Current Medicinal Chemistry (v.19, #31)

Immunoliposomes by E. Paszko, M.O. Senge (5239-5277).
Since their discovery by Bangham about 50 years ago, liposomes have become promising tools in drug delivery systems. This has increased the therapeutic index of many drugs, and offers improved drug targeting and controlled release. In order to further improve the specificity of liposomes for malignant tissues, targeted liposomal formulations have been developed which represent the next step of liposomal drug delivery in medical treatment. Antibodies and antibody fragments are the most widely used targeting moieties for liposomes due to the high specificity for their target antigens. This has given rise to a new class of drug delivery vehicles, the so-called immunoliposomes. Immunoliposomes are generated by coupling of antibodies to the liposomal surface and allow for an active tissue targeting through binding to tumor cell-specific receptors. Such antibody modified liposomes are attracting great interest for their potential use in specific drug delivery to cancer cells, gene therapy, drug delivery through blood brain barrier, or molecular imaging. Thus far, immunoliposomes show promising results in vitro and in vivo and appear to be effective systems for improvements in cancer treatment. This review covers the literature of the past decade with special emphasis on in vitro and in vivo studies.

The Role of a Disturbed Arginine/NO Metabolism in the Onset of Cancer Cachexia: A Working Hypothesis by N. Buijs, J. Luttikhold, A.P.J. Houdijk, P.A.M. van Leeuwen (5278-5286).
Cancer cachexia is a complex catabolic state in patients with a malignancy, associated with increased morbidity and mortality. This syndrome is characterized by a redistribution of the body's protein content and a subsequent muscle wasting. The aetiology of this syndrome seems multifactorial, but remains unclear. It is suggested that this catabolic state occurs in response to the alterations in immune interactions between tumor and host. The amino acid arginine and its derivate nitric oxide (NO) play various roles in anti-tumor immune response and the body’s homeostasis. Glutamine is the precursor for arginine de novo synthesis and the most abundant amino acid in the body, mainly stored in skeletal muscle. Tumors develop a protection mechanism against the specific anti-tumor attack of the immune system by recruiting myeloid derived suppressor cells (MDSC). The MDSC deplete arginine levels and disturb NO production. We here hypothesize that the perturbation of the arginine/NO metabolism plays a significant role in the aetiology of cancer cachexia. Arginine/ NO metabolism is disturbed in patients with cancer. The body will try to correct this perturbation by mobilizing arginine and glutamine from muscles. The decreased arginine levels and the disturbed NO production activate several cascades, which in turn inhibit protein synthesis and promote proteolysis, leading to cachexia. Cachexia remains one of the most frequent and damaging opportunistic syndromes in cancer patients. In this review we will elaborate on a new hypothesised concept and the underlying mechanisms of this syndrome. New studies are essential to ground this hypothesis and to develop interventions to break through the pathological mechanisms underlying cachexia.

Flavonoids, secondary metabolites ubiquitously produced in the plant kingdom, are low molecular weight polyphenolic molecules. They are characterized by variable chemical structures and show a vast array of biological activities (i.e... antiviral, antiinflammatory, antitumor, antimicrobial, estrogenic, antiestrogenic, antioxidant, mutagenic and antimutagenic) targeting different pathways. Some of these compounds such as Genistein, Daidzein or its synthetic derivative Phenoxodiol as well as Luteolin and Quercetin are able to inhibit DNA topoisomerases. This review discusses that Flavonoids targeting DNA topoisomerases may lead to novel drug development with anticancer potential.

Protein kinases (PKs) and lipid kinases (LKs) are good choices for targets of signal transduction therapy as these enzymes are involved in signaling pathways, and are often related to the pathogenesis of lymphoid malignancies. The attractiveness of PKs and LKs as drug able targets is enhanced by the fact that they are enzymes whose biological activity can be turned off by drugs that block their catalytic site. In the last few years small molecular kinase inhibitors (KIs) have been synthesized and become available for preclinical studies and clinical trials. The first KI, introduced into clinical practice in 1998, was imatinib mesylate, which became the first choice drug in chronic myeloid leukemia. More recently, several KIs have been developed to target the proximal B-cell receptor (BCR) signaling pathway including spleen tyrosine kinase inhibitor (Fostamatinib) and Bruton's tyrosine kinase inhibitors (Ibrutinib, AVL-263). These agents are currently evaluated in early clinical trials in chronic lymphocytic leukemia (CLL) and other diseases. Cyclin-dependent kinase (Cdk) inhibitors, flavopiridol (alvocidib), BMS-387032 (SNS-032), sunitinib and sorafenib are currently under evaluation in clinical trials for relapsed/refractory CLL. Multi-tyrosine kinase inhibitors including vandetanib (ZD6474) bosutinib (SKI-606), TKI258 (CHIR-258), pazopanib (GW786034) and axitinib (AG013736) have been also developed for the treatment of lymphoid malignancies. Phosphatidylinositol 3-kinases (PI3K ) are a family of lipid kinases that mediate signals from cell surface receptors. CAL-101 (GS-1101) is an oral PI3Kδ-specific inhibitor which has shown preclinical and clinical activity against CLL. This article summarizes recent achievements in the mechanism of action, pharmacological properties and clinical activity and toxicity of PK and LK inhibitors in CLL.

