F. Da Settimo

Recent advances in the development of dual topoisomerase I and II inhibitors as anticancer drugs.

DNA topoisomerases (topos) are essential enzymes that regulate the topological state of DNA during cellular processes such as replication, transcription, recombination, and chromatin remodeling. Topoisomerase I (Topo I) is a ubiquitous nuclear enzyme which catalyzes the relaxation of superhelical DNA generating a transient single strand nick in the duplex, through cycles of cleavage and religation. Topoisomerase II (Topo II) mediates the ATP-dependent induction of coordinated nicks in both strands of the DNA duplex, followed by crossing of another double strand DNA through the transiently broken duplex. Although the biological functions of Topoisomerases are important for ensuing genomic integrity, the ability to interfere with enzymes or generate enzyme-mediated damage is an effective strategy for cancer therapy and, in this connection, DNA topos (I and II) proved to be the excellent targets of clinically significant classes of anticancer drugs. Actually, specific Topo I and Topo II inhibitors reversibly trap the enzyme-DNA complexes, thus converting Topos into physiological poisons, able to produce permanent DNA damage, which triggers cell death. Given that both enzymes are good targets, it would be desirable to jointly inhibit them, but use-limiting toxicity of sequential or simultaneous combinations of topo I and II poisons include severe to life-threatening neutropenia and anemia. Furthermore, the emergence of resistance phenomena to topo I inhibitors is often accompanied by a concomitant rise in the level of topo II expression and viceversa, leading to the failure of clinical therapies. In this regard, a single compound able to inhibit both Topo I and II may present the advantage of improving antitopoisomerase activity, with reduced toxic side effects, with respect to the combination of two inhibitors. Due to the high interest in such compounds, this review represents an update of previous works dealing with the development of dual Topo I and II inhibitors as novel anti-cancer agents. The newly collected derivatives have been described focusing attention on their chemical structures and their biological profiles.

Synthesis of pyrrolo[3,4-c]pyridine derivatives possessing an acid group and their in vitro and in vivo evaluation as aldose reductase inhibitors

Abstract Derivatives of [pyrrolo[3,4- c ]pyridin-1,3(2 H )-dion-2-yl] alkanoic acids were prepared and their in vitro aldose reductase inhibitory activity was tested on rat lens enzyme. The acetic derivatives 2, 5 and 15a–d proved to be much more potent inhibitors than the propionic derivatives, 7 and 16a–d , and the iso-propionic derivatives, 3 and 6 . The presence of a second planar aromatic area in the benzoyl derivatives 15a–d did not result in any increase in activity. Two of the most active compounds in vitro ( 2 and 5 ) were also evaluated in vivo as inhibitors of glutathione lens depletion in galactosemic rats. None of the compounds was found to be active in maintaining the rat lens glutathione level, suggesting possible problems of ocular bioavailability and metabolism. The aldose reductase inhibitory activity of compounds 2 and 15d was also discussed by taking into account their conformational and electronic characteristics evaluated by means of theoretical calculations.

Inhibition of metalloproteinases derived from tumours: new insights in the treatment of human glioblastoma

Glioblastoma multiforme is the most commonly diagnosed malignant primary brain tumour in adults. Invasive behaviour is the pathological hallmark of malignant gliomas; consequently, its inhibition has been suggested as a therapeutic strategy. Tumour cell-derived gelatinases (matrix metalloproteinase-2, matrix metalloproteinase-9) can be considered prime factors in glioma invasiveness: their expression correlates with the progression and the degree of malignancy. Thus, broad spectrum matrix metalloproteinase inhibitors (MMP inhibitors) have been included in clinical trials. In the present study, the invasiveness, viability and progression of the human glioma cell line U87MG were investigated following treatment with N-O-isopropyl sulfonamido-based hydroxamates (compounds 1 and 2) as MMP-2 inhibitors used at nanomolar concentration. A standard broad spectrum MMP-inhibitor belonging to the classical tertiary sulfonamido-based hydroxamates family (CGS_27023A) was used too. The compounds 1 and 2 resulted in potent inhibition of cell invasiveness (P<0.0001) without affecting viability. In some clinical trials, the combined therapy of temozolomide (an alkylating agent used in glioma treatment) plus marimastat (a broad spectrum MMP inhibitor) has provided evidence of the importance of MMPs to tumor progression and invasiveness. On this basis, the effect on U87MG cells of a combined treatment with temozolomide, plus each of the two MMP inhibitors at nanomolar concentration, was investigated. The obtained data demonstrated the inhibition of cell invasiveness and viability after treatment. These results can help in developing clinical combined therapy using MMP inhibitors that, at low doses, increase the anticancer efficacy of chemotherapeutic drugs, probably without causing the side effects typical of broad-spectrum MMP inhibitors.

Translocator Protein Ligands as Promising Therapeutic Tools for Anxiety Disorders

The Translocator protein (TSPO), formerly known as the peripheral-type benzodiazepine receptor, is an 18 kDa mitochondrial protein primarily involved in steroid biosynthesis in both peripheral and glial cells. It has been extensively reported that TSPO regulates the rate-limiting translocation of cholesterol from the outer to the inner mitochondrial membrane before its transformation by cytochrome P450(scc) into pregnenolone, which is further converted into an array of different steroids. In the brain, neurosteroids such as allopregnanolone and pregnenolone, acting as positive modulators of gamma-aminobutyric type A (GABA(A)) receptors, exert anxiolytic activity. Specific ligands targeting TSPO increase neurosteroid production and for this reason they have been suggested to play an important role in anxiety modulation. Unlike benzodiazepines (Bzs), which represent the most common anti-anxiety drugs administered around the world, selective TSPO ligands have shown anxiolytic effects in animal models without any of the side effects associated with Bzs. Therefore, specific TSPO ligands that are able to promote neurosteroidogenesis may represent the future of therapeutic treatment of anxiety disorders. Furthermore, TSPO expression levels are altered in several different psychiatric disorders in which anxiety is the main symptom. This article reviews the primary and patent literature over the last decade concerning the development of novel TSPO ligands that have resulted effective in various models of anxiety, taking into special consideration their structure-activity relationships.

