Current Medicinal Chemistry - Volume 12, Issue 11, 2005

This review chronicles original literature dating back to 1992 outlining the applications of parallel synthesis and combinatorial chemistry to the synthesis of compound libraries focused towards specific superfamilies of molecular targets. Target families that have received significant literature coverage include kinases, proteases, nuclear hormone receptors and cell surface receptors, notably GPCRs.

This review provides up-to-date information on the inhibition of ribonucleotide reductase (RNR), the enzyme that catalyses the reduction of ribonucleotides into deoxyribonucleotides. Taking in account that DNA replication and repair are essential mechanisms for cell integrity and are dependent on the availability of deoxyribonucleotides, many researchers are giving special attention to this enzyme, since it is an attractive target to treat several diseases of our time specially cancer. This investment has already given some benefits since some of these inhibitors show potent chemotherapeutic efficacy against a wide range of tumours such as non-small cell lung cancer, adenocarcinoma of pancreas, bladder cancer, leukaemia and some solid tumours. In fact a few of them have already been approved for the clinical treatment of some kinds of cancer. All aspects of RNR inhibition and corresponding inhibitors are the subjects of this review. The inhibitors are divided in three main groups: translation inhibitors, which unable the formation of the enzyme; dimerization inhibitors that prevent the complexation of the two RNR subunits (R1 and R2); and catalytic inhibitors that inactivate subunit R1 and/or subunit R2, leading to RNR inactivity. In this last group special focus will be addressed to substrate analogues.

Terpenoids is a class of natural compounds found in higher plants, mosses, liverworts, algae and lichens, as well as in insects, microbes or marine organisms. Through centuries many of these compounds have been used as ingredients of perfumes, drugs, narcotics or pigments. Labdanes, belonging to the bicyclic diterpenoids group, have been found as secondary metabolites in tissues of fungi, insects, marine organisms, and in essential oils, resins and tissues of higher plants. The diterpenes of labdane type, have been reported to have broad spectrum of biological activities. In this study, the reported bioactivities and/or uses of them, the last two decades (1981-2004), are selected as an attempt to underline their role in nature.

Increased concentrations of extracellular adenosine are reached in ischemic or inflamed tissues but have also been detected inside tumoral masses. If this finding may account for an important role of adenosine in the pathogenesis of tumors remains to be determined in view of its contradictory effects on cell survival and proliferation. In particular, adenosine was found to exert its effects on proliferation and on cell death mainly through the A3 adenosine receptor. Therefore, a complete pharmacological characterization of the subtype and number of the expressed A3 adenosine receptors is necessary for the elucidation of the role of adenosine via A3 receptors in a specific cell subtype. The lack of potent and selective radiolabelled A3 receptor antagonists has been, in the past, the major obstacle in the characterization of structure, function and regulation of this adenosine receptor subtype. Recently, our group has identified a series of substituted pyrazolotriazolopyrimidine derivatives as potent and selective antagonists to human A3 adenosine receptors. The most recent results obtained in this field will be summarized in the present review. Furthermore, the review will report the results of the biochemical and pharmacological characterization of A3 receptors in different human tumor cell lines and the multiple A3 receptor-sustained ways that could prime tumor development.

Atrial fibrillation is the most common disorder of cardiac rhythm. In spite of diagnosis simplicity, patients with atrial fibrillation are difficult to treat. In the recent years with the description of the phenomenon called remodelling, it has been possible to better define the principle mechanisms responsible for initiation, maintenance and, in some instances, termination of atrial fibrillation. Electrical, mechanical and anatomical remodelling indicate those alterations that, once established, may vanish any attempt to restore sinus rhythm. Atrial fibrosis is probably the most critical component of the remodelling process and appears to be largely mediated by the activation of the Renin-Angiotensin-Aldosterone System. Both experimental and clinical data have confirmed the pro-arrhythmic role of the Renin-Angiotensin-Aldosterone System and demonstrated an anti-arrhythmic effects of ACE-inhibitors and AT1 receptor blockers. Regarding atrial fibrillation, it has been recently reported that the adjunction of AT1 receptor blocker to amiodarone was more effective than the antiarrhythmic drug alone, in reducing arrhythmia recurrence after electrical cardioversion. This and subsequent clinical observations indicate that pharmacological interventions capable of interfering with the electrical and structural remodelling process are of critical importance in the management of patients with atrial fibrillation. ACE inhibitors and AT1 receptor blockers represent new and efficient therapeutical options to contrast the nearly inevitable progression of this arrhythmia towards its permanent form.

In 1990, the worldwide accepted Shackleton [1] method, which provides a possibility of determining the steroid metabolites from urine, was adopted in our laboratory. The procedure is very useful in the diagnosis of different endocrine diseases and in the recognition of dysfunction or absence of enzymes with an important role in steroid metabolism, and it gives possibility to control the treatment in patients with these diseases. Besides the proximate clinical application, the method gives a convenient tool to study the steroid background of these disorders, helping us understand the mechanism of their development. In the last few years, we have examined the steroid profile of patients with hair (androgen alopecia /AA/, effluvium /E/), psychiatric problems (major depression /MD/, eating disorders /EDS/, especially anorexia nervosa and bulimia) and osteoporosis (OP). In all of the examined hair loss diseases, the levels of main androgen metabolites were increased, and elevated 5α-reductase activity were found. We could observe the alteration of the activity of 11β-hydroxysteroid dehydrogenase (11β-HSD) enzyme and marked gender differences in the changes of the steroid metabolism in patients with major depression (MD). In women with OP, the significantly decreased level of certain metabolites points to the role of testosterone, androstenedione and DHEA in postmenopausal bone loss in women. Our experiences contribute to the knowledge of the nature and steroid background of some endocrine and psychiatric diseases.

Irinotecan (CPT-11, 7-ethyl-10-[4-(1-piperidino)-1-piperidino] carbonyloxycamptothecin) has exhibited clinical activities against a broad spectrum of carcinomas by inhibiting DNA topoisomerase I (Topo I). However, severe and unpredictable dosing-limiting toxicities (mainly myelosuppression and severe diarrhea) hinder its clinical use. The latter consists of early and late-onset diarrhea, occurring within 24 hr or ≥ 24 hr after CPT-11 administration, respectively. This review highlights novel agents potentially inhibiting CPT-11-induced diarrhea, which are designed and tested under guidance of disposition pathways and potential toxicity mechanisms. Early-onset diarrhea is observed immediately after CPT-11 infusion and probably due to the inhibition of acetylcholinesterase activity, which can be eliminated by administration of atropine. Lateonset diarrhea appears to be associated with intestinal exposure to SN-38 (7-ethyl-10-hydroxycamptothecin), the major active metabolite of CPT-11, which may bind to Topo I and induce apoptosis of intestinal epithelia, leading to the disturbance in the absorptive and secretory functions of mucosa. CPT-11 and SN-38 may also stimulate the production of pro-inflammatory cytokines and prostaglandins (PGs), thus inducing the secretion of Na+ and Cl-. Early treatment of severe late-onset diarrhea with oral high-dose loperamide has decreased patient morbidity. Extensive studies have been conducted to identify other potential agents to ameliorate diarrhea in preclinical and clinical models. These include intestinal alkalizing agents, oral antibiotics, enzyme inducers, P-glycoprotein (PgP) inhibitors, cyclooxygenase-2 (COX-2) inhibitors, tumor necrosis factor-α (TNF-α) inhibitors, or blockers of biliary excretion of SN-38. Further studies are needed to identify the molecular targets associated with CPT-11 toxicity and safe and effective agents for alleviating CPT-11-induced diarrhea.