Anti-Cancer Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Anti-Cancer Agents) - Volume 9, Issue 4, 2009

The 8H-thieno[2,3-b]pyrrolizinones, some of which exert very potent cytotoxic activity against tumor cell lines in vitro, are a promising novel series of anti-cancer agents. These compounds belong to the tripentone family and are based on 9H-pyrrolo[1,2-a]indol- 9-one derivatives and their heterocyclic isosteres. This paper inventories the different synthetic strategies for tripentones and reviews their biological effects and therapeutic potential.

Lysophosphatidic acid (LPA) and sphingosine 1-phosphate (S1P) are naturally arising bioactive lipids. The roles of LPA and S1P in angiogenesis, tumor growth and metastasis have recently emerged. Blood platelets are an important source of LPA and S1P in the organism. However, other types of cells including cancer cells expressing autotaxin and sphingosine kinases have the capacity to produce LPA and S1P, respectively. During the past decade, studies revealed that LPA and S1P interact with a large series of G-protein-coupled receptors, at least seven for LPA (LPA1-5, GPR-87, P2Y5) and five for S1P (S1P1-5). This may account for the wide variety of cell types reacting to LPA and S1P stimulation and for the wide range of cellular functions controlled by these lysophospholipids such as proliferation, survival and motility. Genetic and pharmacological approaches were developed to block the activities of LPA or S1P in the context of cancer progression. This article presents recent findings based on extensive cell culture experiments and preliminary in vivo studies which demonstrate that targeting the lysophospholipid tracks would be extremely beneficial for patients suffering from cancer.

Natural product extracts are a rich source of small molecules that display antitumor activity. Cantharidin, in the form of the dried body of the Chinese blister beetles: Mylabris phalerata or M. cichorii, displays antitumor activity and induces apoptosis in many types of tumor cells. Cantharidin has been used as an anticancer agent by the Chinese for the treatment of hepatoma and oesophageal carcinoma for a long time. Although cantharidin is a natural toxin that possesses potent anti-tumor properties, its clinical application is limited due to severe side-effects and highly toxic nature. Therefore, some modified cantharidin analogues are synthesized chemically in order to achieve a comparable antitumour property to the mother compound but simultaneously produce a less toxic effect on non-cancer cells. In recent years, based on the structure of cantharidin, there has been intense interest in developing potent and selective inhibitors of PP1 and PP2A on tumour cells. Though numerous analogues of cantharidin have been synthesized and researched with tumour cell lines, there is little success on clinical application because of the potential toxicity of cantharidin derivates. The focus of this review is to describe how cantharidin and cantharidin derivates participate in antitumour processes in tumour cells, and discuss the molecular mechanisms of cantharidin and cantharidin derivates on tumour cells.

Isatin (1H-indole-2,3-dione) and its derivatives demonstrate a diverse array of biological and pharmacological activities including anticonvulsant, antibacterial, antifungal, antiviral and anticancer properties. This broad spectrum of biochemical targets has been facilitated by the synthetic versatility of isatin, which has allowed the generation of a large number of structurally diverse derivatives including analogues derived from substitution of the aryl ring, and/or derivatisation of the isatin nitrogen and C2/C3 carbonyl moieties. The recent FDA approval of the oxindole sunitinib malate, as a kinase inhibitor for the treatment of advanced renal carcinoma and gastrointestinal stromal tumours, underscores the increasing interest in isatins as a new class of antineoplastic agents. In addition to potent kinase inhibition, the mechanism of action of other isatin derivatives includes the inhibition and/or modulation of proteases, translation initiation, neo-vascularisation and tubulin polymerisation. It was therefore the objective of this review to systematically evaluate the cytotoxic and anticancer properties of various substituted isatins and collate these findings to be used as a guide for future structure-activity relationship and mode of action studies. This is the first review to comprehensively discuss the in vitro and in vivo anticancer activities of isatin and its substituted derivatives.

