Anti-Cancer Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Anti-Cancer Agents) - Volume 9, Issue 8, 2009

ACA-MC is now in its ninth volume. Besides regular general issues reviewing major advances in various areas of anti-cancer agents, two Hot Topic Issues have been published in 2009 with exciting recent developments in the field of enzymes and other proteins inhibitors. For 2010, a large number of authors have proposed review articles covering the latest developments in medicinal chemistry and rational drug design. Several Hot Topic Issues will also be published, the first one on prostate cancer therapy. In this special 2009 Editorial Board Members, nine members of the ACA-MC Editorial Board present various and recent advances in the continuous efforts to develop efficient anti-cancer therapies. The first paper written by Dr. J. Ho reviews the effects of oxymatrine, an active constituent isolated from roots of Sophora flavescens, on cell division of cancer cells. In the second paper, Dr. I. Kostova describes the antitumor properties of titanium and vanadium complexes. Though the exact mechanism of action for these compounds has not been determined, their interaction with DNA seems to be at least partially responsible for their antitumor effects. Dr. Kostova says,“It is a pleasure to thank and express my appreciation to the editorial staff for the work they have been doing and continue to do for the recognition and prosperity of ANTI-CANCER AGENTS IN MEDICINAL CHEMISTRY!” The third paper from Dr. S. Nagini is devoted to hamster buccal pouch carcinogenesis model as a useful system for the study of synthetic and natural chemopreventive agents. In the fourth review, Drs. M. Tolomeo, F. Dieli, N. Gebbia and D. Simoni reported the in vitro and in vivo results obtained with the novel tyrosine kinase inhibitors developed to overcome imatinib resistance in Bcr-Abl expressing hematological disorders. In the fifth paper, the synthesis, the molecular targets, and the antitumor activities of substituted tetrahydro 1-oxopyrano[4,3- b][1]benzopyrans and nanogels for drug delivery are presented by Drs. E. Perchellet, J.-P. Perchellet, C. Ganta, D. Trover, A. Shi, and D. Hua.

Oxymatrine is one of active constituents isolated from Ku Shen, which is the dried root of Sophora flavescens Ait. The herb used in different herbal formulations is commonly known with specific pharmacological properties for treatment of liver disorders and other diseases such as arrhythmia, eczema and skin disorders, leukopenia and bronchitis. Sophora flavescens Ait is known to enhance liver functions and reduce hepatotoxicity due to oxidative stress and liver injury. The protection of cells from chemical toxicity is important in reducing liver damage. Reduction of oxidative stress by active components of herbal medicines is shown to be beneficial and important in regulating the normal functions of the liver. In this study, effects of oxymatrine on cancer cells after treatment of the cell line with DMSO were reported. This review described for cells without oxymatrine pre-treatment, cell injury was implicated as indicated by the decrease in cell viability. Ku Shen showed protective effects on cells from the DMSO-induced toxicity. The results show that oxymatrine can inhibit the G2 and M phase of H4IIE. The findings suggest that anti-inflammatory constituents such as oxymatrine could mediate cell division of cancer cells and reduce cell cytotoxicity due probably to its capacity to inhibit the metabolic activation of hepato-toxin, a critical factor in the pathogenesis of chemical-induced liver injury.

A series of complexes containing titanium and vanadium as a metal centers have shown to possess a wide spectrum of antitumor properties. These series belong to the non-platinum metal antitumor agents that appear to offer a different alternative for cancer chemotherapy which do not follow mechanism of action of the platinum complexes. The antitumor activity of both titanocene and vanadocene complexes has been established against various animal and xenografted human tumors. The exact mechanism of action for these compounds has not been determined, the target is unknown and even the exact chemical nature of the formulated solutions is still unknown. It has been proposed that these species interact with DNA, inhibiting the cell cycle. However, the antitumor mechanism of the titanocenes is most likely a complex pathway, probably involving a number of different biological molecules related to the transport and delivery of Ti species into cancer cells, and, after hydrolysis, subsequent interaction with nucleic acids and/or proteins and/or other potential coordinating constituents present in the intracellular environment. The tendency to hydrolyze seems to be one of the hypotheses for the tumor-inhibiting potency of the titanocene dihalides. Vanadium compounds exert preventive effects against chemical carcinogenesis on animals, by modifying, mainly, various xenobiotic enzymes, inhibiting, thus, carcinogen-derived active metabolites. The anticarcinogenic effects of vanadium, in combination to its low toxicity, established also, by its administration in humans, suggest vanadium as a candidate antineoplastic agent against human cancer. New complexes being more potent and less toxic favor this perspective. The use of these species as chemotherapeutic agents remains relatively unexplored and waits for future investigation. Research proceeded during the recent decades, enriched our knowledge on the chemical and biochemical properties, as well as the mechanisms of systemic, cellular and molecular antitumor effects of titanium and vanadium compounds.

