Current Medicinal Chemistry - Volume 19, Issue 25, 2012

The Editorial Board wishes to dedicate this issue of Current Medicinal Chemistry to the Editor-in-Chief of the journal, Prof. Dr. Atta-ur-Rahman, FRS, on his 70th birthday. The Editorial Board acknowledges the tremendous achievements of Prof. Rahman in the fields of Organic Chemistry in general and on bioactive natural products in particular. Prof. Rahman’s honors include: the first scientist from the Muslim world to have won the prestigious UNESCO Science Prize (1999) in the 35 year old history of the Prize; elected as Fellow of Royal Society (London) in July 2006; conferred honorary doctorate degrees from many prestigious universities, including the University of Cambridge. On a national level his services are acknowledged in the form of four prestigious civil awards of excellence, including: Nishan-e-Imtiaz (2002), Hilal-e-Imtiaz (1998), Sitara-e-Imtiaz (1991) and Tamgha-e-Imtiaz (1983). At an academic level, Prof. Rahman has 856 publications in several fields of organic chemistry including 658 research publications, 21 patents, 113 books and 65 chapters in books published largely by major U.S. and European presses. He is currently the Editor-in-Chief of 12 scientific journals in fields ranging from Medicinal Chemistry to Pharmaceutical Drug Design. Seventy six students have completed their Ph.D. degrees under his supervision. He chairs the Network of Academies of Sciences of Islamic Countries (NASIC) and is the Vice-President (Central & South Asia) of the Academy of Sciences for the Developing World (TWAS) Council, and Foreign Fellow of Korean Academy of Sciences. Prof. Atta-ur-Rahman was the President of the Pakistan Academy of Sciences (2003-2006) and was again elected as the President of the Academy from 1st of January 2011. In particular, as Editor-in-Chief, Prof. Rahman has made outstanding contribution to Current Medicinal Chemistry. The contributions of Prof. Rahman to the uplifting of science in Pakistan in his capacity as the Federal Minister for Science & Technology and later as Chairman Higher Education Commission were acknowledged by a high civil award of the government of Austria and TWAS prize for institution building as well as by four editorials in Nature. The Editorial board wishes health and prosperity to Prof. Atta-ur-Rahman in the years to come.

Diabetes mellitus, a chronic condition caused by defects in insulin secretion, or action, or both, is a group of metabolic disorders, complications of which can contribute significantly to ill health, disability, poor quality of life and premature death. From the three main types of diabetes, Type 2 is by far the most common, accounting for about 90% of cases worldwide. Studies on the role of protein tyrosine phosphatase 1B (PTP1B) have clearly shown that it serves as a key negative regulator of insulin signaling and is involved in the insulin resistance associated with Type 2 diabetes. The present work aims to survey information related to PTP1B research published in the last decade. Emphasis is laid particularly on Quantitative Structure-Activity Relationships (QSAR) based studies that supported so far the design of new, potent and selective PTP1B inhibitors. Finally, the challenges and perspectives of QSAR studies in this field are discussed to show how these method can be used to design new chemical entities with enhanced PTP1B inhibition activity.

Histone deacetylase (HDAC) inhibitors are a group of anticancer drugs which cause growth arrest and apoptosis of several tumor cells. HDAC inhibitors have been also found to increase the anticancer efficacy of several treatment modalities i.e. chemotherapy or radiotherapy. Here, we review the literature on combinations of HDAC inhibitors both with ionizing radiation and with other drugs, highlighting DNA-damaging compounds. The results of numerous studies with several types of cancer cells discussed in this review demonstrate that HDAC inhibitors enhance the effect of DNA damaging agents, such as inhibitors of topoisomerases, inhibitors of DNA synthesis, DNA-intercalators and agents covalently modifying DNA (i.e. doxorubicin, etoposid, 5-fluorouracil, cisplatin, melphalan, temozolomide and ellipticine) or of irradiation. Hence, the use of HDAC inhibitors combined with these antitumor drugs or ionizing radiation is a promising tool which may make treatment of patients suffering from many types of cancer more efficient. Several molecular mechanisms are responsible for the observed higher sensitivity of tumor cells towards therapeutic agents elicited by HDAC inhibitors. These mechanisms are discussed also in this review.

