Current Medicinal Chemistry - Volume 9, Issue 6, 2002

This review presents a historical overview of the discoveries of retinoic acid receptor (RAR) and retinoid X receptor (RXR) class- and subtype-selective synthetic retinoids. These synthetic retinoids are conformationally restricted by having aromatic rings in place of the tetraene bond systems of all-trans- and 9-cis- retinoic acids. Events leading to the design and synthesis of such retinoid transcriptional agonists as RAR subtype β,γ-selective 6-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-2-naph-thalenecarboxyl ic acid (TTNN), the RARγ-selective Z-oxime of 6-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenylcarbonyl)-2-naphthalenec arboxylic acid (SR11254), RAR-selective 4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-anthracenyl) benzoic acid (TTAB), RXR-selective 4-[1-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-cyclopropyl] benzoic acid (SR11246), RXR-selective 4-[1-(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl)-2-methylpropenyl] benzoic acid (SR11345), and RARγ-selective retinoid transcriptional antagonist 2-(6-carboxy-2- naphthalenyl)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-1,3-dith iolane (SR11253) are described.

This review points out that treatment with essential metalloelement (Cu, Fe, Mn, and Zn) chelates facilitate tissue repair processes required for recovery from radiation injury including survival of lethally irradiated mice and rats. Results of studies pertaining to successful uses of bioavailable essential metalloelement chelates and combinations of them as well as aminothiols, Ca-cannel blockers, acyl Melatonin homologs, substituted anilines, and curcumin radioprotectants are included in this review to suggest their use as chelates in overcoming radiation injury. Additional reportsdocument that non-toxic doses of essential metalloelement chelates are effective in increasing survival and repairing radiation injury when administered before irradiation, in the radiation protection paradigm, and effective in increasing survival when used to treat after irradiation, in the radiorecovery paradigm. There are no other agents known to be effective in increasing survival when they are used to treat after irradiation. These approaches to radioprotection and radiorecovery offer promising approaches to facilitating recovery from radiation-induced injury experienced by patients undergoing radiation therapy for their neoplastic disease and by individuals who experience environmental, occupational, or accidental exposure to ionizing radiation. These individuals include those exposed to radiation resulting from nuclear accidents, the use of depleted uranium missiles, and astronauts undertaking space travel. Since there are no existing safe and effective treatments of radiation injury, studies of essential metalloelement chelates and combinations of them, as well as combinations of them with existing radioprotectant aminothiols, Ca-channel blockers, acyl Melatonin homologs, substituted anilines, and curcumin as radioprotectants seem worthwhile.

The discovery of anandamide as an endogenous ligand for the cannabinoid receptors has led to a resurgence of interest in the fatty acid amides. However, N-palmitoylethanolamine (PEA), a shorter and fully saturated analogue of anandamide, has been known since the fifties. This endogenous compound is a member of the N-acylethanolamines, found in most mammalian tissues. PEA is accumulated during inflam-mation and has been demonstrated to have a number of anti-inflammatory effects, including beneficial effects in clinically relevant animal models of inflammatory pain. It is now engaged in phase II clinical development, and two studies regarding the treatment of chronic lumbosciatalgia and multiple sclerosis are in progress. However, its precise mechanism of action remains debated. In the present review, the biochemical and pharmacological properties of PEA are discussed, in particular with respect to its analgesic and anti-inflammatory properties.

The complex taxon embraced in the Pteridium genus, popularly known as bracken fern and notorious weeds in many parts of the world, is one of the few vascular plants known to induce cancer naturally in animals. It has been known for long to be acutely toxic to livestock and sublethal chronic oral feeding of bracken fronds leads to cancerous lesions in the urinary bladder, or bovine enzootic haematuria (BEH) and ileum of cattle. Bracken poisoning has been attributed chiefly to ptaquiloside, a norsesqui-terpene which is also a potent carcinogen inducing various malignancies in laboratory animals. It is capable of alkylating uncoiled DNAbases at key proto-oncogenes of selected organs. Some human populations also eat young bracken shoots and epidemiological studies in Japan and Brazil have shown a close association between bracken consumption and cancers of the upper alimentary tract. In addition, other studies reveal that the mere presence of bracken swards represents a greater risk to die of gastric adenocarcinoma for people who live more than 20 years in such areas or are exposed in childhood. This work reviews the bracken-cancer connections established by in vitro and in vivo experiments and epidemiological studies in various parts of the world, and provides insights into the possible bridges for bracken carcinogens to reach the human diet. Also, specific points where more research is needed are highlighted.

Organic structures with fluorine atom are slightly diffuse in nature.Starting '80s researchers have discovered that the selective introduction of fluorine into biologically active molecules exercised an influence on activity. So an important endeavour in drug design have been described and numerous compounds incorporating fluorine as either a bioisosteric replacement for hydrogen or an isoelectronic replacement for the hydroxyl group have been reported.Parallely, an enormous literature on anthracyclines exists, a class of compounds used in clinical since '70s, as antitumor drugs. Unfortunately, the anthracyclines are known as well for several toxical effects that frequently condition the clinical use.In the last decade a lot of anthracycline derivatives has been described in which has been introduced a fluorine atom in different position of molecule.This review wishes to represent an updated collection of compounds with anthracycline structure where a fluorine atom has been introduced on aglycon or / and sugar moiety.Together with the chemical structures, the synthetic indications are furnished and succinct explanations of biological activity are summarised (if available).

The intracellular cysteine proteinases grouped under the common name of caspases are important participants in the process of programmed cell death called apoptosis. Of the nearly fourteen mammalian members discovered thus far caspase 1 or (interleukin-1β converting enzyme ICE), and possibly other related family members also serve as activator of cytokines. In general, caspases act on a number of cellular targets including other caspase family members leading ultimately to apopto4 4is through a highly integrated and regulated biological, biochemical and genetic mechanism. The proper execution of apoptosis is crucial during developmental stages and continues to be of critical importance for the well being of the mature organism. However, in a number of degenerative diseases the pathological states are characterized by an exacerbated loss of certain types of cells, cellular death that has morphological characteristics of apoptosis. Fortunately, it has been known for sometime that induced apoptosis that proceeds through the activation of caspases can be inhibited to rescue these cells and allow them to remain viable. This realization has attracted attention towards caspases as likely targets for pharmacological intervention, believing that inhibition of their enzymatic activity in the compromised cells will prevent the unwanted high rate of cellular death. Here we survey natural and synthetic inhibitors of caspases that have been reported to date, including some commonly used peptide inhibitors that serve as ”tool reagents“ in research and others that have been used to map inhibitor binding interaction in the active site.