Current Medicinal Chemistry - Volume 18, Issue 33, 2011

Angiogenesis is known to be essential for the development and progression of cancer. Vascular endothelial growth factor (VEGF) is a critical mediator in tumor angiogenesis for many solid malignancies, including breast cancer. Increased levels of VEGF have been associated with poor clinical outcomes, including reduced survival. VEGF has become an attractive target for cancer therapy in view of its pivotal role in angiogenesis. The primary approaches for inhibiting angiogenesis have focused on inhibiting the activity of VEGF, either by targeting the VEGF ligand itself with monoclonal antibodies (mAbs) or by interfering with the signaling events downstream of VEGF through the use of tyrosine kinase inhibitors (TKIs). Bevacizumab is a recombinant, humanized monoclonal IgG1, anti-VEGF antibody that has demonstrated significant clinical benefit in several solid tumors. Bevacizumab has been approved for use in combination with paclitaxel for the first line treatment of patients with metastatic breast cancer (MBC) based on the results of the randomized phase III E2100 trial in which it improves response rate and time to progress when administered with weekly paclitaxel until disease progression. Several trials to define the role of bevacizumab in different setting of disease and in combination with different chemotherapy regimens and targeted therapy in breast cancer patients are ongoing. Other small molecule inhibitors of VEGF tyrosine kinase activity (TKIs) such as sunitinib, vandetanib and sorafenib are being tested in MBC. This review will focus on bevacizumab and on the developements of the main antiangiogenic agents in the treatment of breast cancer.

Although testicular germ cell tumors (TGCTs) are relatively uncommon, they are particularly important as they tend to affect children and young men, representing the most common tumor in male aged from 20 to 40 years, and the incidence has been increasing over the last decades. TGCTs are a heterogeneous group of tumors, with specific peculiarities reflecting on epidemiologic distribution and clinic-pathological features. Seminomas are highly sensitive to both radiation and chemotherapy, with a good prognosis, non- seminomas are sensitive to platinum-based combination chemotherapy and are less susceptible to radiation, with the exception of teratomas. However, up to 30% of patients diagnosed with metastatic nonseminomas do not achieve a durable remission, and in metastatic teratomas cisplatin-based treatment resistance has been observed. The different therapeutic outcome might be explained by inherent properties of the cells from which testicular neoplasia originate. The unique treatment sensitivity of TGCTs is unexplained so far, but it is likely to be related to intrinsic molecular characteristics of the PGCs/gonocytes, from which these tumours originate. In the last years novel markers, including OCT3/4, SOX2, SOX17, HMGA1, HMGA2, PATZ1, GPR30, Aurora B, and others has given further advantages to discriminate between histological subgroups. In addition, therapeutic approaches for the treatment of TGCTs have been proposed: humanized antibodies against receptors/surface molecules on cancer cells, inhibitors of serine-threonine, and tyrosine kinases, angiogenesis inhibitors, and others. In same cases the clinical trials have confirmed the efficacy of these approaches. The review will focus on the molecular alteration identified in post-puberal TGCTs and on novel targeted antineoplastic strategies that could contribute to the cure of chemotherapy resistant TGCTs.

Zinc(II) ions contribute to a number of biological processes e.g. DNA synthesis, gene expression, enzymatic catalysis, neurotransmission, and apoptosis. Zinc(II) dysregulation, deficiency and over-supply are connected with various diseases, particularly cancer. 98 % of human body zinc(II) is localized in the intracellular compartment, where zinc(II) is bound with low affinity to metallothionein (MT). Zinc transporters ZIP and ZnT maintain transmembrane transport from/to cells or organelles. Imbalance of their regulation is described in cancers, particularly prostate (down-regulated zinc transporters ZIP1, 2, 3 and ZnT-2) and breast, notably its high-risk variant (up-regulated ZIP6, 7, 10). As a result, intracellular and even blood plasma zinc(II) levels are altered. MT protects cells against oxidative stress, because it cooperates with reduced glutathione (GSH). Recent studies indicate elevated serum level of MT in a number of malignancies, among others in breast, and prostate. MT together with zinc(II) affect apoptosis and proliferation, thus together with its antioxidative effects it may affect cancer. To date, only little is known about the influence of zinc(II) and MT on cancer, while these compounds may play an important role in pathogenesis. This review concludes current data regarding the impact of zinc(II) on the pathogenesis of breast and prostate cancers with potential outlines of new, targeted therapy and prevention. Moreover, blood plasma zinc(II) and MT levels and dietary zinc(II) intake are discussed in relation to breast and prostate cancer risk.

