Current Medicinal Chemistry - Volume 12, Issue 8, 2005

Coumarins, also known as benzopyrones, are present in remarkable amounts in plants, although their presence has also been detected in microorganisms and animal sources. The structural diversity found in this family of compounds led to the division into different categories, from simple coumarins to many other kinds of policyclic coumarins, such as furocoumarins and pyranocoumarins. Simple coumarins and analogues are a large class of compounds that have attracted their interest for a long time due to their biological activities: they have shown to be useful as antitumoural, anti-HIV agents and as CNSactive compounds. Furthermore, they have been reported to have multiple biological activities (anticoagulant, anti-inflammatory), although all these properties have not been evaluated systematically. In addition, their enzyme inhibition properties, antimicrobial and antioxidant activities are other foremost topics of this field of research. The present work is to survey the information published or abstracted from 1990 till 2003, which is mainly related to the occurrence, synthesis and biological importance of simple coumarins and some analogues, such as biscoumarins and triscoumarins. Data are also highlighted, concerning the development of new synthetic strategies that could help in drug design and in the work on SAR or QSAR.

Matrix metalloproteinases (MMP) and their inhibitors (TIMP) are central factors in the control of extracellular matrix turnover. They are important in normal physiology and also during a range of pathological states. Only recently has their role in cardiovascular disease been explored and their analysis through measurements in blood been studied. We have systematically identified clinical articles relevant to coronary artery disease from the last 10 years using MEDLINE. In this review we outline the structure, function and regulation of metalloproteinases and their key roles in angiogenesis, stable and unstable coronary artery disease. Metalloproteinases and their inhibitors are fundamental mediators of change in aging and atherosclerosis, the cell membrane, and in myocardial and vascular tissue. Defining their overall importance and understanding their complex interrelationships with pressure, thrombosis and local neural and hormonal tone will require detailed clinical study. The modulation of MMP and TIMP activity using drugs that affect the expression and function of these proteins will provide us with new ways to treat these serious and disabling diseases, and we explore potential mechanisms and treatments.

The object of this paper is to summarize for the past two years the most recent development in the field of prostate cancer and 5α-reductase inhibitors. In addition we are also including some results on the synthesis and pharmacological evaluation of new steroidal compounds developed in our laboratory. Most of the new steroidal derivatives are based on the progesterone skeleton and showed a high inhibitory activity for the enzyme 5α-reductase. Presently, similar compounds are used for the treatment of androgen dependent diseases such as: hirsutism, androgenic alopecia, benign prostatic hyperplasia and prostate cancer. Dihydrotestosterone 2 (Fig. 1) a 5α-reduced metabolite of testosterone 1 has been implicated as a causative factor for the progression of these diseases, largely through the clinical evaluation of males who are genetically deficient of the enzyme steroid 5α-reductase. As a result of this study, the inhibition of this enzyme has become a pharmacological strategy for the design and synthesis of new antiandrogenic drugs. The advent of finasteride 7 (Fig. 3) a 5α-reductase inhibitor has greatly alleviated the symptoms associated with benign prostatic hyperplasia. In our laboratory, we recently synthesized several new 16β-methylpregnadiene-3,20-diones: 40, 41 (Fig. 8), 16β-phenylpregnadiene-3,17a-dione derivatives 46 and 47 (Fig. 9) and 49 (C-4 bromoderivative) (Fig. 11), 52- 56 (Fig. 13). The analogue pregnatriene derivatives were also prepared: 44, 45 (Fig. 9) 50, 51 (Fig. 11) and 57- 60 (Fig. 13) These compounds were evaluated as 5α-reductase inhibitors in the following biological models: Penicillium crustosum broths, the flank organs of gonadectomized male hamsters, the incorporation of radiolabeled sodium acetate into lipids, the effect of the new steroids on the reduction of the weight of the seminal vesicles and on the in vitro metabolism of [3H]T to [3H]DHT in seminal vesicles of homogenates of gonadectomized male hamsters. All trienones 44, 45, 50, 51 and 57-60 in all biological models showed consistently a higher 5α-reductase inhibitory activity than the corresponding dienones: 40, 41, 46, 47, 49 and 52-56. We believe that with these compounds the 5α-reductase enzyme is inactivated by an irreversible Michael type addition of the nucleophilic portion of the enzyme to the conjugated double bond of the steroid. The trienones having a more coplanar structure react faster with the enzyme thus showing a higher inhibitory activity.

Chagas Disease, caused by the T. cruzi parasite, is one of the largest public health problems in the Western hemisphere. Although its spread has diminished due to vector eradication programs, effective chemotherapeutics for the disease itself remain elusive. Many efforts towards the development of antiparasitic agents active against a number of targets have been described recently in the literature. This review summarizes developments in trypanosidal agents from 2000 through 2003.

G-protein-coupled receptors (GPCRs) constitute the largest but the most divergent class of cell surface proteins. Although they are thought to share a common 3D-structure composed of seven transmembrane helical domains, they can be activated by extracellular signals as diverse as light, peptides, proteins, lipids, organic odorants, taste molecules, nucleotides or nucleosides. They are involved in an extraordinarily large number of physiological functions and are therefore potential drug targets for many human diseases. During the last decade various GPCRs have been successfully expressed in S. cerevisiae. Yeast is an attractive expression system because it offers the genetic engineering tools typical of a microorganism while possessing an eukaryotic type of secretory pathway and post-translational machinery. This host is particularly attractive for in-vivo manipulation of these receptors due to the high homology between the yeast pheromone signaling pathway and that of mammalian GPCRs. When expressed in yeast, mammalian GPCRs have been shown to couple functionally to either the endogenous yeast Ga (Gpa1), or co-expressed mammalian Ga subunits (wildtype or chimeric), and are characterized by a similar pharmacology in response to agonists or antagonists as in native cells. Heterologous expression of wild type or mutant GPCRs in S. cerevisiae allows a rapid assessment of their ability to detect and transduce extracellular stimulations, through the use of a reporter system. Furthermore, this approach is amenable to high-throughput screening of new drugs, which would provide a determinant advantage in the field of therapeutic research, and also for investigation of the still unknown ligands of orphan receptors. This review will focus on the latest developments of yeast-based technology to screen for potential GPCR agonists/antagonists.

In this review the structural and functional aspects of dipeptidyl peptidase IV (DPP IV) will be described, and the therapeutic potential of DPP IV inhibitors will be highlighted. DPP IV will be situated in clan SC, a group of serine proteases that contains several proline specific peptidases. Structural aspects of DPP IV and its interaction with different types of inhibitors are recently revealed by the publication of several crystal structures. Especially the design and development of new DPP IV inhibitors based on the threedimensional structure, substrate specificity and catalytic mechanism will be discussed. In the last years there was an important development of new pyrrolidine-2-nitriles with very promising therapeutic properties for the treatment of type 2 diabetes. The role of DPP IV in peptide metabolism of members of the PACAP/glucagon peptide family, neuropeptides and chemokines has been thoroughly investigated during recent years. This is directly related to the promising therapeutic potential of DPP IV inhibitors in the treatment of type 2 diabetes and in the treatment of immunological disorders. Several inhibitors are currently under investigation in clinical trials for the treatment of type 2 diabetes and represent a new class of drugs for the treatment of this disease.