Coumarins, also known as benzopyrones, are present in remarkable amounts in plants, although their presence has also been detected in microorganisms and animal sources. The structural diversity found in this family of compounds led to the division into different categories, from simple coumarins to many other kinds of policyclic coumarins, such as furocoumarins and pyranocoumarins. Simple coumarins and analogues are a large class of compounds that have attracted their interest for a long time due to their biological activities: they have shown to be useful as antitumoural, anti-HIV agents and as CNS-active compounds. Furthermore, they have been reported to have multiple biological activities (anticoagulant, anti-inflammatory), although all these properties have not been evaluated systematically. In addition, their enzyme inhibition properties, antimicrobial and antioxidant activities are other foremost topics of this field of research. The present work is to survey the information published or abstracted from 1990 till 2003, which is mainly related to the occurrence, synthesis and biological importance of simple coumarins and some analogues, such as biscoumarins and triscoumarins. Data are also highlighted, concerning the development of new synthetic strategies that could help in drug design and in the work on SAR or QSAR.

The last few decades have provided stunning progresses in the understanding of physiopathology of several diseases. The remarkable progress in research fields, like genetics, immunology, neurobiology, among others, as well as the advent of more powerful tools, have made it possible to characterize, monitor, and understand far more of the basis of physiology and disease. However, for some diseases the treatment remains a problematic issue as the efforts performed so far were not translated into therapeutic solutions. Notwithstanding the steady increase in the total amount of FCUP

Cancer, one of the major causes of death across the world, has shown to be a largely preventable disease, highly susceptible to modulation by dietary factors. Phenolic compounds, abundant in vegetables and fruits ubiquitous in diet, were described to play an important role as chemopreventive agents. Since conventional therapeutic and surgical approaches have not been able to control the incidence of most cancer types, the development of chemopreventive strategies is an urgent priority in public health. The current diet phenolic intake is often insufficient to protect from mutagens (either exogenous or endogenous), which leads to the need for dietary supplementation as an alternative approach. Research efforts are placing increasing emphasis on identifying the biological mechanisms and in particular the signal transduction pathways related to the chemopreventive activities of these compounds. These effects are believed to occur by the regulation of signaling pathways such as nuclear factor-kB (NF-kB), activator protein-1 (AP-1) or mitogen-activated protein kinases (MAPK). Dietary polyphenols can exert their effects on these pathways separately or sequentially and in addition the occurrence of crosstalk between these pathways cannot be overlooked. By modulating cell signaling pathways, polyphenols activate cell death signals and induce apoptosis in precancerous or malignant cells resulting in the inhibition of cancer development or progression. However, regulation of cell signaling pathways by dietary polyphenols can also lead to cell proliferation/survival or inflammatory responses due to increased expression of several genes. The present review summarizes the most recent advances providing new insights into the molecular mechanisms underlying the promising anticarcinogenic activity of dietary polyphenols. ß

Xanthine oxidase (XO) is a highly versatile flavoprotein enzyme, ubiquitous among species (from bacteria to human) and within the various tissues of mammals. The enzyme catalyses the oxidative hydroxylation of purine substrates at the molybdenum centre (the reductive half-reaction) and subsequent reduction of O(2) at the flavin centre with generation of reactive oxygen species (ROS), either superoxide anion radical or hydrogen peroxide (the oxidative half-reaction). Many diseases, or at least symptoms of diseases, arise from a deficiency or excess of a specific metabolite in the body. For an example of an excess of a particular metabolite that produces a disease state is the excess of uric acid which can led to gout. Inhibition of XO decreases the uric acid levels, and results in an antihyperuricemic effect. Allopurinol, first synthesised as a potential anticancer agent, is nowadays a clinically useful xanthine oxidase inhibitor used in the treatment of gout. There is overwhelming acceptance that xanthine oxidase serum levels are significantly increased in various pathological states like hepatitis, inflammation, ischemia-reperfusion, carcinogenesis and aging and that ROS generated in the enzymatic process are involved in oxidative damage. Thus, it may be possible that the inhibition of this enzymatic pathway would be beneficial. In this review the State of the Art will be presented, which includes a summary of the progress made over the past years in the knowledge of the structure and mechanism of the enzyme, associated pathological states, and in the efforts made towards the development of new xanthine oxidase inhibitors.

The antiradical activity of caffeic acid (1), dihydrocaffeic acid (5), and their corresponding n-alkyl esters was evaluated by using the 2,2-diphenyl-1-picrylhydrazyl radical (DPPH(*)) method. Dihydrocaffeic acid (5) was the most potent compound, having an antiradical effect higher than that of (+/-)-alpha-tocopherol, whereas caffeic acid (1) was less efficient. Esterification of the carboxyl group of dihydrocaffeic acid (5) had a dramatic effect on its antiradical potency, but similar effects were not observed for caffeic acid (1) derivatives. The n-alkyl esters of both phenolic series had similar potencies, and their antiradical activities were independent of the alkyl chain length. Dose-dependent scavenger effects were found in both series. Acid-base properties of the compounds, evaluated by using potentiometry and spectrophotometry, showed that the catechol moiety had pK(a2) and pK(a3) values of 9. 24-9.02 and 11.38-10.99 in the dihydrocaffeic series and 8.48-8.24 and 11.38-11.07 in the caffeic series, respectively. Antiradical activity and pK(a) values of the compounds were not related.

Hydroxycinnamic acids (such as ferulic, caffeic, sinapic, and p-coumaric acids) are a group of compounds highly abundant in food that may account for about one-third of the phenolic compounds in our diet. Hydroxycinnamic acids have gained an increasing interest in health because they are known to be potent antioxidants. These compounds have been described as chain-breaking antioxidants acting through radical scavenging activity, that is related to their hydrogen or electron donating capacity and to the ability to delocalize/stabilize the resulting phenoxyl radical within their structure. The free radical scavenger ability of antioxidants can be predicted from standard one-electron potentials. Thus, voltammetric methods have often been applied to characterize a diversity of natural and synthetic antioxidants essentially to get an insight into their mechanism and also as an important tool for the rational design of new and potent antioxidants. The structure-property-activity relationships (SPARs) correlations already established for this type of compounds suggest that redox potentials could be considered a good measure of antioxidant activity and an accurate guideline on the drug discovery and development process. Due to its magnitude in the antioxidant field, the electrochemistry of hydroxycinnamic acid-based antioxidants is reviewed highlighting the structure-property-activity relationships (SPARs) obtained so far.

No abstract

Several phenolic acids-caffeic and gallic acid derivatives-were synthesized and screened for their potential antiproliferative and cytotoxic properties, in different human cancer cell lines: mammary gland and cervix adenocarcinomas and lymphoblastic leukemia. The selected phenols were structurally related, which allowed us to gather important information regarding the structure-activity relationships underlying the biological activity of such compounds. This is proposed to be due to a balance between the antioxidant and pro-oxidant properties of this kind of agent. Distinct effects were found for different cell lines, which points to a significant specificity of action of the drugs tested. It was verified, for the types of cancer investigated, that the trihydroxylated derivatives yielded better results than the dihydroxylated ones. Tests in noncancerous cells, human lung fibroblasts, were also undertaken, in view of determining the toxic side effects of the compounds studied.