Cancer vaccines designed to re-calibrate the existing host-tumour interaction, tipping the balance from tumor acceptance towards tumor control holds huge potential to complement traditional cancer therapies. In general, limited success has been achieved with vaccines composed of tumor-associated antigens introduced to dendritic cells (DCs) generated in vitro. This may in part result from suboptimal maturation of DCs leading to insufficient production of IL-12, a key driver of cellular immunity. Therefore, tremendous efforts have been put into the design of maturation cocktails that are able to induce IL-12 secreting type 1 polarized DCs mimicing pathogen-derived molecular activation of DCs. Correct timing and potential synergisms of clinical-grade toll-like receptor ligands, interferons (IFN) and CD40L enhance IL-12 production in DCs. However, cytokine exhaustion, predominant expression of tolerogenic molecules and activation-induced dendritic cell death should be avoided. Thus, compounds such as IFN-γ may initially induce immunity but later on tolerance. Maturation with PGE2 obviously promotes migration via expression of CCR7 but on the down side PGE2 limits the production of IL-12 especially following encounter with CD40L-expressing cells and furthermore, PGE2 imprints DCs for preferential interaction with tolerogenic T cells. In addition, type 1 polarized DCs matured without PGE2 also seem to be capable of migrating in vivo, although concomitant production of CCL19 seems to transiently affect in vitro migration via autocrine receptor-mediated endocytosis of CCR7. In the current review, we discuss optimal design of DC maturation focused on pre-clinical as well as clinical results from standard and polarized dendritic cell based cancer vaccines.

Proteoglycans (PGs), glycosaminoglycans (GAGs) and hyaluronan as a free GAG, have unique structural characteristics which enable them via specific interactions with matrix proteins and cell surface receptors to regulate key tumor cell functions and thus to affect cancer growth and progression. This article explores the many layers of interdependent signaling among transformed colon epithelial cells, neighboring stromal cells and their respective PGs / GAGs components along the insidious and often deadly route of colon cancer progression. Specifically addressed is the altered deposition of PGs / GAGs by colon cancer cells; the effects of these malignant cells on gene expression and biosynthesis of PGs / GAGs of the surrounding stromal cells and the signaling pathways involved, with the utmost goal to highlight potential therapeutic targets in the rapidly developing field of glycan-based therapy.

The protozoan diseases leishmaniasis, human African trypanosomiasis (HAT) and Chagas disease (CD) are responsible for substantial global morbidity and mortality in tropical and subtropical regions. Environmental changes, drug resistance and immunosuppression are contributing to the emergence and spread of these diseases. In the absence of safe and efficient vaccines, chemotherapy, together with vector control, remains the most important measure to control kinetoplastid diseases. Nevertheless, the current chemotherapeutic treatments are clearly inadequate because of their toxic effects, generation of resistances as well as route and schedules of administration not adapted to the field-conditions. This review overlooks the strategies that can be addressed to meet immediately the patient needs such as the reconsideration of current regimens of administration and the rational combination of drugs in use. In the medium-long term, due to new methodologies of medicinal-chemistry, the screening from natural products and the identification of new therapeutic targets, new lead compounds have great chance to advance through the drug development pipeline to clinic. Modern pharmaceutical formulation strategies and nanomedicines also merit a place in view of the benefits of a single dose of liposomal Amphotericin B (AmBisome ®) against visceral leishmaniasis. BBB-targeted nanodevices could be suited for selective delivery of drugs against HAT encephalitic phase. Bioadhesive nanoparticles can be proposed to enhance the bioavailability of drugs after oral administration by reason of improving the drug solubility, and permeability across the intestinal epithelia.

The interest in the application of machine learning techniques (MLT) as drug design tools is growing in the last decades. The reason for this is related to the fact that the drug design is very complex and requires the use of hybrid techniques. A brief review of some MLT such as self-organizing maps, multilayer perceptron, bayesian neural networks, counter-propagation neural network and support vector machines is described in this paper. A comparison between the performance of the described methods and some classical statistical methods (such as partial least squares and multiple linear regression) shows that MLT have significant advantages. Nowadays, the number of studies in medicinal chemistry that employ these techniques has considerably increased, in particular the use of support vector machines. The state of the art and the future trends of MLT applications encompass the use of these techniques to construct more reliable QSAR models. The models obtained from MLT can be used in virtual screening studies as well as filters to develop/discovery new chemicals. An important challenge in the drug design field is the prediction of pharmacokinetic and toxicity properties, which can avoid failures in the clinical phases. Therefore, this review provides a critical point of view on the main MLT and shows their potential ability as a valuable tool in drug design.