Proteasome inhibitors have proven to be effective anticancer agents. Despite the success of the first on the market proteasome inhibitor bortezomib in chemotherapy, alternative clinically useful proteasome inhibitors are still urgently needed as bortezomib therapy causes severe side effects and is limited by arising drug resistance. Experience from previous proteasome inhibitor studies has thereby demonstrated that the identification of proteasome inhibitor structures with suitable pharmacological properties is a key factor for a successful development of clinically useful proteasome inhibitors. Macrocycles often show distinct and in comparison to linear small molecules superior pharmacological properties. Consequently, macrocyclic proteasome inhibitors might represent promising small molecules for drug development. Here, we want to highlight the current state of the art of macrocyclic proteasome inhibitor research. To this end, we give an overview and critically discuss currently known classes of macrocyclic proteasome inhibitors.

The cytoplasmatic tyrosine in kinase c-Src is involved in the regulation of several cell functions including adhesion, invasion, proliferation, survival and angiogenesis. Src activity is strictly regulated in healthy cells, whereas its overexpression or hyperactivation plays a critical role during tumor development. Recently it has been suggested that the oncogenic potential of Src is linked to its role in the activation of key signalling molecules involved in several cell pathways, rather than its direct activity. For all these reasons Src represents a promising therapeutic target for the treatment of tumors. In this article a number of examples of c-Src inhibitors appeared in selected patents from 2006 to early 2011 will be reported, focusing on their chemical features and, whenever possible, on structure- activity relationships and mechanism of action. Examples of type I or II ATP-competitive inhibitors or substrate competitive inhibitors will be presented. The research in this field is very active and will probably lead to the discovery of therapeutically useful compounds, both c-Src selective and multitargeted inhibitors, that acting on different cell pathways could be more effective in blocking cancer development. However, only the results of clinical trials will show in the near future the most promising compounds.

Toll-like receptors (TLRs) are pattern-recognition receptors responsible for detecting invading pathogens. About 13 TLRs are currently known to be expressed (see Table 1). TLR2 detects lipotechoic acid and bacterial lipoproteins, TLR4 recognizes LPS, TLR5, flagellin and TLR3 detects double-stranded RNA. The unmethylated CPG DNA of bacteria and viruses is detected by TLR9. TLR7 recognizes single-stranded RNA of viruses. TLR 11 in mice recognizes profillin from Toxoplasma gondii. Binding to TLRs expressed on dendritic cells (DCs) can trigger adaptive immune responses and DCs thus serve as a bridge between innate and adaptive immunity. In HIV, it has been shown that polymorphism of the TLR9, 4, 7 and 8 plays a role in disease progression and viral load. In addition, several researchers began investigating using TLR agonists as adjuvants for HIV vaccine candidates. TLR3 has shown good results if used with vaccine proteins selectively delivered to DCs by antibodies to DEC-205/CD205, a receptor for antigen presentation. TLR7/8 and TLR9 agonists enhanced immune responses if conjugated to the vaccine protein. A triple combination of TLR2/6, -3, and -9 agonists and IL-15 synergistically up regulated immune responses to vaccine formulated as recombinant MVA viruses expressing SIVmac239 Gag, Pol, Env and Rev, Tat, Nef. These and other studies are just beginning to unravel the potential of TLRs agonists and much more and broader research is needed in order to revitalize the field of HIV vaccines.

