Daniela Barlocco

Privileged Structures as Leads in Medicinal Chemistry

Among the strategies that can lead to the discovery of new drugs, the identification and use of privileged structures, molecular fragments that are able to interact with more than one target, gained particular attention, in an attempt to find new drugs in a shorter time with respect to other strategies. These structures, that have been identified mainly by empirical observations, can target only a given protein family, or can be able to interact with more, unrelated targets. This review deals with structures not covered in recent papers on this topic, and emphasizes the importance of understanding the structure-target relationships, that confer the privileged status.

Diabetes complications and their potential prevention: Aldose reductase inhibition and other approaches

Despite recent advances both in the chemistry and molecular pharmacology of antidiabetic drugs, diabetes still remains a life‐threatening disease, which tends to spread all over the world. The clinical profile of diabetic subjects is often worsened by the presence of several long‐term complications, namely neuropathy, nephropathy, retinopathy, and cataract. Several attempts have been made to prevent or at least to delay them. The most relevant are reported in this review, including the development of compounds acting as aldose reductase inhibitors, anti‐advanced glycation end‐product drugs, free radical scavengers, vasoactive agents, essential fatty acid supplementation, and neurotropic growth factors.

STAT 3 as a Target for Cancer Drug Discovery

Stat-3 (Signal Transduction and Activator of Transcription) is a member of the Stat family of latent, cytosolic transcription factors that directly relate signals from the plasma membrane to the nucleus. This protein is constitutively activated by aberrant upstream tyrosine kinase activities in a broad spectrum of human tumors, and it has been identified as a promising target for cancer drug discovery. This review deals with the recent developments of peptides and peptidomimetics or even non-peptidic small molecules, able to bind to the SH2 domain of Stat-3, thus blocking its functions. Moreover, several compounds able to alter the Stat-3 pathway by inhibition of kinases upstream to Stat-3, or even with unknown targets, were reviewed.

Thymidylate Synthase Structure, Function and Implication in Drug Discovery

Recent methodologies applied to the drug discovery process, such as genomics and proteomics, have greatly implemented our basic understanding of drug action and are giving more input to medicinal chemists, in finding genuinely new targets and opportunities for the development of drugs with original mechanisms of action. In this paper, an example of the successful application of some new techniques to the target enzymes with the Thymidylate Synthase (TS) function is given. The improved knowledge of the complex mechanism of the biological pathways in which thymidylate synthase is involved represents a unique chance to find new mechanism-based inhibitors, aimed to treat not only cancerous diseases, but also infectious pathologies. Thymidylate synthase (TS or ThyA) has long been considered as one of the best-known drug targets in the anti-cancer area, after which old and new drugs, such as 5-fluoro uracil and the anti-folate ZD1694, have been introduced into chemotherapy to treat solid tumours. Only a few attempts have been made to find non-classical anti-folate inhibitors that are dissimilar to the folate co-factor, with the aim of finding unshared protein target domains on the enzyme structure, in order to specifically inhibit TS enzymes from pathogens. Only recently from omic studies, a new Thymidylate Synthase Complementing Protein (TSCP or ThyX) has been identified in a number of pathogens, showing a different structure with respect to human TS, thus opening new avenues to specific inhibitions. A depiction of the most recent progress in the study of Thymidylate Synthase enzymes is presented in the following sections.

Semicarbazide-Sensitive Amine Oxidase: Current Status and Perspectives

Semicarbazide-sensitive amine-oxidase (SSAO) is present in various human tissues and in plasma. Oxidative deamination of short-chain aliphatic amines is catalyzed by this enzyme to afford the corresponding aldehydes, ammonia and hydrogen peroxide. Methylamine and aminoacetone have been recognized to be physiological substrates for SSAO. There are several pathological states where increased serum SSAO activity have been found, such as diabetes mellitus, congestive heart failure, multiple types of cerebral infarction, uraemia, and hepatic cirrhosis. The role of SSAO in pathophysiology of diabetes has been most extensively investigated. The elevated formation of the potentially cytotoxic products of the enzyme may contribute to the endothelial injury of blood vessels, resulting in the early development of severe atherosclerosis; it may also contribute to the pathogenesis of diabetic angiopathy. It is now suggested that SSAO inhibitors may prevent the development of atherosclerosis and diabetic complications as well. Inhibitors can be conveniently subdivided into the main groups of hydrazine derivatives, arylalkylamines, propenyl- and propargylamines, oxazolidinones, and haloalkylamines. Of them, aryl(alkyl)hydrazines, and 3-halo-2-phenylallylamines are generally very strong SSAO inhibitors. Most of these inhibitors of SSAO have been originally developed for other purposes, or they are simple chemical reagents with highly reactive structural element(s); these compounds have not been able to fulfil all criteria of high potency, selectivity, and acceptable toxicity. New potent compounds with selectivity and low toxicity are needed, which may prove useful tools for understanding the roles and function of SSAO, or they may even be valuable substances for treatment of various diseases.

