ARTICULOS CIENTIFICOS.

Articulo científico: nti-Infective Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Anti-Infective Agents) (v.9, #4)

Structure-based Discovery of Novel Antibacterials by Huan-Qiu Li, Peng-Cheng Lv, Lei Shi, Hai-Liang Zhu (pp. 168-179). 

An increasing fraction of bacterial isolates show reduced susceptibility to our most trusted antibiotics. In order to prevent this serious medical problem, the elaboration of new types of antibacterial agents or the expansion of bioactivity of the previous drugs is a very important task. Different targets in key areas of the bacterial cell cycle have been studied that would be a new weapon against this threat. In this review we attempt to summarize the recent progress made in the field of some represent bacterial enzyme inhibitors and the structure-based drug design of new broad-spectrum antibacterial agents. Based on the structure design and protein target, more and more novel compounds were discovered for the development of new antibacterial agents. It is expected that this review would serve as a stimulant for new thoughts in the quest for rational designs of more effective antibacterial drugs.The interaction of structure design with enzyme targets is fascinating, and this story is still unfolding for us to discover novel antibacterials. 

Novel, Unifying Phagomimetic Mechanism of Vancomycin Therapeutic Action and Toxicity: Polyphenol, Electron Transfer and Reactive Oxygen Species by Peter Kovacic, Ratnasamy Somanathan (pp. 180-186). 

In recent years, vancomycin has received appreciable attention as an antibiotic drug of last resort. The generally accepted mechanism entails interference with bacterial cell wall synthesis. There is negligible attention to other modes, even though drug action is often multifaceted. This review provides a hypothesis for an additional mechanism of antibacterial action based on the polyphenol residue in the glycopeptide. The functionalities present are monophenol, resorcinol and hydroxybiphenyl, all of which have the potential to produce electron transfer (ET) metabolites capable of generating reactive oxygen species (ROS) and oxidative stress (OS). Considerable literature is presented in support of the thesis. Drug toxicity is rationalized based on the fundamental approach to vancomycin action. This review represents another example in support of the prior ET-ROS-OS unifying mechanism for anti-infective and toxic action. Novel insight may aid in improved drug design. 

Emerging Antimicrobial Applications of Nitric Oxide (NO) and NO-Releasing Materials by Genevieve M. Halpenny, Pradip K. Mascharak (pp. 187-197). 

During the past few decades, the potential of treating infections with nitric oxide (NO) has been firmly demonstrated in various laboratories. Both in vitro and in vivo studies have afforded promising results in terms of reducing microbial loads in chronic wounds in addition to its utility in keeping medical devices free of thrombus formation and bacterial adhesion. The latter antimicrobial effects of NO provide great help in successful integration of orthopedic and vascular implants and prolonging their in vivo life. In all such applications, NO is released from various polymeric materials in which nitrite salts, exogenous NO donors, or even simple NO(g) are incorporated. Recent developments in all such formulations of NO-releasing materials and their specific applications in combating bacteria, fungi and parasites are reviewed in this article. 

Investigation of 2-Fluoro Benzoic Acid Derivatives as Influenza A Viral Sialidase Selective Inhibitors by Sadagopan Magesh, Nongluk Sriwilaijaroen, Vats Savita, Hiromune Ando, Taeko Miyagi, Yasuo Suzuki, Hideharu Ishida, Makoto Kiso (pp. 198-204). 

Neuraminidase (NA), a glycoside hydrolase enzyme, plays pivotal roles in controlling biological functions not only of influenza viruses but also of humans. Zanamivir and oseltamivir designed to target influenza neuraminidase have become extensively used for influenza clinical treatment as its high anti-influenza efficacy. Unfortunately, side effects of these two drugs have been reported in clinical use. An aromatic benzene ring has been pursued as a core structure to derive stereo chemically simplified analogues with desired molecular properties. In our previous study, a series of 2-fluoro benzoic acids were synthesized and evaluated against all four human sialidase enzymes. Herein, we further evaluate the same set of 2-fluoro benzoic acids for inhibitory activity against viral sialidases expressed by influenza A virus. The most active compound 11 (4,5-diacetamido-2-fluoro benzoic acid) has an IC50 of 4.5 and#956;M (N1) and 21 and#956;M (N2) that is and#x223C;60-140 fold more active than its non-fluoro counterpart 10 (3,4-diacetamido benzoic acid) that has an IC50 of 640 and#956;M (N1) and 1400 and#956;M (N2). Molecular docking and calculated binding free energies are in good agreement with the experimental data. Of greater significance was the observation of key interaction of 2-fluoro group with active site for improved activity and could be explored further for higher affinity and selectivity over viral sialidases with suitably substituted 2-fluoro benzoic acids. 

