhibited potent inhibitory activity against the urease, but had no anti-H. pylori activity. No chromones (FC1-16) exhibited anti-HIV activity.     

Biological activity of saponins and saponin-like compounds from starfish and brittle-stars

Twenty-four saponins and saponin-like compounds, isolated from starfish and brittle-stars, have been tested in four in vitro tests, based upon bacterial and cell tissue cultures. Saponin-like compounds from brittle-stars have previously not been tested for biological activity. In an antibacterial test based on an agar diffusion test, the Gram positive bacterium S. aureus was affected by the polyhydroxylated steroidal glycosides, polyhydroxylated sterols and disulfated sterols. However, none of the 21 compounds tested were active against the Gram negative bacterium E. coli. In a cytotoxicity test all 21 compounds tested influenced the cells at a concentration of 100 micrograms/ml, while the cells were unaffected at 1 microgram/ml. In an antitumor test, 16 compounds were tested on two lymphoma cell lines. Inhibition of cell growth, at a concentration of 5 ng/ml, was seen for three polyhydroxylated sterols, in one cell line. Weak activity was seen in an antiviral test at a concentration of 10 micrograms/ml.     

Biological activity of terpene compounds produced by biotechnological methods

Context Biotransformation systems are profitable tools for structural modification of bioactive natural compounds into valuable biologically active terpenoids.

Objective This study determines the biological effect of (R)-(+)-limonene and (?)-α-pinene, and their oxygenated derivatives, (a) perillyl alcohol and (S)-(+)- and (R)-(?)-carvone enantiomers and (b) linalool, trans-verbenol and verbenone, respectively, on human colon tumour cells and normal colonic epithelium.

Materials and methods Biotransformation procedures and in vitro cell culture tests were used in this work. Cells were incubated for 24?h with terpenes at concentrations of 5–500?μg/mL for NR, MTT, DPPH, and NO assays. IL-6 was determined by ELISA with/without 2?h pre-activation with 10?μg/mL LPS.

Results trans-Verbenol and perillyl alcohol, obtained via biotransformation, produced in vitro effect against tumour cells at lower concentrations (IC₅₀ value?=?77.8 and 98.8?μg/mL, respectively) than their monoterpene precursors, (R)-(+)-limonene (IC₅₀ value?=?171.4?μg/mL) and (?)-α-pinene (IC₅₀ value?=?206.3?μg/mL). They also showed lower cytotoxicity against normal cells (IC₅₀?>?500 and?>?200?μg/mL, respectively). (S)-(+)-Carvone was 59.4% and 27.1% more toxic to tumour and normal cells, respectively, than the (R)-(?)-enantiomer. (R)-(+)-limonene derivatives decreased IL-6 production from normal cells in media with or without LPS (30.2% and 13.9%, respectively), while (?)-α-pinene derivatives induced IL-6 (verbenone had the strongest effect, 60.2% and 29.1% above control, respectively). None of the terpenes had antioxidative activity below 500?μg/mL.

Discussion and conclusions Bioactivity against tumour cells decreased in the following order: alcohols?>?ketones?>?hydrocarbons. (R)-(+)-limonene, (?)-α-pinene, and their derivatives expressed diverse activity towards normal and tumour cells with noticeable enantiomeric differences.     

Biological activity and structure of antitumor compounds from Plantago media L

Tyrosine kinase inhibition and tumor growth inhibition activity of verbascoside and homoplantaginin are described. Both molecules proved to be equally significant inhibitors of isolated EGF-R tyrosine kinases, nevertheless their in vitro antiproliferative activity was variable in cellular assays. Their different inhibitory efficacies could be interpreted on the basis of conformational analysis and lipophilicity evaluation.     

4-甲基化头孢菌素类化合物的合成和生物活性

为了寻找具有较好抗菌活性的新型头孢菌素,设计并合成一系列2-位甲基化头孢菌素类化合物,经结构确证发现反应产物不是预期的2-位甲基取代的头孢菌素,而是新结构的4-位甲基化头孢烯类化合物.所合成的2个4-甲基化头孢烯类化合物的结构经核磁共振谱、质谱和元素分析确认,并采用抑菌试验测定了该二化合物,结果表明其可作为β-内酰胺酶抑制剂的先导物开展进一步研究.     

Biological investigation of phenyl benzoate,benzophenone, and xanthone compounds

In the present study, we evaluated the antitumor, anti-tyrosinase, anti-pancreatic lipase, antibacterial, antifungal, and anti-α‐glycosidase activities for all or a subset of 20 known compounds. They included 8 phenyl benzoates, 10 benzophenones, and 2 xanthones. Phenyl benzoate compounds 1–8 did not exhibit evident antitumor activity, which was consistent with existing theories. Compounds 16, 17, and 18 exhibited moderate anti-tyrosinase activity. In addition, compounds 11 and 18 exhibited moderate inhibitory activity against Candida albicans, and compound 20 exhibited stronger anti-α-glycosidase activity than quercetin, with an IC₅₀ of approximately 2.45 μM. These results demonstrated that compounds 11, 16–18, and 20 were promising leads for further structural modification.     

