Current Medicinal Chemistry - Volume 12, Issue 19, 2005

Cisplatin is an essential antineoplastic agent whose introduction in clinical use revolutionized the treatment of several solid malignancies, especially those of germinative origin. The unfavorable toxicological profile of this drug, however as well as the resistance of some common malignancies solicited the search of platinum complexes, characterized by lower toxicity and/or broader antitumor spectrum. Thus during the last three decades a plethora of several thousand platinum coordination compounds have been synthesized and evaluated as potential antineoplastic agents. Despite of the numerous compounds investigated however only few of the proved to be of clinical significance and actually none of them could be considered as an ideal substitute for cisplatin regarding both lower toxicity and broader spectrum of anticancer activity. To a great extent the platinum-based drug discovery was confined at structural modification of the parent compound in line with the classic structure-activity relationship concept. Conversely, since the majority of platinum complexes developed so far are closely related structural analogues of cisplatin, it is not surprising that they produce similar cellular effects and any altered pattern of antitumor activity and/or toxicity is likely to be due to pharmacokinetic, rather than truly mechanistic, factors. Studies over the last few years have shown that the structural resemblance to cisplatin is not an absolute requirement for cytotoxicity, which broadens the search for cisplatin analogues towards non-classical compounds with prominent structural/pharmacodynamic dissimilarity to the prototype. This review covers the major approaches to elaboration of non-classical platinum complexes with emphasis on complexes interacting with DNA in a cisplatin-dissimilar fashion and complexes with tumor-targeted cytotoxicity.

The use of antisense oligonucleotides as therapeutic agents has generated considerable enthusiasm in the research and medical community. Antisense oligonucleotides as therapeutic agents were proposed as far back as in the 1970s when the antisense strategy was initially developed. Nonetheless, it has taken almost a quarter of a century for this potential to be realized. The principle of antisense technology is the sequencespecific binding of an antisense oligonucleotide to target mRNA, resulting in the prevention of gene translation. The specificity of hybridization by Watson-Crick base pairing make antisense oligonucleotides attractive as tools for targeted validation and functionalization, and as therapeutics to selectively modulate the expression of genes involved in the pathogenesis of diseases. The last few years have seen a rapid increase in the number of antisense molecules progressing past Phase I, II and III clinical trials. This review outlines the basic concept of the antisense technology, its development and recent potential therapeutic applications.

Obesity and osteoporosis have grave consequences for human health, quality of life, and even the efficiency of the labor force and economy. However, these pathologies share a common cell progenitor, revealing a surprising target for drug research and development. Recent findings show that high adipocyte count in bone marrow is directly related to bone loss, as fat cells replace osteoblasts (or bone-forming cells). The objective of this review is to examine the importance of adipocyte apoptosis in the treatment of obesity and/or osteoporosis, with special emphasis on natural products as promising leads for drug development. We have induced in vivo adipocyte apoptosis, using leptin, ciliary neurotrophic factor (CNTF), beta adrenergic agonists and conjugated linoleic acid (CLA) in rodents. The results of leptin treatments on rats are suppressed food intake, reduced body weight, reduced body fat, adipocyte apoptosis, and elevated energy expenditure. Further, leptin treatment of leptin-deficient (ob/ob) mice increases endosteal bone formation and bone mineral density. Adipocyte apoptosis has also been induced in vitro using tumor necrosis factor-alpha (TNF-α), (-)-epigallocatechin gallate (EGCG) from Camellia sinensis and ajoene, from Allium sativum. Natural products have potential for inducing apoptosis of adipose tissue, inhibiting bone marrow adipogenesis and increasing the expression of osteogenic factors in bone, thereby yielding effective treatments for obesity and osteoporosis.

The antedrug concept was introduced by Lee and Soliman in 1982 in designing potent, yet safer locally active anti-inflammatory steroids. Antedrug is defined as an active synthetic derivative that is designed to undergo biotransformation to the readily excretable inactive form upon entry in the systemic circulation. Thus, are minimizing systemic side effects and are increasing the therapeutic indices. Steroid-21-oate esters have been developed as the first of this kind, which quickly hydrolyzed to the corresponding inactive steroid acids thereby exerting minimal systemic side effects. Later, other steroidal and nonsteroidal antedrugs have also been developed. The cost, complexity and length in development of a new therapeutic drug, in addition to the adverse drug reactions, the potential risk factors causing the withdrawal of the drugs from the market, have made the approach of antedrug design unique and attractive to the scientists involved in drug design. Considering these factors, the concept which strictly designed to eliminate the deleterious adverse systemic effects, is becoming an affordable approach in drug development arena. This review is not intended to be comprehensive; instead the focus will be on the recent advances in steroidal as well as nonsteroidal antedrugs, which appear to offer new leverage to the development of safer and more efficacious therapeutic agents.

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.

Since 1940s, Quinoxaline 1,4-dioxides (QdNO's) are known as potent antibacterial agents, and subtherapeutic levels have been used to promote growth and improve efficiency of feed conversion in animal feed. They have also shown a selective cytotoxicity against hypoxic cells present in solid tumours. Furthermore, recent studies have put in evidence that QdNO's are endowed with antitubercular, antiprotozoal and anticandida activities. On the other hand, several authors have reported about photoallergic and mutagenic effects of some derivatives. QdNO's may also cause the development of antibiotic-resistant bacteria and influence the horizontal transfer of virulence genes between bacteria. In this review article we report the biological properties, the mode of action and Structure Activity Relationship (SAR) studies of the QdNO derivatives. Furthermore, some cytogenetic and genotoxic effects, classical and more recent method of synthesis, the quinoxaline 1,4-dioxides, and some of their most important reactions, were also reported.

Transdermal drug delivery offers numerous advantages over conventional routes of administration; however, poor permeation of most drugs across the skin barrier constitutes a serious limitation of this methodology. One of the approaches used to enlarge the number of transdermally-applicable drugs uses permeation enhancers. These compounds promote drug permeation through the skin by a reversible decrease of the barrier resistance. Enhancers can act on the stratum corneum intracellular keratin, influence desmosomes, modify the intercellular lipid domains or alter the solvent nature of the stratum corneum. Even though, hundreds of substances have been identified as permeation enhancers to date, yet our understanding of the structureactivity relationships is limited. In general, enhancers can be divided into two large groups: small polar solvents, e.g. ethanol, propylene glycol, dimethylsulfoxide and amphiphilic compounds containing a polar head and a hydrophobic chain, e.g. fatty acids and alcohols, 1-dodecylazepan-2-one (Azone), 2-nonyl-1,3- dioxolane (SEPA 009), and dodecyl-2-dimethylaminopropanoate (DDAIP). In this review we have focused on structure-activity relationships of amphiphilic permeation enhancers, including the properties of the hydrophobic chains, e.g. length, unsaturation, and branching, as well as the polar heads characteristics, e.g. hydrogen bonding ability, lipophilicity, and size. We present over 180 examples of enhancers with different polar head to illustrate the structural requirements and the possible role of the polar head. We have given an overview of the methods used for investigation of the mechanisms of permeation enhancement, namely differential scanning calorimetry (DSC), infrared (IR) and Raman spectroscopy, X-ray diffraction and future perspectives in this field. Furthermore, biodegradability and chirality of the enhancers are discussed.