Anti-Cancer Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Anti-Cancer Agents) - Volume 9, Issue 7, 2009

Cancer is the second leading cause of death in developed societies, and epidemiologists predict that in a few years it will overcome cardiovascular diseases to become the leading cause of mortality. Although the death rate of many forms of cancer seems to decrease, nevertheless most human tumours remain essentially incurable once they have spread, even though the chemotherapy era has been starting over 50 years ago. Luckily, our understanding of the physiology of both normal and neoplastic cells has largely increased in recent years, raising the hope that we can comprehend the molecular abnormalities that distinguish a cancer cell from its normal counterpart. This knowledge will foster the development of targeted molecular approaches that will kill tumour cells while leaving normal tissues untouched, thus increasing the “therapeutic index” of current cytotoxic agents or allowing the design of new specific anticancer drugs. In designing such sophisticated cancer treatments, it is necessary to consider the processes that govern normal cellular physiology. Thus, the goal of this Issue is to explore enzymes of particular importance to human cancer. Studies on enzymes in cancer date back to 1924 when Warburg and co-workers reported that cancer tissues exhibit a greater rate of aerobic glycolysis. Subsequently, many authors have studied tissue enzymes in the attempt to extrapolate theories regarding malignant growth and describing enzymes patterns in neoplastic tissues. Purpose of this Issue is to consider tumour-associated enzymes as targets for chemotherapeutic agents acting as enzyme inhibitors or as enzyme-activated prodrugs. These latter would realize the Ehrlich's concept of a “magic bullet” for the treatment of cancer, being the “magic bullets” compounds with low toxicity to normal tissues and high efficacy against neoplastic cells. This idea, originally associated with antimicrobial agents, unfortunately misses its target with conventional anticancer drugs. While it is impossible to present a fully comprehensive overview in a fast-moving field that encompasses most aspects of cellular physiology, the contributions in this Issue were selected to reflect different and somehow new areas of cancer research, providing a panoramic view of four different classes of enzymes controlling critical cellular events, which are commonly subverted in human cancers. In relation to each of these enzymes, several molecules are discussed regarding organ- or tumor-selective action. In addition, it is concluded that the development of enzyme inhibitors as well as prodrugs has been relatively successful even though all compounds lack a complete selectivity. Therefore, further work is required to explore the differences between normal and cancer cells and to develop optimal enzyme ligands. Undoubtedly, the contributions in this Issue reflect the state-of-the-art in one of the most exciting areas of cancer chemotherapy, but also in cell biology, biochemistry, and molecular genetics. Nonetheless, either enzyme-activated prodrugs or enzyme inhibitors are no longer a topic restricted to sophisticated scientific discussions, since they are already regarded as a leading hope for the future of cancer therapy by clinical oncologists around the world. In this exciting era in which scientific advances and medical practice are rapidly converging, the aim of this volume is to inform and inspire both scientists and physicians toward a common area of interest.

Metastatic malignant melanoma remains a highly aggressive form of skin cancer for which no reliable methods for treatment exist. Given the increasing incidence of this cancer, considerable attention has focused on the development of new and improved methods for tackling this disease. Within this article, methods for treating melanoma are reviewed and discussed with particular attention focusing on prodrugs that are activated by the tyrosinase enzyme. This enzyme is up-regulated and is of elevated activity within malignant melanomas compared with healthy melanocytes, providing an ideal in-situ tool for the activation of melanoma prodrugs. By way of background to the prodrug strategies discussed within this review, the causes of melanoma, the enzymology of tyrosinase, and the chemistry of the biosynthetic pathways associated with melanogenesis are presented. Aspects of the design, mode of action, and biological profiles of key prodrugs that are activated by tyrosinase, and that show potential for the treatment of melanoma, are then presented and compared.

The systematic improvement of methods used for unraveling physiological and pathological role of proteases, as well as for elucidation of relevant hydrolase structures contributes to the progress in the area of new inhibitor-like drugs development. Many of protease inhibitors have entered clinics and are now successfully applied for the treatment of various systemic disorders caused by deregulation of physiological processes governed by proteolytic enzymes, including cardiovascular, neurodegenerative and inflammatory diseases. A clinical approach based on targeting of proteases involved in pathomechanism of given diseases also stimulates the interest as anti-cancer strategy alternative, or supplementary, to surgical intervention and radiotherapy. In this survey we present some current achievements on the field of development of protease inhibitors designed as potential anti-cancer drugs and/or tools for studying molecular basis of processes associated with the cancer development and spread. Our intention is to show the results of this research in context of the structure-activity relationship (SAR) studies, which explain inhibitor requirements of the target proteases. We also provide the examples of attempts being made to eliminate drawbacks of the earlier-developed inhibitors (e.g. such as low selectivity or poor pharmacological profile arising from their peptide-like character). Moreover, modern approach to protease targets recognition by means of socalled activity-based protein profiling as well as new ‘fail-off’ methodology of in vivo inhibitor screening, which provide structures potent both in vitro and under physiological conditions are also described. At last, an example proving usefulness of high throughput screening as method for selection of the non-peptidic leads for protease inhibitors can be found in this article.

Besides catalyzing the inactivation of various electrophile-producing anticancer agents via conjugation to the tripeptide glutathione, some cytosolic proteins belonging to the glutathione transferase (formerly glutatione-S-transferase; GST) superfamily are emerging as negative modulators of stress/drug-induced cell apoptosis through the interaction with specific signaling kinases. In addition, several data link the overexpression of some GSTs, in particular GSTP1-1, to both natural and acquired resistance to various structurally unrelated anticancer drugs. Tumor overexpression of these proteins has provided a rationale for the search of GST inhibitors and GSTactivated cytotoxic prodrugs. In the present review we discuss the current structural and pharmacological knowledge of both types of GST-targeting compounds.