Monoclonal antibodies (mAbs) have greatly advanced the field of anti-cancer immunotherapy and have made a major impact in clinical medicine. While more mAbs have been approved by the FDA and entered into the clinical therapeutic arena with indications to treat various solid tumors and hematologic malignancies, extensive efforts have also been made to make mAb therapy more effective. Combination therapy of anti-tumor mAbs with chemotherapeutic drugs has been widely used in the clinical patient care. In addition, many immune stimulating agents have been specifically studied for this very purpose. One compound in particular, β-glucan, has shown very promising and exciting results in pre-clinical animal models and early phase human clinical trials. β-Glucans are naturally occurring, abundant polysaccharides with different structures that can be extracted and purified from fungi, bacteria, oats and barley. The active components of yeast-derived β-glucan exert their unique immune stimulating functions by binding specifically to complement receptor 3 (CR3) via lectin-like domain (LLD) and activating CR3 to promote cellular cytotoxicity of iC3b-coated cancer cells. In addition, particulate yeast-derived β-glucan stimulates both innate and adaptive anti-tumor immune responses. This review covers the anti-cancer mechanisms of anti-tumor mAbs and β-glucans, the pre-clinical studies done with β-glucans in conjunction with anti-tumor mAbs in human carcinoma xenograft models, and the preliminary results of human clinical trials with different β-glucans, as well as those of phase I/II and III studies using the combination of yeast-derived soluble β-glucan and anti-tumor mAbs.

1,4-Dihydropyridines were introduced in the last century for the treatment of coronary diseases. Then medicinal chemists decorated the 1,4-DHP nucleus, the most studied scaffold among L-type calcium channel blockers, achieving diverse activities at several receptors, channels and enzymes. We already described (Ioan et al. Curr. Med. Chem. 2011, 18, 4901-4922) the effects of 1,4-DHPs at ion channels and G-protein coupled receptors. In this paper we continue the analysis of the wide range of biological effects exerted by compounds belonging to this chemical class. In particular, focus is given to the ability of 1,4-DHPs to revert multi drug resistance that, after over 20 years of research, continues to be of great interest. We also describe activities on other targets and the action of 1,4-DHPs against several diseases. Finally, we report and review the interaction of 1,4-DHPs with the hERG channel, transporters and phase I metabolizing enzymes. This work is a starting point for further exploration of the 1,4-DHP core activities on targets, off-targets and antitargets.

Flavonoids have shown anticarcinogenic activity in cancer cell lines, animal models, and some human studies. Quantitative structure-activity relationship (QSAR) models have become useful tools for identification of promising lead compounds in anticancer drug development. However, epidemiological and clinical studies are still scarce. Compounds with flavonoid scaffold have been the subject of many mechanistic studies in cells, but information on human chemopreventive properties is still missing. The knowledge of the mechanisms of action, anti-multidrug resistance, and QSAR studies on flavonoids and related compounds may help to enhance research on these compounds and their bioactivity. Therefore, once the issue is introduced, the mechanisms involved, and QSAR studies developed to predict the activity and toxicity of these chemicals to biological systems are discussed. QSAR studies on flavonoids as inhibitors of breast cancer resistance protein (BCRP/ABCG2), 17β-hydroxysteroid dehydrogenase (17β-HSD), PIM-1 kinase and cyclin-dependent kinases (CDKs) are analyzed. Combined treatment of flavonoids with TRAIL and current chemotherapy agents is also discussed as a promising cancer chemoprevention and/or therapy.

