Anti-Cancer Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Anti-Cancer Agents) - Volume 8, Issue 2, 2008

Cancer has been one of the most deadly diseases characterized by uncontrolled cell divisions and the ability of these cells to spread either by invasion, or by metastasis. It has overtaken the heart disease which is one of the commonest causes of death in some developed countries. Cancer affects people at all ages, but risk tends to increase with age. Worldwide over 11 million people are diagnosed with cancer and 7 million deaths are reported annually. It is estimated that there will be 16 million new cases every year by 2020. In spite of improved understanding of molecular biology of cancer and advances in oncology, replacement of conventional therapies like chemotherapy and radiation therapy still remains impossible. Natural product has been a source of new drugs since ancient times and about 60% anti-cancer drugs available today, are either derived from natural sources or their synthetic analogues. Some of the notable plant based drugs that has entered in the clinical trials are taxol, obtained from the bark of pacific yew trees-Taxus brievifolia, camptothecin isolated from the Chinese ornamental tree Camptpotheca acuminata. Camptothecin showed great promises in the 1970's, but its clinical use was hampered due to its severe side effects. The structure activity relationship studies conducted on camptothecin derivatives resulted in the discovery of anti-cancer drugs such as topotecan and irinotecan. Microorganisms have also been the source of the key drugs for cancer chemotherapy and some of the microorganism based anticancer drugs are bleomycins, dactinomycin, mytomycine, anthracylinones, calchiamycin, dynamycine, daunomycin and doxorubicin (adriamycin). All of these compounds were introduced to the clinic before their mode of action had been determined. The anti-cancer activity of most of these compounds is due to their ability to cleave the DNA through different modes. This especial issue entitled “Recent advances in cancer chemotherapy” provides glimpses of recent development on anti-cancer drugs that includes synthetic, semi-synthetic, natural products and their clinical applications. The articles are written by leading scientists in the field which clearly shows that there are indeed fascinating and fundamentally important problems to be addressed and that considerable advances towards their understanding have been made. The present issue deals with the anticancer agents of natural sources or their synthetic or semi-synthetic derivatives. Enediyne class of compounds has received much attention of the scientist in recent years due to their potential use in the anti-cancer drug discovery programme. Shao et al. describes the recent progress, particularly in the area of biosynthesis, immunoconjugates and clinical studies of lindamycin. The pharmacological applications of lidamycin in cancer therapy and its potential use as anti-cancer agents have also been discussed. Dembitsky et al. presented a comprehensive literature collection on the acetylenic anticancer natural products. The review presents anti-cancer activity of more than 300 acetylenic metabolites isolated from terrestrial and aquatic organisms. Parmar et al. presented an excellent literature collection on the natural polyphenolic compounds as antiinvasive agents. Prof. Beck-Sickinger described the role of radiolabelled receptor binding peptides as a new class of radiopharmaceuticals for tumor scintigraphy and to treat cancers by using peptide receptor radiation therapy (PRRT). Lastly, Bifulco et al. discuss preliminary clinical observation that indicates a possible use of N6-isopentenyladenosine as anticancer drug. Finally, I would like to thank to all contributors and reviewers who helped me to bring this issue in its present shape. In particular, to the authors for generously contributing their expertise in the preparation of this issue. I greatly appreciate the honor given to me by Prof. Michelle Prudhomme, Editor-in-Chief, Anti-Cancer Agents in Medicinal Chemistry, in entrusting me as a Guest Editor of this special issue. Anti-Cancer Agents in Medicinal Chemistry is a high-standard international journal through which important discoveries in the area of anti-cancer research becomes available to the scientific community. I hope that readers will enjoy reading this issue and it will stimulate interactive research with other specialist areas. The mutual interaction among scientist of different disciplines will be helpful for the development of more effective drugs, diagnostics and therapies for the treatment of cancer.

The enediyne antibiotics, the potent anticancer agents that contain diyne-ene functional groups, are appreciated for their novel molecular architecture, their remarkable biological activity and their fascinating mechanism of action. Their anticancer activity is apparently due to their ability to damage DNA through radical-mediated hydrogen abstraction. The enediyne antibiotics show markedly cytotoxicities against cancers in vitro and in vivo. Lidamycin is a member of the enediyne anticancer antibiotic family. This review examines lidamycin with particular emphasis on the discovery, the biological properties and its structure-activity relationships. In addition, the possible mechanisms of action of lidamycin are described. Recent progress, particularly in the areas of biosynthesis, and immunoconjugates are highlighted. Finally, the pharmacological applications of lidamycin in cancer therapy and its potential use as anticancer agents are also discussed.