Oral squamous cell carcinoma (OSCC), a common malignancy worldwide, is an important contributor to the overall international cancer burden. Squamous cell carcinomas (SCCs) induced by 7,12-dimethylbenz[a]- anthracene (DMBA) in the HBP reiterate many of the features observed in human OSCCs. The major risk factors associated with human oral cancer such as tobacco, betel quid and alcohol promote HBP carcinogenesis. SCCs induced by DMBA in the cheek pouch of Syrian hamsters are morphologically and histologically similar to human OSCC. Like human oral carcinogenesis, HBP carcinogenesis is a multistep process that involves sequential progression from hyperplasia to invasive carcinoma through varying degrees of dysplasia. In addition, HBP tumours express several biochemical and molecular markers that are also expressed in human OSCC. Multiple signaling pathways are dysfunctional in both human and hamster OSCCs. In particular, cell proliferation, apoptosis and angiogenesis are intricately interlinked in malignant transformation of the HBP mucosa by DMBA. The HBP carcinogenesis model is the best-known animal system for intervention by chemopreventive agents because of easy accessibility for examination, and follow-up of lesions. A number of synthetic and natural products have been documented to exhibit chemopreventive efficacy in the HBP model. Chemoprevention studies in the HBP model can serve as a crucial link in the potential efficacy assessment of candidate agents for oral cancer prevention and therapy.

Imatinib mesylate (Gleevec) is a drug unique for the treatment of certain forms of cancer. It works by targeting, and turning off, specific tyrosine kinase proteins that cause the uncontrolled cell growth and the inhibition of apoptosis in cancer cells. Imatinib was designed on the basis of the structure of the ATP binding site of the Abl protein kinase with the aim to stabilize the inactive form of Bcr-Abl, an oncoprotein involved in malignant transformation in chronic myelogenous leukemia (CML). However, imatinib can also target other tyrosine kinase proteins different from Bcr-Abl such as Kit, that is the suspected cause of gastrointestinal stromal tumor (GIST). Despite successful clinical results observed in the last years, the long-term effects of imatinib and its ability to completely eradicate CML are still unknown. Moreover, similar to many other anti-cancer drugs, clinical resistance to imatinib has emerged. In this review we will discuss the in vitro and in vivo results obtained with the novel tyrosine kinase inhibitors developed to overcome imatinib resistance in Bcr-Abl expressing hematologiocal disorders.

A class of substituted 1H,7H-5a,6,8,9-tetrahydro-1-oxopyrano[4,3-b][1]benzopyrans (tricyclic pyrones; TPs) was synthesized from a one-pot condensation reaction of 6-substituted 4-hydroxy-2-pyrones and cyclohexenecarboxaldehydes. The reaction involves a 6π-electrocyclic ring closing process, and stereo- and regioselectivities were examined. C3-Pyridyl-containing TPs may represent a novel synthetic class of microtubule de-stabilizing anticancer drugs that inhibit macromolecule synthesis, tubulin polymerization, and the proliferation of a spectrum of wild-type and multi-drug resistant tumor cell lines in vitro. A linear skeleton with a N-containing aromatic ring attached at C3 of the top A-ring, a central pyran B-ring and a six-membered bottom C-ring with no alkylation at C7 are required for the antitumor activities of the lead compounds, a 3-pyridyl benzopyran (code name H10) and its 2-pyridyl regioisomer (code name H19). In addition to interacting with the colchicine-binding site to inhibit tubulin polymerization and increase the mitotic index, these TP analogs also block the cellular transport of nucleosides to inhibit DNA synthesis more effectively than other antimitotic agents. The anticancer potential of TPs in vivo is suggested by the fact that i.p. injections of H10 decrease the growth of solid tumors in mice inoculated with lung or ovarian carcinomas. A drug-delivery system involving nanogels was studied. We incorporated the anticancer compound, 6-hydroxymethyl-1,4-anthracenedione (code name AQ10) into PEG-PEI nanogel, and found that AQ10-encapsulated nanogel PEG-PEI is significantly more effective in altering the growth of Pan 02 (pancreatic cancer) cells compared to AQ10 or nanogel PEG-PEI alone. Since AQ10 is insoluble in water, PEG-PEI encapsulation represents a way to solubilize and deliver this as well as other poorly soluble compounds.