Terpene Compounds in Nature: A Review of Their Potential Antioxidant Activity by E. Gonzalez-Burgos, M.P. Gomez-Serranillos (5319-5341).
Reactive Oxygen Species are involved in the pathological development of many important human diseases such as neurodegenerative diseases, cardiovascular processes, diabetes and many others. The most promising strategy to prevent from the oxidative damage caused by these reactive species is the use of antioxidant molecules. These compounds can act as direct antioxidants through free radical scavenging mechanisms and/or as indirect antioxidants by enhancing the antioxidant status (enzymatic and non-enzymatic). Terpenes, one of the most extensive and varied structural compounds occurring in nature, display a wide range of biological and pharmacological activities. Here we highlight their antioxidant properties. Due to their antioxidant behaviour terpenes have been shown to provide relevant protection under oxidative stress conditions in different diseases including liver, renal, neurodegenerative and cardiovascular diseases, cancer, diabetes as well as in ageing processes. Evidence for this comes from the increasing number of publications on this issue in recent years. This review provides a complete overview of the natural terpenes with potential antioxidant properties, focusing on their source, structures, antioxidant mechanisms through which they exert their pharmacological and possible therapeutic activities.

Synthesis of Biologically Active Bridged Diazabicycloheptanes by G. Murineddu, B. Asproni, G. Pinna, M.M. Curzu, A. Dore, A. Pau, F. Deligia, G.A. Pinna (5342-5363).
The chemistry underlying how diazabicycloheptanes are assembled is described, subdivided according to chemical structure of two types, the 3,6 diazabicyclo[3.1.1]heptane and the 2,5-diazabicyclo[2.2.1]heptane ring system. Detailed information on myriad of activities of compounds derived from the two scaffolds are reported.

Structure-Activity Relationship Studies on Clinically Relevant HIV-1 NNRTIs by R.K. Rawal, V. Murugesan, S.B. Katti (5364-5380).
In addition to the nucleoside reverse transcriptase inhibitors (NRTIs), protease inhibitors (PIs) and integrase inhibitors (INIs), nonnucleoside reverse transcriptase inhibitors (NNRTIs) have contributed significantly in the treatment of HIV-1 infections. More than 60 structurally different classes of compounds have been identified as NNRTIs, which are specifically inhibiting HIV-1 reverse transcriptase (RT). Five NNRTIs (nevirapine, delavirdine, efavirenz, etravirine and rilpivirine) have been approved by US Food and Drug Administration (FDA) for clinical use. The NNRTIs bind with a specific ‘pocket’ site of HIV-1 RT (allosteric site) that is closely associated with the NRTI binding site. Due to mutations of the amino acid residues surrounding the NNRTI-binding site, NNRTIs are notorious for rapidly eliciting resistance. Though, the emergence of resistant HIV strains can be circumvented if the NNRTIs are used either alone or in combination with NRTIs (AZT, 3TC, ddI, ddC, TVD or d4T) and PIs (Indinavir, nelfinavir, saquinavir, ritonavir and lopinavir etc.) as shown by both a decrease in plasma HIV-1 RNA levels and increased CD4 T-cells. Here we are going to discuss recent advances in structure activity relationship studies on nevirapine, delavirdine, efavirenz, etravirine, rilpivirine and 4-thiazolidinones (privileged scaffold) HIV-1 NNRTIs.

Emerging Concepts on Inhibitors of Indoleamine 2,3-Dioxygenase in Rheumatic Diseases by P. Filippini, N. Del Papa, D. Sambataro, A. Del Bufalo, F. Locatelli, S. Rutella (5381-5393).
The enzyme indoleamine 2,3-dioxygenase 1 (IDO1) finely regulates both innate and adaptive immune responses through the degradation of the essential amino acid tryptophan into kynurenine and other downstream metabolites, which suppress effector T-cell function and promote the differentiation of regulatory T cells. A novel role for IDO1 as a signaling molecule and a modifier of innate inflammatory responses is now emerging. In particular, IDO1 can either support or antagonize inflammation in a context- and tissuedependent manner. Studies in experimental arthritis have unravelled a previously unappreciated role for IDO in controlling B-cell activation and autoantibody production. IDO dysregulation has been documented in patients with systemic lupus erythematosus, systemic sclerosis and Sjogren's syndrome, as well as in severe sepsis and chronic kidney disease. This article summarizes the contribution of IDO to the pathophysiology of inflammatory/autoimmune disorders, and discusses whether strategies to restore metabolic equilibrium in the kynurenine pathway might be pursued in diseases states such as rheumatoid arthritis and systemic sclerosis.