This review is a comprehensive survey of acetylenic anticancer agents obtained from living organisms. Acetylenic metabolites belong to a class of molecules containing triple bond(s). They are found in plants, fungi, microorganisms, and marine invertebrates. Although acetylenes are common as components of terrestrial plants, fungi, and bacteria, it is only within the last 30 years that biologically active polyacetylenes having unusual structural features have been reported from plants, cyanobacteria, algae, invertebrates, and other sources. Naturally occurring aquatic acetylenes are of particular interest since many of them display important biological activities and possess antitumor, antibacterial, antimicrobial, antifungal, phototoxic, HIV inhibitory, and immunosuppressive properties. There is no doubt that they are of great interest, especially for the medicinal chemistry, and/or pharmaceutical industries. This review presents structures and describes cytotoxic activities of more than 300 acetylenic metabolites isolated from living organisms.

Because invasion is, either directly or via metastasis formation, the main cause of death in cancer patients, development of efficient anti-invasive agents is an important research challenge. We have established a screening program for potentially anti-invasive compounds. The assay is based on organotypic confronting cultures between human invasive cancer cells and a fragment of normal tissue in three dimensions. Anti-invasive agents appeared to be heterogeneous with regard to their chemical nature, but plant alkaloids, polyphenolics and some of their synthetic congeners were well represented. Even within this group, active compounds were quite diverse: (+)-catechin, tangeretin, xanthohumol and other prenylated chalcones, 3,7-dimethoxyflavone, a pyrazole derivative, an isoxazolylcoumarin and a prenylated desoxybenzoin. The data gathered in this system are now applied in two projects. Firstly, structure-activity relationships are explored with computer models using an artificial neural network approach, based on quantitative structural descriptors. The aim of this study is the prediction and design of optimally efficient anti-invasive compounds. Secondly, the metabolism of orally ingested plant polyphenolics by colonic bacteria is studied in a simulator of the human intestinal microbial ecosystem (SHIME) and in human intervention trials. This method should provide information on the final bioavailability of the active compounds in the human body, with regard to microbial metabolism, and the feasibility of designing pre- or probiotics that increase the generation of active principles for absorption in the gastro-intestinal tract. The final and global aim of all these studies is to predict, synthesize and apply in vivo molecules with an optimal anti-invasive, and hence an anti-metastatic activity against cancer.

Regulatory, receptor-binding peptides could be considered as future agents of choice for diagnostic imaging and therapy of cancers because their receptors are overexpressed in various human cancer cells. Peptides exhibit several advantages over classical macromolecules or drugs, e.g., from the chemical point of view: they are easy to synthesize and can withstand harsh chemical conditions which are required for chelation and radiolabeling. From the biological point of view, peptides exhibit fast blood clearance and high target- to-background ratios through receptor-mediated internalization. Furthermore, they are effective carriers for the delivery of cytotoxic drugs to target the affected tissues, thus avoiding normal cells from non-specific toxicity of anticancer agents. Owing to these features, radiolabeled receptor-binding peptides have emerged as a new class of radiopharmaceuticals for tumor scintigraphy and, more recently, to treat cancers by using peptide receptor radiation therapy (PRRT). The challenge in this scenario is to modify bioactive peptide hormones and to synthesize new sequences with improved metabolic stability without affecting the receptor binding properties after labeling with a chelator for incorporation of a radiometal. At the present time, however, the radiolabeled cholecystokinin-2 (CCK2)- and octreotide somatostatin-receptor selective analogs are the only examples that are being used in clinical practice. Other peptides such as neurotensin-, substance P-, gastrin-releasing peptide-, glucagons-like peptide 1 and neuropeptide Y (NPY) are under investigation to target breast, prostate, ovary, pancreas and brain tumors, in which overexpression of these peptide receptors has been reported. Among these peptides, neuropeptide Y (NPY) seems to be a very promising candidate because the change in its subtype receptor expression correlates with neoplastic changes. Here, we summarize the variety of experiences gained in the development of various peptide analogs, chelator/ radiolabeling techniques for applications in tumor imaging and therapy.

