Anti-Cancer Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Anti-Cancer Agents) - Volume 7, Issue 5, 2007

This review deals with the most important results published on the structures, reactivity and biomedical applications of palladium( II) complexes in the cancer therapy in the last five years. Biological mechanisms of palladium(II) complexes, especially of palladacycle compounds were boarded. Among the most recent advances in the studies involving correlations between chemical structures of palladacycle compounds and biological activities we mention i) the synthesis of metallic isomer complexes containing ligands derivatives of pyridine and imines in trans position having high antitumoral activities, ii) the development of cationic complexes with biological activity, iii) the discovery of preferential nucleotides for the intercalation of metallic complexes in the double helix of DNA of cancerous cells, configuring irreparable lesions in the macromolecule and iv) the interaction of metallic complexes with other biological molecules, like proteins and peptides, through terminal amine groups, carboxylate groups, imidazolic group of histidine and mostly with the thiol group of methionine. Some of these interactions are related to drug nefrotoxicity effect, which understanding is of fundamental importance. v) Novel ortho-cyclopalladated compounds synthesized from p-isopropylbenzaldehyde thiosemicarbazone have been described with specific cytotoxic properties in tumor cells sensitive to cis-diamminedichloroplatinum(II). The lysosomal cysteine proteinases cathepsins B and L have been implicated in a variety of pathological conditions, especially in diseases involving tissue-remodeling states, such as tumor metastasis. Our research group is studying inhibition of Cathepsin B by new palladacycle compounds derived from N, Ndimethyl- 1-phenethylamine and having biphosphine ligands. New palladacycle compounds derived from N,N-dimethyl-1- phenethylamine and the ligand bis(diphenylphosphine)ferrocene were presented as effective antitumoral agents.

Colorectal cancer is a major global health problem with more than a million new cases diagnosed worldwide in 2005. In the United States, this malignancy is the third most common with 145,000 new cases and the second most lethal with 56,000 deaths in 2005. Unfortunately, preclinical diagnostic screening in the U.S. population is less than 30-40 percent. The last decade has ushered in exciting new advances for medical oncologists caring for patients with colorectal cancer. The older cytotoxic chemotherapy drug 5-fluorouracil underwent new formulation, and two new drugs, oxaliplatine and irinotecan, were investigated as adjunctive therapies. Finally, targeted therapies, including monoclonal antibodies against vascular endothelial growth factor (bevacizumab) and the epidermal growth factor receptor (cetuximab), are now standard treatment for metastatic colorectal carcinoma. Systemic adjuvant chemotherapy can be lifesaving in patients with locally advanced colorectal carcinomas, which represent 60-70 percent of cases. For patients with metastatic colorectal cancer, the survival rate has doubled. With more effective drugs in the therapeutic armamentarium, new controversies have arisen. Questions regarding the best schedules for classical cytotoxic chemotherapy were largely answered by contemporary clinical trials. The potential of molecular genetic markers for prognosis or prediction of drug-specific toxicity and efficacy have been explored, but their utility for clinical practice is still being investigated. We will review the rapidly changing, state-of-the-art combination chemotherapy for adjuvant and metastatic disease. We will discuss in detail the c-ERBB family of tyrosine kinases as therapeutic targets in colorectal cancer.

The TGF-β signaling pathway is central to the control of diverse biological processes including cellular proliferation, cell survival, apoptosis, extracellular matrix deposition/remodeling, migration, invasion and immune regulation/inflammation. Given the pleiotropic effects of this cytokine, it comes as no surprise that numerous pathological conditions are associated with alterations in the TGF-β pathway, including chronic fibrosis, airway remodeling (asthma), cardiovascular disease and cancer. Thus, there are increasing efforts to develop reagents and therapeutic strategies to impair TGF-β signaling. Here we review several classes of inhibitors, including knockdown strategies aimed at signaling components of the TGF-β pathway, TGF-β neutralizing antibodies, TGF-β receptor extracellular domains that function as ligand traps and small molecule kinase inhibitors. Strategies with potential for application as anti-cancer therapeutics that have been evaluated in pre-clinical animal models will be discussed. TGF-β action is complex, shifting from a tumor suppressor to a promoter of tumor cell invasion and metastasis in several types of cancer. This raises important issues regarding not only the status of the TGF-β pathway in the individual patient but also the precise stage during disease progression that such inhibitors should be employed. Potential consequences of targeting the TGF-β pathway will also be considered.

Poly(ADP-ribose) polymerase 1 (PARP-1) is a DNA-binding enzyme that is activated by DNA breaks, converting them into an intracellular signal via poly(ADP-ribosyl)ation of nuclear proteins. Negatively charged polymers of ADP-ribose (PAR) attached to PARP-1 itself and histones lead to chromatin relaxation, facilitating the access of base excision/single strand break repair proteins and activating these repair enzymes. PARP inhibitors have been developed to investigate the role of PARP-1 in cell biology and to overcome DNA repair-mediated resistance of cancer cells to cytotoxic therapy. Since the early benzamide inhibitors of the 1980s PARP inhibitors, developed through structure-activity relationships and crystal structure-based drug design, that are 1,000x more potent have been identified. These novel PARP inhibitors have been shown to enhance the antitumour activity of temozolomide (a DNA-methylating agent), topoisomerase poisons and ionising radiation in advanced pre-clinical studies and are now under clinical evaluation. PARP inhibitors can also selectively kill cells and tumours with homozygous defects in the hereditary breast cancer genes, BRCA1 and BRCA2.

