Structure-activity relationship of trans-resveratrol and its analogues.

Cancer is one of the main causes of death in both men and women, claiming over 6 million people each year worldwide. Chemoprevention in combination with anti-cancer treatment is therefore important to reduce morbidity and mortality. Stilbene-based compounds have over the years attracted attention of many researchers due to their wide ranging biological activities. One of the most relevant and extensively studied stilbenes is trans-resveratrol, a phytoalexin present in grapes and other foods. One of the most striking biological activities of trans-resveratrol soundly investigated during recent years has been its cancer-chemopreventive potential. It has been found that the biological activity of trans-resveratrol and its analogues depends significantly on the structural determinants, which are (i) number and position of hydroxyl groups, (ii) intramolecular hydrogen bonding, (iii) stereoisomery and (iv) double bond. The observation that trans-stilbene compounds having 4 -hydroxy group, double bond and bearing ortho-diphenoxyl or para-diphenoxyl functionalities possess remarkably higher chemopreventive activity than trans-resveratrol gives us useful information for further chemopreventive drug design.

Improved synthesis, antibacterial activity and potential carcinogenicity of 5-amino-1 ,2,4-thiadiazol-3(2H)-one.

This paper reports on the preparation of 5-amino-1,2,4-thiadiazol-3(2H)-one, a sulfur-containing analogue of cytosine with the -CH=CH- group between the positions 5 and 6 of the pyrimidine ring replaced by the divalent sulfur (-S-). Improved procedures for the preparation of thiobiuret, some of its methyl derivatives and 5-amino-1,2,4-thiadiazol-3(2H)-one are documented. Thiobiuret and its N-methyl derivatives were obtained by addition of hydrogen sulfide to the respective 1-cyanoureas. Subsequent oxidation of thiobiuret with hydrogen peroxide in alkaline medium produced 5-amino-1,2,4-thiadiazol-3(2H)-one. This substance was traced back converted to the starting thiobiuret by reaction with cysteine hydrochloride. Alkaline degradation of thiadiazol led to the formation of 1-cyanourea isolated as its silver salt. An investigation of the thiadiazol biological activities has shown that it inhibits the growth of E. coil by 10% at 8.5 microM concentrations, but exhibited no cytostatic activity in L1210, HeLa S3 and HL-60 cell lines. Potential carcinogenicity of the prepared compounds was determined by a DC polarographic method. While the values of the parameter of carcinogenicity for all intermediates indicate only marginal carcinogenic potential, the value of the parameter of carcinogenicity for the thiadiazole indicates possible carcinogenicity of this compound.

Pentacyclic triterpenoic acids: new chemoprotective compounds. Minireview.

Ursolic acid and oleanolic acid are pentacyclic triterpenoic acids having a similar chemical structure and are the major components of some oriental and traditional medicine herbs wildly distributed all over the world. There is a growing interest in the elucidation of the biological roles of both these triterpenoid compounds. This review summarizes the biological activities of presented triterpenoid acids (anti-inflammatory, hepatoprotective, gastroprotective, anti-ulcer, anti-HIV, cardiovascular, hypolipidemic, antiatherosclerotic and immunoregulatory effects). Our interest has been focussed especially on their anti-tumor and chemopreventive activity. Both compounds have been shown to act at various stages of tumor development, including inhibition of tumorigenesis, inhibition of tumor promotion, and induction of tumor cell differentiation. They effectively inhibit angiogenesis, invasion of tumor cells and metastasis. However, the mechanisms by which they act are poorly understood. Ursolic acid and oleanolic acid are relatively non-toxic and could be use as chemopreventive/chemoprotective agents in clinical praxis.

Taraxasterol and beta-sitosterol: new naturally compounds with chemoprotective/chemopreventive effects.