A common modification of eukaryotic and bacterial tRNAs is isopentenylation of the adenosine at position 37, with the formation of isopentenyladenosine. N6-Isopentenyladenosine plays a major role in posttranscriptional processes, including the function of mammalian selenocysteine tRNA. This molecule seems to have metabolic effects that, for its relationships with isoprenoid metabolism and its direct biological activities, affects mammalian cell cytoskeleton, proliferation and apoptosis. In addition, preliminary clinical observation seems to indicate a possible use of N6-Isopentenyladenosine as anticancer drug.

Antifolates that inhibit the key enzymes thymidylate synthase (TS) and dihydrofolate reductase (DHFR) have found clinical utility as antitumor and antiopportunistic agents. Methotrexate {MTX, (1)} and 5-fluorouracil (5-FU) were among the first clinically useful DHFR and TS inhibitors, respectively. The development of resistance to 5-FU, its occasional unpredictable activity and toxicity resulted in the search of novel antifolates. Pemetrexed (4) and raltitrexed (5) are newer antifolates that specifically inhibit TS, and are clinically useful as antitumor agents. A major mechanism of tumor resistance to clinically useful antifolates is based on their need for polyglutamylation via the enzyme folylpoly-γ-glutamate synthetase (FPGS). Recently, classical antifolates that do not need to be polyglutamylated have also been developed and include plevitrexed (6) and GW1843 (7). Nolatrexed (8), trimethoprim {TMP, (11)} and piritrexim {PTX, (12)} are nonclassical antifolates for antitumor and parasitic chemotherapy that passively diffuse into cells and hence do not have to depend on FPGS or the reduced folate carrier (RFC). Structural requirements for inhibition with antifolates have been studied extensively and novel agents that exploit key interactions in the active site of TS, DHFR, FPGS, and RFC have been proposed. This two-part review discusses the design, synthesis and structural requirements for TS and DHFR inhibition and their relevance to antitumor and parasitic chemotherapy, since 1996. Monocyclic and 6-5 fused bicyclic antifolates were discussed in Part I. The 6-6 bicyclic and tricyclic antifolates will be discussed here in Part II.

Gene-directed enzyme prodrug therapy (GDEPT) involves the treatment concept of having maximal efficacy and minimal adverse effects. Several GDEPT strategies have been developed combining cytosine deaminase and 5-fluorocytosine, cytochrome P450 2B1 and cyclophosphamide, and carboxylesterase (CES) and irinotecan in experimental models. The active forms of these prodrugs, however, are not a frontline therapy for the treatment of ovarian cancer. It would be beneficial to develop a more effective prodrugenzyme combination for the treatment of this disease. Paclitaxel (TaxolR; TAX) is currently one of the most important anti-cancer drugs in chemotherapy of ovarian cancer. One of TAX prodrugs, 2'-ethylcarbonate-linked paclitaxel (TAX-2'-Et), was generated and examined regarding its pharmacological aspects. The prodrug of TAX-2'-Et converts into active form TAX by carboxylesterase (CES). TAX-2'-Et did not exhibit polarized transport in the Caco-2 cells expressing P-glycoprotein (P-gp) in the absence or presence of verapamil which is a inhibitor of P-gp, suggesting that TAX-2'-Et is not a target of P-gp like TAX and rhodamine123. Moreover, SKOV3/TAX60 cells which are overexpressing P-gp did not also exhibit any change in cellular uptake of TAX-2'-Et regardless of the absence or presence of verapamil. Consequently, the uptake of TAX-2'-Et into the TAX-resistant cells was quantitatively similar to that internalized in the parental SKOV3 cells which are P-gp-negative. In the CES-transfected SKOV3 cells, the EC50 value of TAX (10.6 nM) was approximately 4-fold higher than that of TAX-2'-Et (2.5 nM). We herein provide evidence that TAX-2'-Et could circumvent P-gp-associated cellular efflux of TAX, suggesting that this combination therapy is a potential GDEPT strategy for ovarian cancer in the future. Finally, this review focuses on the development, application and potential of various GDEPTs for treating ovarian cancer, and the scope and progress of new GDEPTs are discussed.