Current Medicinal Chemistry - Volume 16, Issue 30, 2009

Most patients diagnosed with non-small cell lung cancer (NSCLC) have advanced disease. Chemotherapy has apparently reached a plateau of effectiveness in improving survival in this subgroup of patients. Considerable efforts have been initiated to identify novel targets for new biological agents which may be safely and effectively administered to NSCLC patients. New blood vessel formation, known as angiogenesis, is a fundamental event in the process of tumor growth and metastatic dissemination. The vascular endothelial growth factor (VEGF) and its receptors play an essential role in tumor proliferation. Approaches to limit VEGF activity include monoclonal antibodies (mAbs) and small molecules inhibiting the corresponding receptor-tyrosine kinase activity. Bevacizumab, an anti-VEGF recombinant humanized mAb, is the first targeted agent which, when combined with chemotherapy, has shown superior efficacy versus chemotherapy alone as first-line treatment of advanced NSCLC. Future clinical developments of bevacizumab in NSCLC treatment include the combination with other targeted therapies in advanced disease, and the integration into the combined modality approaches for the treatment of early and locally advanced disease stages. Vandetanib, a small molecule targeting VEGF tyrosine-kinase activity, due to first indications of antitumor activity and the excellent toxicity profile seems to be a promising agent for the treatment of advanced NSCLC. Other antiangiogenic drugs, such as sorafenib, sunitinib, VEGF Trap and a new class named ‘vascular disrupting agents’, which includes ASA404, are being tested in ongoing clinical trials which will further define their role in the management of NSCLC.

It is currently believed that the development of a clinically relevant tumor needs new vessel formation provided by both angiogenesis (primary involving endothelial cells) and postnatal vasculogenesis (primary involving bone marrowderived cells). Clearly, it is important to identify factors that help to enhance the growth and “health” of tumors, as well as their further vascularization. The Insulin and Insulin-like Growth Factors (IGFs) systems play a key role in cellular metabolism, differentiation, proliferation, transformation and apoptosis, during normal and malignant growth. Moreover, these molecules seem essential in promoting tumor vascularization. Due to the complexity of these systems, the review has been focused on the role of insulin and IGFs signaling in the regulation of tumor angiogenesis and postnatal vasculogenesis. Since targeting on IGF for cancer therapy is rapidly becoming a clinical reality, a better understanding of IGFsmediated pathways has a relevant impact, providing new insights to help the design of newly developed drugs.

Polyphenolic molecules produced by higher plants in response to biotic and abiotic stresses exert numerous effects on tumorigenic cell transformation, and on tumor cells in vitro and in vivo, and may interact with conventional antitumor therapies. In the present review, we collected and critically discussed data on: (i) redox-dependent and redoxindependent mechanisms underlying cytotoxic/cytostatic effects of PPs and their metabolites towards tumor cells and cytoprotection of normal cells; (ii) mechanisms of anti-angiogenic and anti-metastatic action of PPs; (iii) PPs-associated phototoxicity against tumor cells and photoprotection of non-tumor cells; (iv) PPs effects on drug-metabolizing enzymes as a basis for their synergism or antagonism with chemotherapy; (v) molecular pathways leading to tumor chemoprevention by PPs; and (vi) PPs as protectors against toxic effects of chemo-, radio-, and photodynamic therapies.

Paclitaxel belongs to the most successful anticancer drugs developed and utilised during the past two decades. Nevertheless, the development of resistance of tumor cells and severe side effects in the patients require further improvement of the drug. In this review, we provide a detailed overview of the state-of-the-art in the medicinal chemistry of paclitaxel and its analogues. A number of strategies have been explored to obtain sufficient amounts of paclitaxel for clinical use from natural resources. Semi-synthesis from its precursor, 10-deacetylbaccatin III, which can be extracted from Taxus leavesturned out as the most appropriate method for commercial production. So far, many paclitaxel derivatives have been synthesized, and their effect on microtubules stabilization and cytotoxicity were investigated in terms of structure-activity relationships (SAR). One of them, docetaxel, was approved as a more potent anticancer agent than paclitaxel towards a variety of tumor types. This review summarizes current possibilities to harvest sufficient amount of drugs from natural sources, including the production of taxanes in bioreactors and synthetic approaches for paclitaxel and its analogues, their mechanism of action and structure-activity relationships. In addition, future developments and perspectives for this class of compounds are outlined.

Endothelial cell abnormalities and the effects on the surrounding microvasculature is a focal point in the pathogenesis of Systemic Sclerosis disease and may even be the sentinel event for the initiation of this disorder. A better understanding of these processes may improve our understanding of the pathophysiology of Systemic Sclerosis and more specifically the vasculopathy observed. Such knowledge will help us to further current treatments options and design novel therapies for Systemic Sclerosis and other fibrotic disorders.