Bacillus anthracis, the causative agent responsible for anthrax infections, poses a significant biodefense threat. There is a high mortality rate associated with untreated anthrax infections; specifically, inhalation anthrax is a particularly virulent form of infection with mortality rates close to 100%, even with aggressive treatment. Currently, a vaccine is not available to the general public and few antibiotics have been approved by the FDA for the treatment of inhalation anthrax. With the threat of natural or engineered bacterial resistance to antibiotics and the limited population for whom the current drugs are approved, there is a clear need for more effective treatments against this deadly infection. A comprehensive review of current research in drug discovery is presented in this article, including efforts to improve the purity and stability of vaccines, design inhibitors targeting the anthrax toxins, and identify inhibitors of novel enzyme targets. High resolution structural information for the anthrax toxins and several essential metabolic enzymes has played a significant role in aiding the structure-based design of potent and selective antibiotics.

Non-synonymous single nucleotide polymorphisms (nsSNPs) are genetic variations that affect the encoded protein by an amino acid change. In humans, many naturally-occurring nsSNPs cause protein dysfunction and increase vulnerability to disease. Identification of such nsSNPs provides an important opportunity to develop drugs/nutrients with precise therapeutic targets. Therefore, current biomedical research and medicinal chemistry look for targets and functional nsSNPs, to establish correlation with disease susceptibility and foster rational drug design. We review the molecular bases of missense mutation effects at the protein level, namely on sequence conservation, including stability, conformation, biophysical parameters, and protein-protein interaction. Further, we summarize some computational methods, available information resources, and the current approaches used to predict nsSNPs functionality in human genome, most of which based on protein structures and/or evolutionary conservation. Finally, using an approach paradigmatic of the nsSNPs-gene interactions, we evaluate the functional consequences and phenotypic effects of nsSNPs on two genes associated with cholesterol response. Biophysical changes produced by exchanged amino acids I638V (rs5908) from the 3-hydroxy-3-methylglutaryl- coenzyme A reductase gene, and A370T (rs11669576) from the low density lipoprotein receptor gene have been analyzed with an emphasis on stability, activity, and structure of their related proteins. Based on available data and the results of our study, we propose that, even though the extent and precise nature of nsSNPs' role in health and disease is yet to be fully elucidated, targeted investigations are warranted and will - in the future - provide useful tools to develop targeted drugs.

The innate immune system is the first line of defense against microbial diseases. Antimicrobial proteins produced by snake venoms have recently attracted significant attention due to their relevance to bacterial infection and potential development into new therapeutic agents. Staphylococcus aureus is one of the major human pathogens causing a variety of infections involving pneumonia, toxic shock syndrome, and skin lesions. With the recent emergence of methicillin (MRSA) and vancomycin (VRSA) resistance, S. aureus infection is a serious clinical problem that will have a grave socio-economic impact in the near future. Although S. aureus susceptibility to innate antimicrobial peptides has been reported recently, the protective effect of snake venom phospholipase A2 (svPLA2) proteins on the skin from S. aureus infection has been understudied. This review details the protective function of svPLA2s derived from venoms against skin infections caused by S. aureus. We have demonstrated in vivo that local application of svPLA2 provides complete clearance of S. aureus within 2 weeks after treatment compared to fusidic acid ointment (FAO). In vitro experiments also demonstrate that svPLA2 proteins have inhibitory (bacteriostatic) and killing (bactericidal) effects on S. aureus in a dose-dependant manner. The mechanism of bacterial membrane damage and perturbation was clearly evidenced by electron microscopic studies. In summary, svPLA2s from Viperidae and Elapidae snakes are novel molecules that can activate important mechanisms of innate immunity in animals to endow them with protection against skin infection caused by S. aureus.

