Anti-Cancer Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Anti-Cancer Agents) - Volume 8, Issue 3, 2008

Cancer has remained one of the biggest health threats to the human life and many approaches are being explored for its treatment. Photodynamic therapy (PDT) is one of such approach and it has cured thousands of patients so far. The photodynamic agents selectively enter to the cancerous cells, and exhibit biological response only after exposure to the light. The exact reasons by which photosensitizers are selectively retained in the tumor cells and the mechanisms by which they show tumoricidal effect are not very clear, but for its biological response, PDT requires three components: oxygen, photosensitizer and light. Photodynamic therapy differs from radiation therapy as they interact differently with molecular oxygen. Ionizing radiation produces highly reactive oxygen-derived radical, whereas photodynamic agents are first excited by light and excited sensitizer transfers energy to molecular oxygen which produces singlet oxygen and that reacts with the cellular targets. The ionizing radiations are considered to be very toxic as they target DNA, while photodynamic agents are considered to be relatively safer, as they target cytoplasm, nuclear, mitochondrial and organelle membranes. Efforts are also underway to increase the tumor-specificity by developing target-specific photosensitizers. The present issue deals with the recent advancement in the area of photodynamic therapy (PDT). First three articles deal with the recent progress on the photodynamic therapy. Prof. Pandey et al. summarizes the concept of PDT, the selection criteria for designing the effective photosensitizers and the utility of porphyrin-carbohydrate conjugates in PDT. Kokube et al. describes the recent advancement in the two-photon absorption (2PA) PDT, which allows a more selective treatment of deeper-locating cancers. Mark Wainbringt has made an elegant comparison in the first and second-generation PDT agents. Prof. Zaleski describes the role of diazo compounds in the development of phototherapeutic agents for biomedical applications. Authors emphasized that natural or synthetic diazo compounds are susceptible to redox activated N2 loss, so transition metal complexes containing redox-active excited states that absorb in the tissue transparent therapeutic window have potential to be used as new therapeutic agents. Interestingly, highly π- conjugated molecules such as porphyrins and chlorins, which serve as the primary pigment for current PDT, have been able to support conjugated diazoketone functionality at the macrocycle periphery. These synthetic advances have made diazo constructs to serve as in situ biological labels or as recognition elements to probe biochemical mechanisms. I sincerely thank to all authors and reviewers for their contribution in the preparation of this especial issue. I sincerely thank to Prof. Michelle Prudhomme, Editor-in-Chief, Anti-Cancer Agents in Medicinal Chemistry, for giving me an opportunity to act as a guest editor of this prestigious international journal. It is my believe that readers will enjoy this special issue and will stimulate interactive research with other specialist areas.

In recent years, a number or review articles describing the utility of porphyrin-based compounds in photodynamic therapy have been published.1 Currently, efforts are also underway in various laboratories to increase the tumor-specificity by developing targetspecific photosensitizers. One of such attempts has been to synthesize a series of carbohydrate-porphyrin conjugates and investigate their ability to target carbohydrate- recognized proteins, which are known for their high expression in certain tumors. The present article is focused on the synthesis and biological significance of carbohydrate conjugated photosensitizers.

Photodynamic therapy (PDT) is a treatment for tumors and accepted in several countries in the world. Introduction of twophoton absortion (2PA) into PDT allows spatially selective treatment of cancers. Possibilities and limitations of the use of two-photon excitation in PDT are discussed, and many literatures in this area are reviewed. The conclusions are that 2PA-PDT has an advantage for higher selectivity than one-photon absorption PDT, and femtosecond pulsed laser is more suitable for 2PA-PDT than pico- and nanosecond pulses. However, most of photosensitizers used in the past studies had low 2PA cross section values less than 50 GM, and resulted in a low PDT efficiency under two-photon irradiation conditions. To realize 2PA-PDT, much larger 2PA cross sections must be required.

The first 20 years of anticancer photodynamic therapy (PDT) were based on the utility of the oligomeric mixture haematoporphyrin derivative (HpD) in various forms. More recently new derivatives have become available, both porphyrin-derived and employing new chromophores, for example from the phthalocyanine and phenothiazinium families. In addition, a major research effort has been rewarded with the clinical acceptance of the porphyrin precursor 5-aminolaevulinic acid (ALA). New photosensitisers intended for clinical use must exhibit advantageous drug performance profiles compared to the first-generation porphyrin derivatives. This can be seen, in vitro, in improved photophysical properties such as the extension of the useful light absorption spectrum into the near infrared - offering greater tissue penetration - as well as in the synthesis of pure compounds rather than mixtures. In this review, recent developments in photosensitiser families are discussed with respect to in vitro performance indicators and to potential application in oncology.