During the last decades multidrug resistance (MDR) emerged as main problem in the anti-cancer therapy with cytostatically active agents. Classical as well as recently developed cytostatics develop the phenomenon of loosing activity in former drug-sensitive cells. Although MDR is a multifactorial process, the main obstacle is the expression of multidrug-efflux pumps that lowers the intracellular drug levels. P-glycoprotein (P-gp) is the longest identified efflux pump. As the attempt to overcome MDR by the use of inhibitors of the efflux pump activities turned out as most promising effect, the development of P-gp inhibitors has been a challenge for medicinal chemists. The article reviews the advances in P-gp inhibitor development by focussing on structure-activity relationships in the different compound classes to document improvements. The success has been the reduction of cytotoxic properties. The undesired activities could be much lowered in the case of compound classes that were derived from pharmacologically active drugs. Undesired drug interactions and limited in vivo activities are still a problem.

Many cancer cells are known to have defects in the apoptosis machinery. Therefore identification of compounds that can activate or promote apoptosis in cancer cells is an attractive approach for targeted therapies. By applying a novel cell- and caspase-based Anti-cancer Screening Apoptosis Program (ASAP) HTS assay, 4-aryl-4H-chromenes were identified as potent apoptosis inducers. 4- Aryl-4H-chromenes were found to induce nuclear fragmentation and PARP cleavage, as well as to arrest cells at the G2/M stage followed by apoptosis as determined by the flow cytometry analysis assay in multiple human cell lines (e.g. Jurkat, T47D). These compounds were found to be highly active in the growth inhibition MTT assay, including for paclitaxel resistant, p-glycoprotein overexpressed, MESSA/ DX5 tumor cells. Functionally, they were found to be potent inhibitors of tubulin polymerization and to effectively inhibit the binding of colchicine to tubulin. In addition, several 4-aryl-4H-chromenes were also found to be effective vascular disrupting agents (VDA). One of the lead compounds, EPC2407, is currently in clinical trials as a novel tumor vascular disrupting agent.

Omega-3 fatty acids (ω3-FA) were shown to attenuate growth and induce apoptosis in a variety of human cancer cell lines derived from colonic, pancreatic, prostate, and breast cancer. In addition, recent findings indicate that ω3-FA act synergistically with chemotherapeutic agents and may also be used to enhance tumour radiosensitivity. The mechanisms underlying the anti-tumour effects of ω3-FA are complex. Incorporation of ω3-FA in biological membranes alters the profile of lipid mediators generated during inflammatory reactions. Furthermore, ω3-FA act as ligands of nuclear peroxisome proliferator- activated receptors that attenuate transcription of NF-κB-dependent genes. Thereby, the cyclooxygenase-2/prostaglandin E2- dependent production of pro-angiogenic vascular endothelial growth factor and levels of anti-apoptotic bcl-2 and bcl-XL are decreased. Eicosanoid-independent pro-apoptotic pathways include enhanced lipid peroxidation, modulation of mitochondrial calcium homeostasis and enhanced production of reactive oxygen species as well as activation of p53. This review article will give a comprehensive overview over the pleiotropic actions of ω3-FA and will discuss the potential of ω3-FA and derivatives like conjugated eicosapentaenoic acid as important nutritional adjuvant therapeutics in the management of various human cancer diseases and the impact of nutritional ω-3 FA on cancer prevention.

Within the past ten years, a huge volume of research on the synthesis, structure-activity relationships (SAR), and anticancer activities of the urea derivatives was reported. Many aromatic urea derivatives such as N-phenyl-N'-(2-chloroethyl)ureas (CEUs) and benzoylureas (BUs) show good anticancer activity, and these compounds have mainly been proved to be tubulin ligands that inhibit the polymerization of tubulin. Heterocyclic urea derivatives play an important role in anticancer agents because of their good inhibitory activity against receptor tyrosine kinases (RTKs), raf kinases, protein tyrosine kinases (PTKs), and NADH oxidase, which play critical roles in many aspects of tumorigenesis. Thiourea derivatives are also of wide interest because of their diverse anticancer activity against various leukemias and solid tumors. In this review, the anticancer activity of the urea derivatives mentioned above is summarized in detail. It is hoped that increasing knowledge of the SAR and cellular processes underlying the antitumor-activity of urea derivatives will be beneficial to the rational design of new generation of urea anticancer drugs.