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) 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). Novel antifolates have been developed that do not need to be polyglutamylated and include plevitrexed (6) and GW1843 (7). Nonclassical antifolates for antitumor and parasitic chemotherapy, such as nolatrexed (8), trimethoprim {TMP, (11)} and piritrexim {PTX, (12)}, can passively diffuse into cells and hence do not have to depend on FPGS or the reduced folate carrier (RFC). Variations in the structures of antifolates have helped delineate the structural influence on the interaction with TS, DHFR, FPGS, and RFC utilization. The differences in the active site of human and pathogen DHFR have also been exploited. The literature contains excellent reviews on the design and synthesis of antifolates prior to 1996. 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 will be discussed in Part I, while 6-6 bicyclic and tricyclic antifolates will be discussed in Part II.

During the past decade, radiolabeled receptor-binding peptides have emerged as an important class of radiopharmaceuticals for tumor diagnosis and therapy. The specific receptor binding property of the ligand can be exploited by labeling the ligand with a radionuclide and using the radiolabeled ligand as a vehicle to guide the radioactivity to the tissues expressing a particular receptor. The concept of using radiolabeled receptor binding peptides to target receptor-expressing tissues in vivo has stimulated a large body of research in nuclear medicine. Receptor binding peptides labeled with gamma emitters (123I, 111In, 99mTc) can visualize receptor-expressing tissues, a technique referred to as peptide-receptor radionuclide imaging (PRRI). In addition, labeled with beta emitters (131I, 90Y, 188Re, 177Lu) these peptides have the potential to irradiate receptor-expressing tissues, an approach referred to as peptide-receptor radionuclide therapy (PRRT). The first and most succesful imaging agent to date is the somatostatin analog octreotide. It is used for somatostatin receptor scintigraphy and PRRT of neuroendocrine tumors. Other peptides such as Minigastrin, GLP-1, CCK, bombesin, substance P, neurotensin, and RGD peptides are currently under development or undergoing clinical trials. In this review, an overview of the criteria of peptide ligand development, the selection of radioisotopes, labeling methods, and chemical aspects of radiopeptide synthesis is given. In addition, the current state of clinical use of radiopeptides for diagnosis and therapy of tumors is discussed.

Development of molecular devices endowed with tumor-targeting functions and carrying cytotoxic components should enable the specific delivery of chemotherapeutics to malignant tissues, thus increasing their local efficacy while limiting their peripheral toxicity. Such molecular vectors can pave the way for the development of new classes of therapeutics, fighting against protagonists of neoplastic development. In line with this concept, peptide ligands containing the Arginine-Glycine-Aspartate (RGD) triad, which display a strong affinity and selectivity to the αVβ3 integrin, have been developed to target the tumor-associated cells expressing the αVβ3 receptors. Among the validated ligands, the leader compound is the cyclic pentapeptide c[-RGDf(NMe)V-] (Cilengitide) developed by kessler et al. (J. Med. Chem., 1999, 42, 3033-3040). This compound has entered phase II clinical trials as an anti-angiogenic agent. Further studies have been directed to develop molecular conjugates of the parent c[-RGDfK-] with conventional chemotherapeutics or with labels for non-invasive imaging technologies. More recently, multimeric RGD containing compounds have been exploited to improve the targeting potential as well as cell-membrane breaching, through receptor-mediated endocytosis. The latter have been constructed on various scaffolds (polylysines or polyglutamates, liposomes, nanoparticles...). Our group has developed a chemical system combining all these properties where multivalent RGD targeting functions are associated with functional molecules through a cyclopeptide template. The latter represents a relevant non-viral vector for tumor targeting, imaging and therapy. This review describes the considerations for the design of the diverse RGD ligands developed so far and reports an overview of the main applications of these structures in cancer research.

Colorectal cancer is one of the leading causes of premature death in people worldwide. Due to the fact that malignant conversion of normal colonic cells requires several steps and often proceeds over considerable time periods, primary prevention of this process should include several approaches, with optimization of nutrition and diet being among most important. During past decades, several groups of chemicals (both naturally occurring as well as synthetic) have been studied in terms of their potential chemopreventive role in colorectal cancer development. Naturally occurring plant polyphenols have recently come into scientific focus because of their presence in various popular natural products (wine grapes, teas, berries, peanuts) and, more importantly, due to their reported antiproliferative and cytostatic abilities in various in vitro and in vivo models. This review seeks to summarize the currently known targets and mechanisms whereby polyphenolic compounds interfere with colonic cancer cells while evaluating their chemopreventive potential in vivo.

Regulation of gene expression is mediated by several mechanisms such as DNA methylation, ATP-dependent chromatin remodeling, and post-translational modifications of histones. The latter mechanism includes dynamic acetylation and deacetylation of η- amino groups of lysine residues present in the tail of the core histones. Enzymes responsible for the reversible acetylation/deacetylation processes are histone acetyltransferases (HATs) and histone deacetylases (HDACs), respectively. There are three mammalian HDAC families, namely HDACs I, II and III based on their sequence homology. Inhibitors of HDACs induce hyperacetylation of histones that modulate chromatin structure and gene expression resulting in growth arrest, cell differentiation, and apoptosis of tumor cells. In addition, HDAC inhibitors enhance efficacy of anticancer agents that target DNA. Several formidable challenges associated with their development include non-specific toxicity and poor PK properties, including cell permeability. In this review, we comment on the current progress in design, discovery, in vitro/ex vivo activity and clinical potential of the synthetic modulators of HDACs.