Protein kinases are one of the largest known families of enzyme characterized by having a well conserved ATP binding pocket. Most of the synthetic kinase inhibitors are ATP-competitive, but display some potential problems, like selectivity, discrepancy between the in vitro and in vivo inhibition assays and an high risk of developing mutation inside the ATP-binding pocket. Recently some new inhibitors with a non-competitive mechanism of action were reported, with intresting results both in vitro and in vivo.

Wilms' tumor gene (WT1) possesses oncogenic functions and is expressed in various kinds of malignancies, which suggests that the gene's product, the WT1 protein, should be one of the most promising cancer antigens. In fact, the WT1 protein was shown to be highly immunogenic in cancer patients. WT1 peptides that could induce WT1-specific CTLs (WT1 CTL peptides) were identified, and vaccination of cancer patients with these WT1 CTL peptides induced immunological responses, which were assessed by ex vivo immunomonitoring, such as the tetramer assay, and in vivo immuno-monitoring, such as the peptide-specific delayed type hypersensitivity reaction. The induced immunological responses then led to clinical responses such as solid tumor shrinkage, a decrease in leukemia cells, and reduction of M-protein (multiple myeloma). Long-term stabilization of disease with good quality of life, which might be characteristic of cancer vaccine therapy, was also reported. It is noteworthy that injection of a “single” kind of WT1 peptide elicited an immunological response strong enough to induce a clinical response, indicating that the WT1 peptide vaccine has therapeutic potential. The number of reports of the successful treatment of cancer patients (not only adult but also childhood malignancies) with WT1 vaccination is increasing. Strategies for further improvement in the efficacy of therapy, including combined use of chemotherapy drugs, molecular-target-based drugs, or WT1 helper peptides, are being proposed. WT1 peptide vaccination in an “adjuvant setting” should be considered a promising treatment to protect against progression or relapse of malignancies in cases with minimal residual disease.

Nitric oxide (NO) prodrugs of the diazeniumdiolate class are routinely used as reliable sources of nitric oxide in chemical and biological laboratory settings. O2-(2,4-dinitrophenyl) diazeniumdiolates, which are derivatized forms of ionic diazeniumdiolates, have been found to show potent anti-proliferative activity in a variety of cancer cells, presumably through the effects of NO. One important member of this class of diazeniumdiolates, O2-(2,4-dinitrophenyl) 1-[(4-ethoxycarbonyl)piperazin-1-yl]diazen-1-ium-1,2-diolate (JS-K), has shown promise as a novel cancer therapeutic agent in a number of animal models. This review describes the developments in chemical and biochemical characterization and structure-activity relationship of JS-K and its analogues. In addition, some molecular mechanistic insights into the observed anti-proliferative activity of JS-K are discussed. Finally, a structural motif is presented for O2-(aryl) diazeniumdiolate nitric oxide prodrugs that show potency comparable with that of JS-K.

The pyranoacridone acronycine (1) exhibits antitumor properties against a large panel of solid tumor models, but its moderate potency and low water solubility severely hampered the subsequent clinical trials. Development of synthetic analogues followed the isolation from several Sarcomelicope species of acronycine epoxide (17), which led to a hypothesis of bioactivation of acronycine by transformation of the 1,2-double bond into the corresponding oxirane. 1,2-Diacyloxy-1,2-dihydroacronycine derivatives exhibited antitumor properties, with a broadened spectrum of activity and an increased potency. The demonstration that acronycine interacted with DNA led to the development of benzo[a], [b], and [c]acronycine analogs. 1,2-Dihydroxy-1,2-dihydrobenzo[b]acronycine esters and diesters were active in human orthotopic models of cancers xenografted in nude mice. The activity of these compounds, exemplified by cis-1,2- diacetoxy-1,2-dihydrobenzo[b]acronycine (49), developed in phase I clinical trials under the code S23906-1, was correlated with their ability to give covalent adducts with DNA, involving reaction between the N-2 amino group of guanines in the minor groove and the ester group at the benzylic position of the drug. The influence of the kinetics of DNA alkylation on the cytotoxic and antitumor properties showed a strong correlation between antiproliferative activity and DNA alkylation kinetics, with the most cytotoxic compounds, appearing as the slowest DNA alkylators. Hybrid compounds associating the acridone or benzo[b]acridone chromophore of acronycine derivatives and the epoxyfuran alkylating unit present in psorospermin also displayed potent antiproliferative activities, alkylating DNA guanine units at position N-7 in the major groove, as natural xanthones belonging to the psorospermin series.

Tumor cells depend on and are able to modulate the tumor stroma establishing a permissive and supportive environment of their own. Targeting the tumor stroma has evolved as a novel concept that has attracted attention of cancer researchers aiming at the treatment of metastatic cancer. The novel paradigm is that modulating the stroma will possibly not cure the cancer, but will make it a manageable disease for long periods of time by prohibiting the cancer from growing beyond a certain mass. Accordingly, in the last years, a multitude of stroma-targeting agents were developed comprising either classic small molecule drugs (e.g. sorafenib, an inhibitor of multiple tyrosine kinases) or recombinant antibodies (e.g. anti-VEGF) for targeting of tumor angiogenesis. Apart from these specifically targeted drugs, some well established drugs, primarily designed for non-oncologic diseases, have revealed antitumor activity on the basis of nuclear receptor modulation unfolding pleiotropic biological effects including stroma modulation. Peroxisome Proliferator Activated Receptor (PPAR) agonists, particularly thiazolidinedione derivatives such as pioglitazone and ciglitazone, are promising examples as they exert both a direct antitumoral and a broad spectrum of anti-stromal, antiangiogenic and immuno-modulating activities. This review will focus on the stroma-mediated anticancer activities of PPAR agonists.