Matrix metalloproteinases (MMPs) are essential for the degradation and turnover of components of the extracellular matrix (ECM) and, when pathologically elevated, mediate connective tissue loss (including bone destruction) in various inflammatory and other diseases. Tetracyclines (TCs) are known inhibitors of mammalian-derived MMPs, and non-antibiotic formulations of Doxycycline are FDA-approved to treat periodontitis and the chronic inflammatory skin disease, rosacea. Because the C-11/ C-12 diketonic moiety of the tetracyclines is primarily responsible, through zinc-binding, for MMP inhibition, we have uniquely modified curcumin as a “core” molecule, since it contains a similar enolic system and is known to have beneficial effects in diseases where connective-tissue loss occurs. Specifically we have developed new congeners which exhibit improved zinc-binding and solubility, and potent reduction of excessive MMP levels and activity. We now describe a series of curcuminoid bi- and tri-carbonylmethanes in which all of these properties are substantially improved. An N-phenylaminocarbonyl derivative of bis-demethoxycurcumin (CMC2.24) was selected as the “lead” substance because it showed superior potency in vitro (i.e., the lowest IC50) against a series of neutral proteases (MMPs) associated with tissue erosion. Moreover, CMC2.24 administered to diabetic rats orally (30mg/kg), reduced the secretion of pathologically-excessive levels of MMP-9 to normal in cultured peritoneal macrophages with no evidence of toxicity. Thus, this (and other similar novel) compound(s) may be useful in various diseases of connective-tissue loss.

Coronary Artery Disease (CAD) and Objectives: Sleep Disordered Breathing (SDB) are both oxidative stress disorders. SDB intermittent hypoxia induces oxidative stress, and reduces NO• availability, causing endothelial dysfunction. Low-density lipoprotein (LDL) peroxidation is involved in atherosclerosis, and is reported in SDB. Oxidized LDL (ox-LDL) and malondialdehyde (MDA) are lipid peroxidation markers. High-density lipoprotein (HDL) presents antiatherosclerotic properties related to paraxonase-1 (PON-1) activity. PON-1 hydrolyseyses lipid peroxides as ox-LDL. This study compares the relationship of HDL and PON-1, the lipid peroxidation markers ox-LDL and MDA, and 8-OHdG DNA damage marker in the association of SDB and CAD. Design and Methods: 29 controls and 27 cases with CAD (defined as > 30% coronary narrowing) patients were included. The apnea-hypopnea index (AHI), and several lipid and oxidative stress parameters were measured in these patients. Results: AHI is increased in CAD patients, and PON-1 activity and HDL levels are decreased. Regression analyseyses showed that lower PON-1 activity and higher ox-LDL levels are important CAD predictors, compared to HDL or MDA levels and present an age-dependent increase. Nitrites and nitrates, indirect NO• markers, are positive vs correlated with PON-1 and are negatively correlated to ox-LDL. SDB is not correlated to PON-1 activity decrease or ox-LDL increase. AHI is inversely correlated to HDL levels. Conclusions: These results indicate that PON-1 and ox-LDL are important predictors of CAD, however they may not be directly related to SDB.

The pH equilibria and the zinc ion and bovine serum albumin (BSA) binding behavior of curcumin and two chemically modified curcumins (CMCs), namely 4-methoxycarbonylcurcumin (CMC 2.5) and 4-phenylaminocarbonyl bis-demethoxy curcumin (CMC 2.24), were studied, in order to understand the basis of their differential effects on the zinc-enzyme matrix metalloproteinases (MMPs) as well as the effect of charge state on their behavior in vivo. Moreover, all three compounds transform rapidly in the pH range 5-10, CMC 2.5 largely in one step, and CMC 2.24 and curcumin first in a rapid process to an intermediate form that still displays an enolic and two phenolic hydrogen-ion equilibria, and then more slowly to forms absorbing primarily in the lower UV and lacking the strong absorbance in the visible characteristic of the enol-centered chromophore. The binding of these compounds in one of the hydrophobic pockets of the major transport protein, serum albumin, was therefore studied. CMC 2.24 binds more strongly to BSA than curcumin, with a dissociation constant of 0.56±0.08 μM compared to 1.32±0.17 μM. Binding to BSA shifts the decomposition half-lives from tens of seconds to tens of hours. The zero-time acid dissociation constants (pKa) for species H3D, H2D-, and HD2- are 8.41, 9.94 and 11.2; 6.98, 8.40 and 9.8; and 6.50 and 8.82 ; for curcumin, CMC 2.24, and CMC 2.5 respectively (there is no distinguishable pKa3 for CMC 2.5). Zn2+ binds most strongly to CMC 2.24 compared to CMC 2.5 and curcumin, with dissociation constants of 0.77±0.02, 1.88±0.07, and 1.39±0.09 mM. The increased acidity and Zn2+ and BSA affinities of CMC 2.24 correlate with its greater biological activity.