Current Bioactive Compounds - Volume 6, Issue 2, 2010

Chromones (1-benzopyran-4-ones) and chromone derivatives are naturally occurring compounds ubiquitously found in the plant kingdom, and therefore present in representative amounts in a normal human diet. These phytochemicals possess a wide spectrum of biological activities — such as anti-inflammatory, antifungal, antimicrobial, antiviral, antitumour and anticancer — mainly due to their well-recognised antioxidant properties, which stem from their ability to neutralise active forms of oxygen and to cut off free radical processes. Since oxidative stress is known to be the basis for numerous severe pathologies, from cardiovascular and neurodegenerative disorders to cancer, the development of effective antioxidant agents from natural origin (namely dietary constituents) has been the object of vigorous research in the last decade, in view of establishing novel chemopreventive strategies against such diseases which are nowadays the main cause of death worldwide. In fact, the chromone moiety is an important element of pharmacophores of many biologically active molecules displaying diverse medicinal applications. These potential health benefits arising from the antioxidant activity of chromone derivatives are ruled by strict structure-activity/ structure-property relationships, which, apart from determining their biological action, modulate their systemic distribution and bioavailability in sites of oxidation within the cell. The present work aims at reviewing the main reported studies on the cytoprotective and anticancer activities of chromone derivatives, with particular emphasis on the effect of their structural features and conformational behaviour on activity, which is the basis of a tailored design of novel chromone-based antioxidants for chemopreventive and chemotherapeutic use.

d-chiro-inositol (DCI) and manganese were administered orally singly and together to streptozotocin (STZ)- induced diabetic rats for 21 days and blood glucose values and body weights determined. At blood glucose values above 500 mg/dL, values were unchanged with DCI, manganese sulfate, or both over ten days. Insulin was administered to reduce the hyperglycemia to approximately 300 mg/dL. Over 12 days, DCI alone significantly reduced blood glucose (23%), and the combination of DCI and manganese sulfate reduced hyperglycemia even more effectively (40%) as compared to control animals. Of further interest, body weights both of female and male rats administered DCI and manganese were reduced, with females 25% compared to controls and males 21% compared to controls over the 21-day period. Metabolic mechanisms of actions of DCI and manganese to explain these results are discussed.

Tetrapyrrolic macrocycles occupy a central place in bioorganic chemistry. On the basis of their photophysical properties, natural and synthetic porphyrin derivatives have found specific biomedical applications, particularly in the field of detection and treatment of neoplastic tissues. Photodynamic therapy (PDT) consists in the administration of a photosensitizer, which is selectively retained by the malign cells. The subsequent irradiation with visible light in the presence of oxygen specifically leads to cell death and tumor destruction. In the last years, methoxyphenyl porphyrin derivatives were evaluated as active phototherapeutic agents. Therefore, this review deals with the evolution of these photosensitizers with potential applications in PDT. The photodynamic activity of 5,10,15,20-tetrakis(4-methoxyphenyl) porphyrin was studied in different biomimetic and biological media. This synthetic porphyrin and its complexes with metals are effective photosensitizers, which were used as model compounds to investigate the theoretical and instrumental aspects of PDT. Modifications in the structure of methoxyphenyl porphyrins were performed to obtain an increase in the efficiency and selectivity of the agents. In these compounds, the presence of methoxy groups appears to be beneficial from the standpoint of tumor localization. Biochemical studies using a monocationic porphyrin showed efficient tumor regression and the cellular damage was mainly dependent on caspase-3 activity signaling response associated with apoptosis. Also, methoxyphenyl porphyrins attached to other structures, such as porphyrin and fullerene C60 were investigated as phototherapeutic drugs. In particular, porphyrin-C60 dyad was found to be an active compound, even under anoxic condition. The studies indicated that porphyrins bearing methoxy groups in the periphery of the macrocycle are interesting photosensitizers with potential application in photodynamic tumor therapy.

Food additives have been used by mankind for centuries. Most food additives are considered safe; however, some are known to be toxic or carcinogenic. Aldehydes occur as natural (flavoring) constituents in a wide variety of foods and food components. This review highlights the nephrotoxicity of the major flavoring agent - cinnamaldehyde. Cinnamaldehyde has been in public use since 1900. It is a yellowish liquid with a strong pleasant fragrance derived from the bark of Cinnamomum cultivated trees. Cinnamaldehyde also occurs in several brands of cinnamon breads, cereals, cookies, puddings, and fruit juices. Cinnamaldehyde is chemically related to toxicologically more active compounds, like acrolein and crotonaldehyde. Besides cinnamaldehyde, acute toxicity of other major components of Cinnamomum - cinnamic acid and cinnamyl alcohol were observed in rats. Thus, concern about the safety of cinnamaldehyde in general was raised. Many species of the genus Cinnamomum, the main source of cinnamaldehyde, are distributed in different regions of India. Cinnamaldehyde is widely found in many Indian foods and medicinal and cosmetic products. Thus, cinnamaldehyde has a high potential for human consumption in India. This research work on the toxic effects of cinnamaldehyde on kidney was conducted at the World Health Organization (WHO) suggested Acceptable Daily Intake (ADI) level (0.7 mg / kg body weight). Histopathological changes of kidney were accompanied by alterations in the antioxidant status, level of marker enzymes and other chemical constituents. Finally, it was concluded that cinnamaldehyde has a toxic effect on the rat kidney and its effect is time and dose dependent.

Bovine viral diarrhea virus (BVDV) infection is distributed worldwide, and is responsible for a major loss in cattle leading to significant economic loss to producers. Although vaccines are used in some countries in an attempt to control the pestivirus disease, the degrees of success are variable. An alternative approach could be the use of anti-BVDV agents. Recently, a number of anti-BVDV compounds have been reported. However, there are no antiviral treatment options for controlling the pestivirus disease currently, and the emergence of BVDV strains resistant to antiviral compounds would be inevitable. Thus, development of anti-BVDV agents with a novel scaffold structure is needed. In addition, BVDV is also considered to be a valuable surrogate for the hepatitis C virus (HCV) in antiviral drug research. Therefore, development of a novel scaffold for anti-BVDV agents and obtaining the structure-activity relationship (SAR) information would contribute to the development of novel anti-HCV agents. Under such circumstances, we performed structural development studies of anti-BVDV agents with a novel scaffold structure. As a result, we identified fused heteroaromatic structure as a superior thalidomide-derived scaffold for candidate drugs with potent anti-BVDV activity, by means of antiviral activity screening in Madin-Darby bovine kidney (MDBK) cells infected with BVDV. Among the compounds, 3,4,5-trimethyl-γ-carboline SK3M4M5M (44) possessed the most potent anti-BVDV activity with the EC50 (concentration causing 50% reduction of BVDV replication-induced cell destruction) value of 3.5 nM and low cytotoxicity. The process of the structural development and SAR studies are reviewed.