Current Pharmaceutical Design - Volume 8, Issue 27, 2002

The enediynes remain among the most potent antitumoral agents to have been discovered in the past decade. Following prodrug activation, the enediynes undergo cycloaromatization reactions resulting in formation of highly reactive diradical intermediates. The diradical species engage in atom-transfer chemistry to produce neutral arene products, in the process inducing damage to key macromolecules. Several of the naturally occurring members of the enediyne family of antibiotics have entered clinical trials, and this has prompted the design of synthetic enediynes, where the enediyne ‘warhead’ is conjugated to a targeted delivery vehicle. This review will describe ecent efforts using chemical synthesis to identify and improve the target specificity of designed enediynes, and to establish efficient methods to achieve prodrug activation. Finally, new horizons will be examined, including the use of post-cycloaromatized enediyne templates as recognition elements for unique DNA and RNA microenvironments.

Gene therapy will change medicine by treating the diseases at their core levels revolutionizing the way to deliver functional proteins. The development of this technology relies in designing optimal systems for DNA transfer and expression (transfection), cationic lipids being a promising alternative. Being safer than viral vectors, they also allow the delivery of larger plasmids and can be easily GMP-manufactured and stored. The main problem associated with the use of these vectors is their transfection efficiency, which is still inferior to viral methods. In this paper we present an overview of the correlations between the chemical structure and biological activity for the principal classes of cationic lipids. Key issues in the design of this class of transfection agents are presented, as well as the future trends.

Binding of ligands such as polycyclic aromatic hydrocarbons to the Aryl hydrocarbon Receptor (AhR) and the sequence of events leading to induction of xenobiotic-metabolising enzymes such as the cytochrome P450 isoform 1A1 and subsequent generation of DNA adducts is historically associated with the process of chemical carcinogenesis. Cancer chemopreventative agents, on the other hand, often exert their biological effect at least in part through antagonism of AhR-induced carcinogenesis. A third scenario associated with AhR binding could occur if the induction of xenobiotic enzymes and subsequent DNA damage causes apoptosis. If this occurs selectively in tumour cells whilst sparing normal tissue, the AhR ligand would have a therapeutic cytotoxic effect. In this review we survey for the first time the major classes of reported AhR ligands and discuss the biological consequences of AhR binding in each case. The use of AhR ligands as cancer chemotherapeutic agents, as illustrated by the case of the 2-(4-aminophenyl)benzothiazole prodrug Phortress, is discussed as a therapeutic strategy.

Telomerase is a cellular ribonucleoprotein reverse transcriptase responsible for the maintenance of telomeres, the tandemly repeating guanine-rich nucleic acid sequences at the 3'-ends of eukaryotic chromosomes that serve to protect chromosomal stability and maintain integrity. Telomerase enzyme activity is essential for the sustained proliferation of most immortal cells, including cancer cells, and is currently an important recognised target for the development of novel and potentially tumour-specific anticancer chemotherapeutics. Herein, we review recent advances in the design and development of telomerase inhibitors for the treatment of cancer. To date, these have included antisense strategies, reverse transcriptase inhibitors, and agents capable of interacting with high-order telomeric DNA tetraplex (or “G-quadruplex”) structures in such a way as to prevent enzyme access to its required linear telomeric DNA substrate. Critical appraisal of each distinct approach is provided together with highlighted areas for continued development necessary to further refine the present disparate classes of telomerase inhibitors for use in clinically viable therapies.

Camptothecins are cytotoxic agents with a wide spectrum of antitumor activity. The unique mechanism of action, the impressive preclinical efficacy and the clinical success of irinotecan and topotecan have stimulated intensive efforts to identify novel analogues. The development of novel camptothecins was recently rationalized on the basis of the detailed knowledge of mechanism of drug-target interaction and was aimed to overcome the major limitations of these drugs (i.e. lactone ring instability and reversibility of topoisomerase I-DNA cleavage complexes). The development of novel series of analogues (7-substituted camptothecins, silatecans and homocamptothecins) resulted in identification of promising compounds, which are currently in clinical development. Considering the lack of precise correlations between preclinical activity and clinical efficacy of camptothecins, the potential advantages of novel analogs in clinical therapy remains to be documented. However, a rational basis for drug selection and development is now provided by the recognition of major limitations of these agents and by a detailed knowledge of multiple interactions between drug, cellular target and serum albumin. Inhibition of the nuclear enzyme DNA topoisomerase I has proven to be a promising strategy in the design of antitumor agents, in spite of a limited cellular basis of selectivity in cytotoxic action of camptothecins (i.e., overexpression of the target enzyme in tumor cells, and increased sensitivity of proliferating cells). The interest in topoisomerase I as a therapeutic target promoted various efforts to identify other chemotypes effective as topoisomerase inhibitors and chemical / modelling efforts to rationally design specific analogs among known inhibitors. Additional approaches, including drug delivery / formulation, optimization of dose / schedule and route of administration, are expected to improve the therapy with camptothecins and other inhibitors.