Substantial attention has been given to primary cancer prevention in daily life. Dietary factors are through to contribute to as much as one-third of the factors influencing the development of cancer. Ones of the components of a plant-based diet are beta-sitosterol and taraxasterol, compounds attracting our specific attention. This review summarizes the biological activities of presented phytosterols (anti-inflammatory, cholesterol-lowering, anti-microbial, anti-bacterial, anti-fungal effects). Our interest has been focussed especially on their anti-tumor and chemopreventive activity. They have been shown experimentally to inhibit colon and breast cancer development. They act at various stages of tumor development, including inhibition of tumorigenesis, inhibition of tumor promotion, and induction of cell differentiation. They effectively inhibit invasion of tumor cells and metastasis. With regard to toxicity, no obvious side effects of phytosterols have been observed in studies to date, with the exception of individuals with phytosterolemia. The exact mechanism by which dietary phytosterols act is not fully understood. However, some mechanisms have been offered. Therefore, they have a bright future in clinical application. Further investigation to explore their potential in tumor treatment may prove to be worthwhile.

Physico-chemical properties and spectrophotometric determination of biologically active 1-alkyl-2-(2-pyridyl)pyridinium bromides.

Physico-chemical properties of compounds prepared from 2,2'-bipyridine, 1-alkyl-2-(2-pyridyl)pyridinium bromides, were investigated by DC polarography and by GC-MS. Their ionization potentials were calculated. Additionally, the formation of associates with bromothymol blue and methyl orange during the spectrophotometric determination was measured. It was determined that 1-alkyl-2-(2-pyridyl)pyridinium ions are reduced by 2 one-electron steps in a DC polarography system. The reduction potentials are not related to the ionization potential values calculated for the substances investigated. The carcinogenic potential (tg alpha) of the parent compound 2,2'-bipyridine and of a series of 1-alkyl derivatives was very low indicating that the compounds are not carcinogenic. The MS fragmentation patterns indicate the low stability of the 1-alkyl substituents. It was shown that 2,2'-bipyridine is either fragmented to two pyridine ions or the--N=CH--fragments are removed. Additionally, spectrophotometric determinations of colored associates of 1-alkyl-2-(2-pyridyl)pyridinium bromides with bromothymol blue and methyl orange were investigated and the optimal condiditions for these determinations are reported.

Rapid HPLC analysis of melphalan applied to hyperthermic isolation limb perfusion.

Hyperthermic isolated limb perfusion (HILP) with melphalan (MH) as a standard cytotoxic drug has been performed in 28 patients suffering from malignant melanoma. MH has been administered by HILP via extracorporeal circulation system. The drug given locoregionally reduces subsequent toxicity of organs. For all that residues can leak into the systemic circulation during HILP. Because of known carcinogenic potential and secondary cancer formation, the main interest of this work is to determine MH concentration profile in the patient plasma during and after HILP and evaluation of its potential toxicity in patients. Reversed-phase HPLC assay, which uses isocratic elution and fluorimetric detection has been shown to be sensitive, reliable and suitable for routine analyses. The assay was validated for the concentration range of 50-2500 ng.ml-1 with the limit of detection (LOD) 6.881 ng.ml-1. The samples were treated by methanol precipitation with the recovery more than 80%. The stability of standard solutions and methanolic extracts of MH were also followed. The concentration profile of MH in patient samples has been pursued in three time points during and after chemoperfusion (45 min after application of MH in extracorporeal circulation, 10 min after the joining the extremity to systemic circulation and one hour after the great vessels reconstruction). The concentrations of MH ranged 100-1500 ng.ml-1 and varied from patient-to-patient. Some complications were observed after HILP in 11 patients and are correlated with the higher con- centrations of MH (over 150 ng x ml-1) found in plasma.

Study of antioxidant effect of apigenin, luteolin and quercetin by DNA protective method.

A DNA protective capacity of three flavonoids, apigenin (AP), luteolin (LU) and quercetin (QU) against free radicals generated by H202, resp. Fe2+ is reported. This effect corresponding with scavenging of free radicals or with chelating of iron was assayed at two concentrations of flavonoids studied (1 microM and 10 microM). The quantitative analysis has shown that LU possesses the highest DNA protective effect of flavonoids investigated in the presence of H2O2. On the other hand, in the presence of 10 microM Fe2+, AP exhibited the highest DNA protective effect at the concentration of 1 microM and the following order was reached at the stoichiometric concentrations (10 microM) of Fe2+. It is believed that this discrepancy is caused by the ability of LU and QU iron-complex formation as it was separately investigated using UV-VIS spectrometry.