Current Medicinal Chemistry - Volume 13, Issue 5, 2006

Designing and developing truly tumor-specific prodrugs remains a challenge in the field of cancer chemotherapy. Active targeting strategies, on the one hand, aim at exploiting membrane-associated receptors or antigens for drug delivery; on the other hand, the enhanced vascular permeability and retention of macromolecules in tumor tissue substantiates the concept of passive targeting. Consequently, research efforts have concentrated on conjugating anticancer agents with a wide spectrum of carriers including antibodies, peptides, serum proteins, and synthetic polymers. Conversely, low-molecular weight prodrugs of anticancer agents have been developed that do not bear an active or passive targeting moiety, but are activated by tumorassociated enzymes at the tumor site. Anthracyclines probably represent the class of anticancer agents that has been most widely used for the development of prodrugs. This overview gives an update of the various low- and high-molecular weight prodrugs of anthracyclines, e.g. with antibodies, peptides, carbohydrates, serum proteins or synthetic polymers, that have been developed over the past 20 years and that exemplify the salient features of a respective drug delivery system. A detailed description will be dedicated to anthracycline prodrugs that have reached an advanced stage of preclinical testing or that have entered clinical trials.

As one of the most important essential transition metals, copper is involved in a variety of biological processes such as embryo development, connective tissue formation, temperature control and nerve cell function. It is also related to severe diseases such as Wilson's and Menkes diseases and some neurological disorders. Novel components of copper homeostasis include copper-transporting P-type ATPases, Menkes and Wilson proteins, and copper chaperones in humans have been identified and characterized at the molecular level. These findings have paved the way towards better understanding of the role of copper deficiency or copper toxicity in physiological and pathological conditions. Therefore, organic compounds that can interfere with copper homeostasis may find therapeutic application in copper-dependent diseases. The antitumor activity of copper complexes was reported several decades ago, and many new complexes have demonstrated great antitumor potential. Copper complexes may have relatively lower side effects than platinum-based drugs, and are suggested to be able to overcome inherited or acquired resistance of cisplatin. In this overview, the most recent advances in copper homeostasis, copper-related chelation therapy and design of copper-based antitumor complexes will be summarized.

This update covers the literature for 2002 and 2003 dealing with the main topic of the previous review entitled Heterocyclic nucleosides. Chemical synthesis and biological properties and published in Curr. Med. Chem.-AIA, 2002, 1, 389. As in the first review, the papers in this survey are grouped by the type of the heterocyclic system that acts as a spacer between the hydroxymethyl group and the base moiety.

A better understanding of the biological roles and the pathological consequences of thiol-dependent enzymes has emerged in recent years, and hence considerable progress has been made in identifying and delineating cysteine proteases that can be considered promising drug targets from those involved in housekeeping functions. Cysteine proteases have been implicated in a wide variety of disease processes ranging from cardiovascular, inflammatory, viral and immunological disorders to cancer. The first milestone in drug development of cysteine protease inhibitors has probably been reached, as IDN-6556 (a broad spectrum caspase inhibitor) has recently received Orphan Drug label by the U.S. Food and Drug Administration for use in the treatment of the patients undergoing liver transplantation and other solid organ transplantation. IDN-6556, which blocks apoptosis, is in Phase II human clinical trial in patients undergoing liver transplantation. In addition, more than ten cysteine protease inhibitors are presently at various phases of clinical development/trials for diverse diseases. This review emphasises on the new development from the literature reports since the year 2000 in the exploration of potential cysteine proteases as prospective drug targets, and the investigation of promising inhibitors that can potentially be developed for the treatment of human diseases. Transglutaminases, another class of thiol-dependent enzymes, are not discussed here.

AMP-activated protein kinase (AMPK) is an enzyme that works as a fuel gauge, being activated in situations of high-energy phosphate depletion. Upon activation, AMPK functions to restore cellular ATP by modifying diverse metabolic pathways. AMPK is activated robustly by skeletal muscle contraction and myocardial ischemia, and may be involved in the stimulation of glucose transport and fatty acid oxidation produced by these stimuli. In liver, activation of AMPK results in enhanced fatty acid oxidation and in decreased production of glucose, cholesterol, and triglycerides. Recent studies have shown that AMPK is the cellular mediator for many of the metabolic effects of drugs such as metformin and thiazolidinediones, as well as the insulin sensitizing adipocytokines leptin and adiponectin. These data, along with evidence from studies showing that chemical activation of AMPK in vivo with 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) improves blood glucose concentrations and lipid profiles, make this enzyme an attractive pharmacological target for the treatment of type 2 diabetes and other metabolic disorders.

Parkinson's disease (PD) is a slowly progressive neurodegenerative disorder characterized by the loss of dopaminergic neurons in the Substantia Nigra pars compacta (SNpc), striatal dopamine deficiency and appearance of Lewy bodies. Inflammatory and immune, or even autoimmune, stigmata, have been described in post-mortem brains of PD patients. Although disputed in humans, a reactive astrocytosis and a lymphocytic infiltration in the SNpc have been observed in animal models of PD, which need further examination. This review summarizes the current knowledge on brain inflammation in humans with PD, and how inflammation and/or (auto)immune reactions within the SNpc could be linked to other pathophysiological mechanisms that have been hypothesized for the etiology of PD, such as oxidative stress, exposure to neurotoxins, and postinfectious or post-traumatic injuries. In particular, we discuss how microglial cells could be activated during the course of PD, and present a new hypothesis that PD-linked protein (α-synuclein, in particular) aggregates could be implicated in their activation, to induce a chronic and sustained inflammation involved in the progression, at least, of the disease. The current status of anti-inflammatory agents, either already tried in PD clinical trials or putatively usefull as adjuvant therapies for PD, is also discussed.