DNA is an established biological target for many organic natural products that react by alkylation or H-atom abstraction via key functional groups such as cyclopropane, aziridine, enediyne, and terminal diazo functionalities. Remarkably, although more than 20 natural product derivatives compose the latter class, the precise mechanism of action and specific biological target remain to be elucidated. Despite these biochemical uncertainties, more than 100 years of diazo/diazoketone chemistry exists. Much of this work involves photochemical N2 extrusion to generate an initial carbene intermediate capable of insertion (singlet), H-atom abstraction (triplet), or ketene formation and subsequent nucleophilic addition (Wolff rearrangement). The trigger advantage of photochemical reactivity, coupled with the entropic gain of deazetation, and the high reactivity of the resulting intermediate, have led researchers to consider diazo compounds as potential phototherapeutric agents for medical applications. Such a strategy could serve as an alternative to 1O2 generation in photodynamic therapy (PDT), particularly in solid tumors or other hypoxic environments. Since diazoparaquinone natural products, and diazo compounds in general, are susceptible to redox activated N2 loss, transition metal complexes containing redox-active excited states that absorb in the tissue transparent therapeutic window have potential as new therapeutic agents. Moreover, highly π-conjugated molecules such as porphyrins and chlorins, which serve as the primary pigment for current PDT due to intense absorption bands throughout the region of 600-850 nm, have only recently been able to support a conjugated diazoketone functionality at the macrocycle periphery. These synthetic advances have now made diazo activation through visible region photolysis possible, and have led to characterization of a range of remarkable molecular photoproducts including azeteoporphyrinoids and O-H/N-H insertion products. In addition to protein or DNA alkylation, the latter reactivity leads to potential for these constructs to serve as in situ biological labels or as recognition elements to probe biochemical mechanisms.

Cells can obtain energy through the oxygen-dependent pathway of oxidative phosphorylation (OXPHOS) and through the oxygen-independent pathway of glycolysis. Since OXPHOS is more efficient in generating ATP than glycolysis, it is recognized that the presence of oxygen results in the activation of OXPHOS and the inhibition of glycolysis (Pasteur effect). However, it has been known for many years that cancer cells and non-malignant proliferating cells can activate glycolysis in the presence of adequate oxygen levels (aerobic glycolysis or Warburg effect). Accumulating evidence suggests that the persistent activation of aerobic glycolysis in tumor cells plays a crucial role in cancer development; the inhibition of the increased glycolytic capacity of malignant cells may therefore represent a key anticancer strategy. Although some important knowledge has been gained in the last few years on this growing field of research, the basis of the Warburg effect still remains poorly understood. This communication analyzes why cancer cells switch from OXPHOS to glycolysis in the presence of adequate oxygen levels, and how these cells manage to avoid the inhibition of glycolysis induced by oxygen. Several strategies and drugs that may interfere with the glycolytic metabolism of cancer cells are also shown. This information may help develop anticancer approaches that may have clinical relevance.

Of late medicinal plants and functional foods rich in bioactive phytochemicals have received growing attention as potential agents for cancer chemoprevention. Accumulating evidence from epidemiological studies as well as laboratory data supports the anticancer properties of garlic widely used as a medicinal herb and spice. Garlic and its organosulfur compounds (OSCs) appear to exert their anticarcinogenic effects through multiple mechanisms that include modulation of carcinogen metabolism, inhibition of DNA adduct formation, upregulation of antioxidant defences and DNA repair systems, and suppression of cell proliferation by blocking cell cycle progression and/or inducing apoptosis. Since multiple signaling pathways are dysfunctional in cancer and new oncogenic mutations accumulate with carcinogenic progression, dietary agents such as garlic with its rich array of bioactive OSCs that modulate cancer cascades offer promise as potential chemopreventive and chemotherapeutic agents.

Proteolytic caspase enzymes play a central role in cell apoptosis, or programmed cell death, often as integrating elements of different stimuli leading to the cell death. Since blockade of apoptotic pathways are fundamental for cell survival and proliferation, particularly in cancer cells, the activation of caspases is an attractive target for anticancer therapy. This review describes some of the druggable therapeutic targets thus far identified within the core apoptotic machinery, the corresponding drugs that have been developed, their effects on caspase-dependent apoptotic pathways and their potential impact on the therapy of cancer. With several successful anticancer drugs on the market and numerous compounds in preclinical and clinical developments, modulators of caspase-dependent apoptotic pathways belong to the most important category of anticancer agents.

c-Src is a proto-oncogene involved in the genesis of and invasion by many cancers. This non-receptor tyrosine kinase also plays a crucial role in bone homeostasis, since inhibition or deletion of c-Src impairs the function of osteoclasts, the bone resorbing cells. It is thus conceivable that c-Src could be a suitable target for the pharmacological treatment of cancers, skeletal metastases and diseases of bone loss, such as osteoporosis. The pyrrolo-pyrimidines CGP77675 and CGP76030 proved to be effective in preventing bone loss in animal models, while the effect of AZD0530, a dually active inhibitor of c-Src and Bcr-ABL, on bone resorption, has been tested in a Phase I clinical trials with promising results. As far as the metastatic bone disease is concerned, c-Src inhibitors could potentially have inhibitory effects both on osteoclasts and on tumour cells, and could disrupt the vicious circle established between these cell types in the bone microenvironment. In accord with this idea, CGP76030 is able to reduce the incidence of osteolytic lesions and of visceral metastases, and to suppress morbidity and lethality in a bone metastasis mouse model without obvious adverse effects. The purine-based c-Src inhibitor AP23451 and the dual c-Src/Abl inhibitors AP22408 and AP23236 proved efficacious in reducing bone metastases in preclinical studies. These results open a new avenue for the development of innovative therapies for the treatment of bone metastatic disease.