Induction of Apoptosis in Macrophages via Kv1.3 and Kv1.5 Potassium Channels by L. Leanza, M. Zoratti, E. Gulbins, I. Szabo (5394-5404).
We have previously shown that the mitochondrial potassium channel Kv1.3 (mtKv1.3) in T lymphocytes is a novel target of Bax. Mutation of Bax at lysine 128 (BaxK128E) abrogates its inhibitory effects on mtKv1.3 and prevents apoptosis. The importance of mtKv1.3 inhibition was underscored by the finding that membrane-permeant Kv1.3 inhibitors induced Bax/Bak-independent cell death and reduced the volume of an mtKv1.3-expressing tumor by 90% in a mouse model. However, the possible involvement of other Kv channels in apoptosis has not been clarified. Here we report that, like Kv1.3, Kv1.1 and Kv1.5 also interact with Bax. Transfection of Kvdeficient lymphocytes with Kv1.1 restores sensitivity to cell death in apoptosis-resistant CTLL-2 lymphocytes. SiRNA down-regulation of Kv1.3 and Kv1.5 expression in macrophages confers resistance to apoptosis. We further report that J774 macrophages express Kv1.3 and Kv1.5 in their mitochondria and that inhibition of both channels with specific membrane-permeant drugs can efficiently induce apoptosis in a macrophage cell line. Thus, our results indicate that the mechanism proposed for Kv1.3 can be extended to other Kv channels and suggest that membrane-permeant drugs may be a novel pharmacological tool for inducing apoptosis in macrophages, important players in the immune system. This result could be exploited for the depletion of tumor-associated macrophages, which have been shown to foster tumor growth.

4'-Aminochalcones As Novel Inhibitors of the Chlorinating Activity of Myeloperoxidase by M.L. Zeraik, V.F. Ximenes, L.O. Regasini, L.A. Dutra, D.H.S. Silva, L.M. Fonseca, D. Coelho, S.A.S. Machado, V.S. Bolzani (5405-5413).
The excessive activation of neutrophils generates reactive oxygen species (ROS) and the secretion of primary granular enzymes, such as myeloperoxidase (MPO), which is implicated in numerous inflammatory diseases. The aim of this study was to evaluate chalcones as inhibitors of the chlorinating activity of MPO using in vitro and ex vivo assays. In addition to cytotoxic properties, the inhibition of respiratory burst, the scavenger capacity, and the oxidation potential were measured. 4'-Aminochalcone (1), 4'-amino-4- fluorochalcone (2), and 4'-amino-4-methylchalcone (3) exhibited potent inhibition of the chlorinating activity of MPO, as evaluated in a neutrophil system and a free cell system, to the following degree: (1) IC50 = 0.265 ± 0.036 μmol L-1; (2) IC50 = 0.250 ± 0.081 μmol L-1; and (3) IC50 = 0.250 ± 0.012 μmol L-1. These values were similar to those for 5-fluorotryptamine (IC50 = 0.192 ± 0.012 μmol L-1), a compound considered to be a potent MPO inhibitor. These aminochalcones were not toxic to neutrophils at concentrations below 100 μmol L- 1, as determined by the trypan blue exclusion assay. Compounds 1–3 presented a high oxidation potential (Epa1 ≉ 0.80 V), low scavenger capacity against DPPH• and HOCl, and low inhibition of respiratory burst. These data indicated that aminochalcones are potent inhibitors of MPO chlorinating activity, a new property for chalcone derivatives, given that they are neither antioxidant agents nor inhibitors of respiratory burst. In conclusion, the selected aminochalcones have potential as pharmacological agents for inflammatory diseases.

Toxins from Physalia physalis (Cnidaria) Raise the Intracellular Ca2+ of Beta-Cells and Promote Insulin Secretion by C.M. Diaz-Garcia, D. Fuentes-Silva, C. Sanchez-Soto, D. Dominguez-Perez, N. Garcia-Delgado, C. Varela, G. Mendoza-Hernandez, A. Rodriguez-Romero, O. Castaneda, M. Hiriart (5414-5423).
Physalia physalis is a marine cnidarian from which high molecular weight toxins with hemolytic and neurotoxic effects have been isolated. In the present work, two novel toxins, PpV9.4 and PpV19.3 were purified from P. physalis by bioactive guideline isolation. It involved two steps of column chromatography, gel filtration and RP-HPLC. The molecular weights were 550.7 and 4720.9 Da for PpV9.4 and PpV19.3, respectively. In the light of the Edman sequencing results, the structure of these toxins included the presence of modified amino acids. Both toxins increased the percentage of insulin secreting beta-cells and induced cytosolic Ca2+ elevation. To date, this is the first report of low molecular weight toxins increasing insulin secretion purified from cnidarians, by constituting a new approach to the study of beta-cells physiology.