Current Medicinal Chemistry - Anti-Cancer Agents - Volume 1, Issue 2, 2001

Anthracycline antibiotics play an important role in cancer chemotherapy. The need for an improvement of their therapeutic index has stimulated an ongoing search for anthracycline analogues with improved properties. Analogue development was originally limited by a lack of information on the cellular drug target, nevertheless almost 20 years ago the mechanism of action of doxorubicin and daunorubicin was revealed and DNA topoisomerase II was recognised to be their main cellular target.Several anthracyclines interfere with topoisomerase II functions by stabilizing a reaction intermediate in which DNA strands are cut and covalently linked to tyrosine residues of the enzyme. Investigations on the sequence specificity of doxorubicin in vitro and in nuclear chromatin of living cell have led to a molecular model of drug receptor on the topoisomerase II-DNA complex. Anthracyclines are likely placed at the interface between the DNA cleavage site and the active site of the enzyme, forming a DNA-drug-enzyme ternary complex. Moreover, a quite detailed structure-function relationship has been established for anthracyclines. First, drug intercalation is necessary but not sufficient for topoisomerase II poisoning; second, the removal of the 4-methoxy and 3-amino substituents greatly increases the drug activity and third, the 3 substituent of the sugar moiety markedly influences the sequence selectivity of anthracycline-stimulated DNA cleavage. These relationships have been exploited during the last decade by several groups, including ours, in the search for new anthracycline drugs with lower side effects and higher activity against resistant cancer cells. This review will focus on areas of the anthracycline field including synthesis of new analogues, new strategies of synthesis and recent developments in the area of drug delivery.

Amphidinolides A-V represent a family of cytotoxic marine natural products with diverse structural features and pronounced biological activities. Kobayashi and his research group have been reporting over the years the discoveries of these remarkable molecules, one after another, since 1986 when the first report of the series appeared. Thanks to their perseverance and painstaking research, the family is still expanding. The unique structural features and biological activity profiles of these macrolides have obviously attracted the attention of organic chemists worldwide. The total syntheses of three members of the family, amphidinolides J, K and P, have already been achieved. This review tries to chronicle the fascinating chemistries of amphidinolides, studies on the syntheses of some of these molecules and their biological activity profiles.

The loss of p53 function is a very important event in cancer. The absence of a functional p53 in tumours favours cancer development, and it has been suggested that it also influences the efficacy of both chemotherapy and radiotherapy. The p53 pathway is therefore the subject of intense research, both in academia and in industry, to identify new compounds targeting tumours with an altered p53. Different strategies are currently under investigation. They can be divided into two groups: biological and chemical strategies. The biological strategies utilise the immune system to eliminate the tumours overexpressing p53 mutants. Alternatively they use vectors delivering a functional p53 gene in tumours or engineered viruses, which selectively target p53-defective cells. The chemical strategies are based on the design of compounds that stabilise or activate the p53 mutant proteins, inhibit the interaction between p53 and hdm2, or act on the p53-binding chaperone proteins. In this review, the current progress in these different approaches will be analysed.

Over the past two decades, a number of chemical entities have been investigated in the continuing quest to reverse P-glycoprotein (PGP) mediated multidrug resistance (MDR) in cancer. The complexity of interactions between these agents and the proteins responsible for MDR in conjunction with the challenges associated with developing SAR / QSAR relationships for MDR modulators has hampered our ability to develop agents that modulate MDR with enhanced specificity of target, increased efficacy, and minimized toxicity when coadministered with anticancer drugs. With an increased understanding of the molecular interaction, target-mediated SAR and combinatorial chemistry approaches, newer more selective inhibitors have been recently reported. These agents have shown remarkable promise in preclinical trials although their ultimate clinical therapeutic utility remains to be established. The emphasis of this review is placed on the current understanding of modulator-drug transport protein interactions and to review the advances in the structure-based design, synthetic efforts and the cellular pharmacology of MDR modulating activity of a number of known PGP inhibitors.

It has been known for some time that porphyrins and related compounds have the ability to selectively accumulate in tumor tissues, and to persist there for long periods of time. This property, along with the well-described photophysical and photosensitizing properties of porphyrin-type molecules, has led to their potential use as adjuvants and sensitizers in a variety of medical applications, such as in photodynamic therapy (PDT), boron neutron capture therapy (BNCT), radiation therapy (RT) and in magnetic resonance imaging (MRI). Both PDT and BNCT are binary cancer therapies that involve activation of tissue-localized sensitizers with either light (in PDT) or low-energy neutrons (in BNCT). In both of these therapeutic methodologies, local tumor control with minimal side effects relative to other forms of cancer treatment (surgery, radiotherapy, chemotherapy) can be achieved. Porphyrins constitute a major class of pharmacological agents currently under investigation. Photofrin, a porphyrin derivative, has been approved in the USA as a PDT drug by the U.S. Food and Drug Administration (FDA), and also in Japan, Canada and in eleven European countries. Recently, the FDA approved Visudyne, another porphyrin derivative for the PDT treatment of the wet-form of age-related macular degeneration. In addition to cancer treatment porphyrins are also under investigation for application in the treatment of a variety of other diseases.

The prodigiosin-group natural products are a family of tripyrrole red-pigments that are produced by microorganisms such as Streptomyces and Serratia and contain a common 4-methoxy-2,2- bipyrrole ring system. They were first isolated in 1929 and studied as antibiotic and cytotoxic agents in the 1960s, but were not developed clinically due to their high systemic toxicity. However, during the past decade some prodigiosins have shown potentially useful immunosuppressive activity when administered at doses that are not toxic. They have also been found to exhibit selective cytotoxicity against melanoma and liver cancer cells. These results have fueled various studies on the biological mechanisms of the prodigiosins and it has now been established that they inhibit phosphorylation and activation of JAK-3, a cytoplasmic tyrosine kinase associated with the cell surface receptor component called common g-chain. They also uncouple lysosomal vacuolar-type ATPases through promotion of H+ / Cl symport and facilitate oxidative double-strand DNA cleavage in the presence of copper. A simple and elegant synthesis of the prodigiosins has also been developed, which has allowed a number of the natural prodigiosins and synthetic analogues to be prepared. These studies have served to renew interest in the prodigiosin-group natural products. In this review the recent advances on the synthesis, proton-affinity and biological activities of the prodigiosins are discussed. With regard to their anti-cancer properties, particular attention is given to their ability to facilitate oxidative DNA damage, which provides a rationale for the cytotoxic properties of the prodigiosin-group natural products.