Monoamine oxidase plays a significant role in the control of intracellular concentration of monoaminergic neurotransmitters or neuromodulators and dietary amines. The rapid degradation of these molecules ensures the proper functioning of synaptic neurotransmission and is critically important for the regulation of emotional and other brain functions. The development of human MAO inhibitors led to important breakthroughs in the therapy of several neuropsychiatric disorders. Different families of heterocycles containing 2 or 4 nitrogen atoms have been used as scaffolds for synthesizing selective monoamine oxidase inhibitors, but the early period of the MAO-inhibitors started with hydrazine derivatives. Pyrazole, pyrazoline, and pyrazolidine derivatives can be considered as a cyclic hydrazine moiety. This scaffold also displayed promising antidepressant and anticonvulsant properties as demonstrated by different and established animal models. Diversely substituted pyrazoles, embedded with a variety of functional groups, are important biological agents and a significant amount of research activity has been directed towards this chemical class.

A dramatical decline in human male reproductive function has been reported for the past 20 years. Many recent epidemiological, clinical and experimental findings suggest that the reproductive dysfunction could result from prenatal and neonatal chemical compound exposure. Even if numerous studies argue for a relationship between male infertility and environmental and/or occupational exposure, the molecular mechanisms by which these anti-reproductive compounds act are still unclear. Recent findings showed that a family of transmembranous proteins, connexins, regulates numerous physiological functions involved in the development such as cell proliferation, differentiation, migration and apoptosis. In the testis and the ovary, connexins are known to be essential for the establishment and the maintenance of spermatogenesis in males and oogenesis and folliculogenesis in females. Moreover, mutation of connexin genes leads to several developmental human diseases (myelin-related diseases, hearing loss, congenital cataract, skin disorders or more complex syndromes such as the oculodendrodigital dysplasia....) and altered connexin expression, trafficking and degradation are often associated with the tumoral process. We propose, in the present work, to give an overview of connexin expression and intercellular gap junction coupling during development: in preimplantation, implantation and postimplantation embryos. Moreover, we underline the impact of maternal chemical exposure on connexin expression during fetal gonad development and we link this effect to future offspring fertility.

Obesity is a major problem of modern societies that sometimes, but not necessarily, is associated with binge-eating disorder BED), a relatively new disorder characterized by binge eating without purging. The purpose of this article is to review the rationale for the potential use of pharmacological treatments in BED, and the potential use of the recently proposed compounds. Therefore, a careful medline of published articles from 1980 to December 2010 was carried out using the following keywords: BED and treatment, topiramate, zonisamide, sibutramine, venlafaxine, duloxetine, ghrelin, opiate blockers. Single case reports, observational studies, opinion articles, and studies concerning adults with syndromes resulting in BED (i.e., night eating syndrome) were also reviewed. All examined papers would indicate that the pharmacological treatment of BED is still heterogenous and poorly established, mainly for the lack of controlled studies in large samples of patients. In any case, the data on serotonin and norepinephrine reuptake inhibitors and on novel anticonvulsants seem quite promising in terms of efficacy and tolerability. In addition, the preliminary findings on the possibility of modulating appetite through the interference with the ghrelin system suggest new and intriguing ways of intervention in BED.

Spinal cord injury (SCI) is a very severe traumatic disease of the central nervous system (CNS). Because of its high incidence rate in causing disabilities, it brings great burdens to patients and society. Both Traditional Chinese Medicine (TCM) and Western Medicine have been adopted to ameliorate SCI with promising outcomes. In TCM, the use of Governor Vessel electro-acupuncture has achieved remarkable results on the rehabilitation of patients with SCI. In the past decade, Governor Vessel electro-acupuncture has also been used in experimentally induced SCI and this has resulted in promising functional recovery. Both neural stem cells (NSCs) and bone marrow mesenchymal cells (MSCs) have been used extensively in recent years for improvement of functional recovery of CNS disorders. We have used a combined approach by integrating the basic and clinical research in SCI in recent years. In this connection, transplantation of NSCs or MSCs coupled with the Governor Vessel electro-acupuncture (GV-EA) has been adopted to improve the recovery of SCI. Our study suggests that GV-EA may activate the process of cell metabolism, and initiate synthesis and secretion of endogenous neurotrophic factors in the ambient tissues at the lesion site of spinal cord. It is proposed that the new combined strategy could promote a better structural and functional recovery of injured spinal cord.