CD4 down-modulating compounds with potent anti-HIV activity

The use of HAART with double or triple drug combinations has significantly improved the survival of AIDS patients. However, the emergence of virus-drug resistance and both short- and long-term drug-related side effects are among the main reasons for continuing the development of new classes of effective anti-HIV drugs that target the replicative cycle at different sites. In recent years, tremendous progress has been made in understanding HIV-1 entry, a multistep process that comprises viral attachment, coreceptor interactions and fusion. The mechanistic insight gained from these studies has enabled the design of specific agents that can inhibit each step in the HIV entry process. The successful results from clinical trials with enfuvirtide (T-20), the first approved entry inhibitor, indicate that targeting of HIV entry will soon be an important component of antiretroviral therapy and further encourage the development of effective entry inhibitors. In this article the recent developments of therapeutic agents endowed with inhibitory properties against the binding of the HIV envelope glycoprotein gp120 to the CD4 receptor (e.g., PRO 542, BMS-378806, TNX-355, PRO 2000 and CV-N) are briefly outlined. Major focus is placed on the anti-HIV activity of cyclotriazadisulfonamides (CADA), a novel class of compounds with a unique mode of action by down-modulating the CD4 receptor in lymphocytic and monocytic cells.     

Biological activities of guanidine compounds

Background: The guanidine group defines chemical and physicochemical properties of many compounds of medical interest and guanidine-containing derivatives constitute a very important class of therapeutic agents suitable for the treatment of a wide spectrum of diseases. Objective: To review the most important pharmacological properties, mechanisms of action and therapeutic uses of simple guanidine derivatives, cyclic analogues of guanidines as well as peptides, peptidomimetics and peptoids incorporating arginine. Methods: The review presents both the recent patent literature and original papers dealing with guanidine derivatives that show interesting biological activity and emphasizes the newest developing drugs. Conclusion: Recent achievements in the synthesis of guanidine-containing molecules with diverse chemical, biochemical and pharmacological properties make them of great importance to the design and development of novel drugs acting at CNS, anti-inflammatory agents, inhibitors of Na⁺/H⁺ exchanger, inhibitors of NO synthase, antithrombotic, antidiabetic and chemotherapeutic agents as well as guanidinium-based transporters and vectors.     

Synthesis of new cyclitol compounds that influence the activity of phosphatidylinositol 4-kinase isoform, PI4K230

The synthesis, chemical derivatization, and investigation of the inhibitory properties of novel cyclitol derivatives on the phosphatidylinositol 4-kinase enzymes PI4K55 and PI4K230 involved in the phosphatidylinositol cycle are reported. Some of the prepared cyclitol derivatives (i.e. 9, 11, 12, and 14) proved to be very powerful and specific irreversible inhibitors of PI4K230 at or below a concentration of 1 mM.     

Radical generation, radical-scavenging activity, and cytotoxicity of eugenol-related compounds

To clarify the possible link between radicals and cytotoxicity of eugenol-related compounds, dimeric compounds were synthesized from eugenol (4-allyl-2-methoxy-phenol), butylated hydroxyanisole (BHA) (2-t-butyl-4-methoxyphenol) or MMP (2 methoxy-4-methylphenol); bis-EUG (3,3'-dimethoxy-5,5'-di-2-propenyl-1,1'-biphenyl-2,2'-diol), bis-BHA (3,3'-di-t-butyl-5,5'-dimethoxy-1,1'-biphenyl-2,2'-diol), and bis-MMP (3,3'-di-methoxy-5,5'-dimethyl-1,1'-biphenyl-2,2'-diol). The cytotoxic activity of these compounds was determined using a salivary gland tumor cell line (HSG), oral squamous cell carcinoma cell line (HSC-2) and human promyelocytic leukemia cell line (HL-60). A parabolic relationship between the cytotoxicity and log P (the octanol-water partition coefficient) was observed, showing that both BHA and bis-MMP, with a log P of 3-4, were the most cytotoxic. The cytotoxic activity of the 2-methoxy derivatives, eugenol, MMP and bis-MMP, against HSG cells was significantly enhanced by visible-light irradiation, possibly due to their high redox potential. Electron spin resonance (ESR) spectroscopy indicated that eugenol and BHA alone produced radicals under alkaline conditions (pH > 9.5), and eugenol most efficiently scavenges reactive oxygen species (O2-). Antioxidative reactivity of eugenol-related compounds was determined by measuring the inhibiting periods of the AIBN (2,2'-azobisisobutyronitrile)/MMA (methyl methacrylate) polymerization system, and the number of moles of peroxy radical trapped by moles of the relevant phenols (stoichiometric factor, n). It was found that the n values of eugenol and MMP were approximately 1, whereas those of BHA >2, suggesting that eugenol and MMP undergo dimerization through radical-radical couplings through quinone methides, whereas BHA undergoes the competitive interaction with poly-MMA radicals after oxidation by AIBN-peroxy radicals. BHA was an efficient peroxy radical-scavenger, but possibly reacted with polymer radicals of the lipid, thus mediating the cytotoxicity. The n value of bis-BHA was two, whereas those of bis-EUG and bis-MMP were 1.6-1.7, suggesting that the latter were further oxidized. The enthalpies of phenoxyl radical formation were determined using the semi-empirical PM3 quantum-mechanical method and the possible link to redox potential was discussed.