Arylsulfonamide inhibitors of aggrecanases as potential therapeutic agents for osteoarthritis: Synthesis and biological evaluation

Aggrecanases, in particular aggrecanase-2 (ADAMTS-5), are considered the principal proteases responsible for aggrecan degradation in osteoarthritis. For this reason, considerable effort has been put on the discovery and development of aggrecanase inhibitors able to slow down or halt the progression of osteoarthritis. We report herein the synthesis and biological evaluation of a series of arylsulfonamido-based hydroxamates as aggrecanase inhibitors. Compound 18 was found to have a nanomolar activity for ADAMTS-5, ADAMTS-4 and MMP-13 and high selectivity over MMP-1 and MMP-14. Furthermore, this compound proved to be effective in blocking ex vivo cartilage degradation without having effect on cell cytotoxicity.

1-substituted 2-benzylaminobenzimidazole derivatives: compounds with H1-antihistaminic activity

Abstract The preparation of 1-substituted 2-benzylaminobenzimidazole derivatives 13–24 is described. Although these compounds have a different structure from the general structure I of antihistamines, they showed some antihistaminic activity (pA2: 5–7) when tested in vitro on guinea pig ileum. The introduction of an additional basic centre as in the Mannich bases 25–27 did not cause any improvement of activity. All the compounds tested proved to be inactive in in vivo induced passive cutaneous anaphylaxis (PCA) and cutaneous vasopermeability in rats.

Isosteric replacement of the indole nucleus by benzothiophene and benzofuran in a series of indolylglyoxylylamine derivatives with partial agonist activity at the benzodiazepine receptor

Summary A number of benzothienyl- and benzofurylglyoxylylamine derivatives, which are analogues of previously described indolylglyoxylylamines with a partial agonist activity, are reported in this paper. They were synthesized and tested to verify the importance of the presence of the indole NH group in the interaction of this class of compounds with the benzodiazepine agonist receptor site, since it was reported in literature that a hydrogen bond donor group such as NH was not necessary to elicit an agonist response. Several thienylglyoxylylamine derivatives were also prepared and tested. None of the compounds showed a high affinity at the BzR, demonstrating that the indole NH plays a decisive role in the interaction of the agonist glyoxylylamine ligands with the receptor site.

Allosteric Modulators for Adenosine Receptors: An Alternative to the Orthosteric Ligands

Adenosine is a ubiquitous homeostatic substance which exerts its action by triggering four different cell membrane G protein-coupled receptors, classified as A(1), A(2A), A(2B), and A(3). Being widely distributed and deeply involved in several physiological functions, as well as pathological disorders, these receptors represent an excellent drug target and the development of specific ligands has been tested as a promising therapeutic concept. Among the obtainable ligands, allosteric modulators offer higher advantages with respect to classical orthosteric compounds, as they possible to achieve greater selectivity and better modulatory control at disease mediating receptors. Actually, synergizing with adenosine bound to the primary binding site, these compounds may modify receptor functions through interaction with an additional binding site. As a consequence, their actions depend directly on the release of the endogenous agonist. A number of compound have been developed as effective allosteric modulators. Most of them target adenosine A(1) and A(3) receptor subtypes as, to date, little or no research attempt have been made to improve the field of A(2A) and A(2B) ligands. This review updates literature on the allosteric modulators that has appeared in the last few years, focusing its attention on medicinal chemistry, in terms of chemical structure and structure-activity relationships. This will provide new perspectives on existing data and an exciting starting point for the development of novel and more effective modulators.

Receptor Tyrosine Kinase Kit and Gastrointestinal Stromal Tumours: An Overview

Kit is a growth factor receptor of the type III tyrosine kinase family, whose gain-of-function mutations have been identified as driving causes of different kinds of tumours. It thus represents a viable drug target, and the development of Kit inhibitors has been shown to be a promising therapeutic concept. This review will focus on structural and signalling properties of both wild-type and mutant Kit, as well as its role in the development of human cancers. Special attention will be dedicated to gastrointestinal stromal tumours, GISTs. Progress in research on the aetiopathogenesis of GISTs and their therapeutic approaches will be fully discussed, focusing on the latest tendencies for the treatment of these kinds of tumours.

Geometrically Constrained Derivatives of Indolylglyoxylamides as Ligands Binding the GABAA/BzR Complex

Indolylglyoxylamides are a class of distinctive benzodiazepine receptor ligands, proposed in the mid-eighties as open analogues of -carbolines. Thorough and long-lasting studies of their structure-activity relationships led to the development of a great deal of derivatives, to satisfy increasingly structural and pharmacophoric requirements of the benzodiazepine binding site in the central nervous system. Efforts to pre-organize their flexible structure in the three-dimensional shape adopted when bound to the receptor led to the identification of two novel classes of rigid ligands, characterized by planar tricyclic heteroaromatic cores: the [1,2,4]triazino[4,3-a]benzimidazol-4(10H)-one and the [1,2,3]triazolo[1,2-a][1,2,4]benzotriazin-1,5(6H)-dione. The present review focuses on these selected classes of ligands, whose rational development, in terms of chemical structures and structure-activity relationships, will be fully discussed.