Despite recent progress in surgical procedures and therapeutic modalities, the outcomes of treatment for pancreas cancer are still not satisfactory. Chemotherapy can provide symptom relief in some patients, but its impact on survival has been modest and it can lead to unacceptable levels of toxicity. To develop novel and potentially less toxic forms of cancer therapy, molecular targeting therapy is being based initially on the knowledge of cellular signal transduction. The new approaches in treatment have originated from biochemical studies in combination with recent technology to block the progress of carcinogenesis or invasion. As one of the most successful of such agents, an antibody or antagonist against the receptor of epidermal growth factor or vascular endothelial growth factor has been proven in carcinoma treatment, and recent steps have been taken to apply this type of treatment to pancreas cancer. However, there are still serious problems for these receptor-associated signaling blockers; namely, the antibody or antagonist has no efficacy if the target cells grow independently of the receptor-related signaling. On the other hands, extra-cellular signal-regulated kinase (ERK) is well known to represent a convergent point for the intracellular signaling pathways in whole cancer cells. In the present, by reviewing our recent studies that evaluate the usefulness of the vitamin K3 (menadione, 2-methyl-1,4-naphthoquinone; VK3)-induced growth inhibitory effect through ERK pathway, this novel approach to cancer therapy and its potential in future clinical applications will be highlighted.

The MDM2 oncogene is overexpressed in various human cancers. Its expression correlates with the phenotypes of high-grade, late-stage, and more resistant tumors. The auto-regulatory loop between MDM2 and the tumor suppressor p53 has long been considered the epitome of a rational target for cancer therapy. As such, many novel agents have been generated to interfere with the interaction of the two proteins, which results in the activation of p53. Among these agents are several small molecule inhibitors synthesized based upon the crystal structures of the MDM2-p53 complex. With use of high-throughput screening, several specific and effective agents for inhibition of the protein-protein interaction were discovered. Recent investigations, however, have demonstrated that many proteins regulate the MDM2-p53 interaction, and that MDM2 may have p53-independent oncogenic functions. In order for novel MDM2 inhibitors to be translated to the clinic, it is necessary to obtain a better understanding of the regulation of MDM2 and of the MDM2-p53 interaction. In particular, the implications of various interactions between certain regulator(s) and MDM2/p53 under different circumstances need to be elucidated to determine which pathway(s) represent the best targets for therapy. Targeting both MDM2 itself and regulators of MDM2 and the MDM2-p53 interaction, or use of MDM2 inhibitors in combination with conventional treatments, may improve prospects for tumor eradication.

The androgen receptor (AR) plays a crucial role in the physiological and pathological functions of androgen. As a transcription factor, the AR modulates androgen activity by regulating the transcription of target genes that are involved in numerous physiological functions and pathological disorders, such as acne vulgaris, androgenetic alopecia, benign prostate hyperplasia (BPH), and prostate cancers. Although many natural and synthetic curcumin analogues have been reported to possess anticancer activity through a common cytotoxic property against proliferating tumor cells, none has been reported to inhibit cancer cell growth through a more specific mechanism or target in the cancer cells. Recently, new curcumin analogues were studied extensively regarding their synthesis, structure-activity (i.e., anticancer activity) relationships, and mechanism of action. These compounds, such as ASC-J9 and its analogues (3 and 4), have now been shown to inhibit prostate cancer proliferation through a novel mechanism of enhancing AR degradation.

Naturally occurring cytotoxic compounds have been considered to be a valuable pool of lead compounds in the development of potential anticancer drugs. Currently, some cytotoxic compounds of terrestrial plants are being used as cancer therapeutic drugs and more candidates are under clinical trials along with cytotoxic small molecules of terrestrial microorganisms and marine organisms. In the present review, the structures and representative cytotoxicities of new organic small molecules (over 200 molecules) obtained from terrestrial plants between 2001 and 2004 are presented.