Pharmacological approaches to the treatment of diabetic complications

Diabetes is often accompanied by several long-term complications such as neuropathy, nephropathy, retinopathy, cataract and angiopathy; their occurrence has been linked to the modification of the physiological levels of glycaemia. Several interrelated metabolic pathways have been implicated in the toxic effects of glucose; the polyol pathway was one of the first considered. However, while in diabetic animal models the inhibitors of aldose reductase (ALR2, the first enzyme of this pathway) seem to be active, 16 years of clinical trials, based mainly on neuropathy, have been inconclusive; only one drug currently being marketed. Newer potent and selective aldose reductase inhibitors have been discovered in the last few years, but the lack of commercial success has probably led to the very rapid decrease in the number of patents relating to newer aldose reductase inhibitors. Inhibition of the second enzyme of this pathway, sorbitol dehydrogenase (SDH), has been shown to be detrimental. Other approaches for the prevention and the delay of progression of diabetic complications seem to be more promising, namely, the inhibition of the formation of advanced glycated end products (AGEs) or protein kinase C (PKC) β2 inhibition; compounds acting on these two pathways have proved effective in retarding the development of diabetic complications in animal models and some products are in clinical trials at the moment. Renewed attention has been paid to vascular involvement in the pathogenesis of diabetic neuropathy; the biological activity of C-peptide and the role of endothelin-1 (ET-1) in diabetic vascular disease are emerging as a new research area for the treatment of diabetic complications.

New aldose reductase inhibitors as potential agents for the prevention of long-term diabetic complications

The results of recent clinical trials emphasise the importance of an improved glycaemic control in diabetic patients in order to prevent or at least to delay long-term complications. The difficulty in obtaining normalisation of blood glucose values has underlined the importance of the search for new and effective aldose reductase inhibitors (ARIs) to control the consequences of elevated glucose levels, therefore delaying the onset and retarding the progression of diabetic complications such as neuropathy, nephropathy, retinopathy and cataract. Although the physiological role of aldose reductase (ALR2) has not been clearly elucidated yet, it has been shown that this enzyme, the first of the polyol pathway, is responsible for the production of sorbitol from glucose. There are several pieces of evidence which link this process to the occurrence of diabetic complications. Orally active aldose reductase inhibitors can be grouped into two chemical classes: cyclic imide and carboxylic acid derivatives. This revi...

Signal transducer and activator of transcription 3 (STAT3): a promising target for anticancer therapy

Signal transducer and activator of transcription 3 (STAT3) is an oncogenic protein whose inhibition is sought for the prevention and treatment of cancer. In this review, the validated therapeutic strategy to block aberrant activity of STAT3 in many tumor cell lines is evaluated by presenting the most promising inhibitors to date. The compounds are discussed in classes based on their different mechanisms of action, which are critically explained. In addition, their future clinical development as anticancer agents is considered. Furthermore, the efforts devoted to the comprehension of the structure-activity relationships and to the identification of the biological effects are brought to attention. The synthetic and technological approaches recently developed to overcome the difficulties in the obtainment of clinically suitable drugs are also presented.

Semicarbazide-Sensitive Amine Oxidase/Vascular Adhesion Protein 1: Recent Developments Concerning Substrates and Inhibitors of a Promising Therapeutic Target

SSAO/VAP-1 is not only involved in the metabolism of biogenic and xenobiotic primary amines and in the production of metabolites with cytotoxic effects or certain physiological actions, but also plays a role, for example, as an adhesion molecule, in leukocyte trafficking, in regulating glucose uptake and in adipocyte homeostasis. Interest in the enzyme has been stimulated by the findings that the activities of the SSAOs are altered (mostly increased) in various human disorders, including diabetes, congestive heart failure, liver cirrhosis, Alzheimers disease and several inflammatory diseases, although the underlying causes are often unknown. On the basis of their insulin-mimicking effect, SSAO substrates are possibly capable of ameliorating metabolic changes in diabetes, while SSAO inhibitors (somewhat of a contradiction) are of potential benefit in preventing diabetes complications, atherosclerosis and oxidative stress contributing to several disorders or modulating inflammation, and hence may be of substantial therapeutic value. Great efforts have been made to develop novel compounds which may lead to future drugs useful in therapy, based on their effects on SSAO/VAP-1, and some of the results relating to novel substrates and inhibitors are surveyed in the present review.

4,5-Functionalized 6-phenyl-3(2H)-pyridazinones : synthesis and evaluation of antinociceptive activity

Abstract A series of 2-substituted 4,5-functionalized 6-phenyl-3(2 H )-pyridazinones were synthesized and their antinociceptive activities were evaluated in the mouse abdominal constriction model. Single dose studies showed that compounds 11, 18a and 23 were more active than the reference drug, Emorfazone, in inhibiting the effects of the noxious chemical stimulus, p -phenylquinone. Subsequent dose—response studies revealed 18a to be almost seven-fold more potent than Emorfazone.