Antimicrobial resistance is an emerging worldwide concern in light of the widespread antimicrobial drug use in humans, livestock and companion animals. The treatment of life-threatening infections is especially problematic because clinical strains rapidly acquire multiple-drug resistance. Antimicrobial peptides have long been considered to be viable alternatives to small molecule antibiotics. However, the peptides' parenteral use is frequently hampered by inadequate safety margins and rapid renal clearance leaving them suitable only for topical applications. The proline-rich peptide A3- APO represents a family of a new class of synthetic dimers that kill bacteria by a dual mode of action and carry domains for interaction with both the bacterial membrane and an intracellular target. From a series of designer antibacterial peptides, A3-APO emerged as a viable preclinical candidate by virtue of its superior ability to disintegrate the bacterial membrane, inhibit the 70-kDa heat shock protein DnaK alone or in synergy with small molecule antibiotics, lack of eukaryotic toxicity and withstand proteolytic degradation in body fluids. As many other proline-rich peptides, A3-APO binds to the C-terminal helical lid of bacterial DnaK and inhibits chaperone-assisted protein folding in bacteria but not in mammalian Hsp70. In this review, the structure, pharmacokinetic properties, antimicrobial spectrum of peptide A3-APO and its in vivo metabolite are summarized and the in vitro and in vivo antimicrobial effects (antimicrobial susceptibilities, postantibiotic effects, resistance induction) are discussed in detail.

Staphylococcus aureus is a facultative, Gram-positive coccus well known for its disease-causing capabilities. In particular, methicillin and vancomycin resistant strains of S. aureus (MRSA and VRSA, respectively) isolated globally represent daunting medical challenges for the 21st Century. This bacterium causes numerous illnesses in humans such as food poisoning, skin infections, osteomyelitis, endocarditis, pneumonia, enterocolitis, toxic shock, and autoimmune disorders. A few of the many virulence factors attributed to S. aureus include antibiotic resistance, capsule, coagulase, lipase, hyaluronidase, protein A, fibronectin-binding protein, and multiple toxins with diverse activities. One family of protein toxins is the staphylococcal enterotoxins (SEs) and related toxic shock syndrome toxin-1 (TSST-1) that act as superantigens. There are more than twenty different SEs described to date with varying amino acid sequences, common conformations, and similar biological effects. By definition, very low (picomolar) concentrations of these superantigenic toxins activate specific T-cell subsets after binding to major histocompatibility complex class II. Activated T-cells vigorously proliferate and release proinflammatory cytokines plus chemokines that can elicit fever, hypotension, and other ailments which include a potentially lethal shock. In vitro and in vivo models are available for studying the SEs and TSST-1, thus providing important tools for understanding modes of action and subsequently countering these toxins via experimental vaccines or therapeutics. This review succinctly presents the pathogenic ways of S. aureus, with a toxic twist. There will be a particular focus upon the biological and biochemical properties of, plus current neutralization strategies targeting, staphylcoccocal superantigens like the SEs and TSST-1.

The natriuretic peptide family is comprised of atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), C-type natriuretic peptide (CNP), dendroaspis natriuretic peptide - DNP and urodilatin. They play a role in the diagnosis of several diseases, especially those involving the cardiovascular system. Sepsis is a complex condition that can lead to multiorgan failure, shock and death. The number of people developing sepsis is still increasing (approximately 750,000 cases of sepsis occur annually in the USA). Both ANP and pro-ANP have attracted interest as new markers for sepsis. Reports indicate that ANP or BNP levels are elevated in septic patients. However, many mechanisms are still unexplained. This situation is complicated by the fact that contradictory results have been published. There are several reasons for this controversy including differences in the techniques used to assay natriuretic peptides. Nevertheless, natriuretic peptides might eventually prove useful for the diagnosis and/or the treatment of septic patients.

With a view to the rational design of selective quinoxaline derivatives, 2D and 3D-QSAR models have been developed for the prediction of anti-tubercular activities. Successful implementation of a predictive QSAR model largely depends on the selection of a preferred set of molecular descriptors that can signify the chemico-biological interaction. Genetic algorithm (GA) and simulated annealing (SA) are applied as variable selection methods for model development. 2D-QSAR modeling using GA or SA based partial least squares (GA-PLS and SA-PLS) methods identified some important topological and electrostatic descriptors as important factor for tubercular activity. Kohonen network and counter propagation artificial neural network (CP-ANN) considering GA and SA based feature selection methods have been applied for such QSAR modeling of Quinoxaline compounds. Out of a variable pool of 380 molecular descriptors, predictive QSAR models are developed for the training set and validated on the test set compounds and a comparative study of the relative effectiveness of linear and non-linear approaches has been investigated. Further analysis using 3D-QSAR technique identifies two models obtained by GA-PLS and SA-PLS methods leading to anti-tubercular activity prediction. The influences of steric and electrostatic field effects generated by the contribution plots are discussed. The results indicate that SA is a very effective variable selection approach for such 3D-QSAR modeling.