Synthesis of Some New Monocyclic β-Lactams Bearing a Morpholine Moiety at their N1 Positions as Antifungal Agents by Aliasghar Jarrahpour, Masoumeh Eskandari, Kamiar Zomorodian, Elham Barati, Raheleh Ashori, Mostafa Salehi Vaziri, Keyvan Pakshir (pp. 205-219). 

The synthesis of 40 new monocyclic and#946;-lactams bearing a morpholine moiety at their N1 positions is described. The structures of these compounds have been confirmed by IR, 1H-NMR, 13C-NMR, Mass spectra and Elemental analysis. The antimicrobial activities of the synthetic compounds have been tested against clinically important fungi including Candida, Aspergillus and Microsporum and Epidermophyton species by broth microdilution method as recommended by CLSI. Inhibition studies showed that some of the tested compounds, in particular those with phenoxy groups, exhibited strong antifungal activities against all tested fungi at concentrations of less than 8 and#956;g/mL, while others only inhibited the growth of dermatophytes or Aspergillus species. These results suggest that the derivatives should be investigated further for possible use in antimicrobial products. 

2.

Infectious Disorders - Drug Targets (Formerly Current Drug Targets - Infectious Disorders) (v.7, #1)

Author Index To Volume 6 by Publishers (pp. i-ii). 

Subject Index To Volume 6 by Publishers (pp. iii-vii). 

Editorial [ Infectious Diseases: What is in our future? ] by Robert Goldman (pp. 1-2). 

Current Drug Targets-Infectious Disorders (CDT-ID) was launched in May of 2001 and is now starting its seventh year with the March 2007 issue, although under a new name: Infectious Disorder - Drug Targets. Special Topics issues, organized by a Guest Editor, are published twice a year and have been well received since their inception in 2001. Two Special Topics issues are scheduled for 2007: 1) Drs. Robert Goldman and Barbara Laughon (Complications and Coinfections Research Branch, National Institutes of Health, Bethesda, MD) will be the Guest Editors of our June 2007 Special Topics issue on Tuberculosis Targets and Drug Discovery and Development; and 2) Dr. Christopher F. Basler (Mount Sinai School of Medicine) will be the Guest Editor of our December 2007 Special Topics issue on Influenza Virus Epidemics and Drug Targets. Someone dies of tuberculosis (TB) every 15 seconds, and in spite of global control and treatment efforts some regions of the world are experiencing a crisis that will likely spread. The discovery of streptomycin in the 1943 by the Nobel Laureate Selman Waksman's group at Rutgers University and subsequent demonstration of its efficacy against TB proved that effective chemotherapy could be administered. However, in only a few years of clinical use the specter of resistance arose and became a major concern. Today we have to deal with multidrug resistant TB (MDR-TB) and extensively drug resistant TB (XDR-TB) strains. MDR-TB strains are defined as those resistant to both isoniazid and rifampicin, two of the most effective first-line drugs. XDR-TB was initially defined as MDR-TB with further resistance to three or more of the six main classes of second-line antitubercular drugs (aminoglycosides, polypeptides, fluoroquinolones, thioamides, cycloserine and para-aminosalicylic acid). This definition was changed to resistance to isoniazid and rifampicin plus resistance to any fluoroquinolone and at least one of three injectable second-line drugs (amikacin, kanamycin, or capreomycin). Regardless of semantic definitions, multiple drug resistance in TB has led to a developing global health-care crisis over the past decade, one that was brought to the forefront when a deadly outbreak of XDR-TB occurred in a rural area in KwaZulu Natal, South Africa. The initial report described infection in 53 persons (44 know to be HIV positive) that lead to death in 52 of 53 patients with a median survival of 16 days from time of diagnosis (Neel R Gandhi, Anthony Moll, A Willem Sturm, Robert Pawinski, Thiloshini Govender, Umesh Lalloo, Kimberly Zeller, Jason Andrews, Gerald Friedland, The Lancet Vol. 368, November 4, 2006, page 1575). Since then the outbreak has increased to over 500 known cases. A more detailed review of XDR-TB will appear in the June 2007 Special Topics issue. The March 2007 issue of Infectious Disorders - Drug Targets presents a range of topics covering many exciting developments in infectious disease research. Targeting Bacterial Secretion Systems: Benefits of Disarmament in the Microcosm (C. Baron and B. Coombes): Bacterial pathogens use specialized secretion systems to deliver virulence factors temporally and spatially in the infected host. The assembly and function of type II, type III and type IV secretion systems in Gram-negative bacteria are reviewed in the context of structure and function, as well as strategies for identifying potential inhibitors. Novel Targets for the Development of Anti-herpes Compounds (A. Greco, J-J Diaz, D. Thouvenot and F. Morfin): Herpes simplex (HSV) viruses represent a major infectious disease problem for millions of people, especially those who are immunocompromised. Reliance on a single agent, acyclovir, as the major therapy has led to resistance selection. Viral and cellular targets involved in HSV replication and infection are reviewed along with progress in discovering new inhibitory agents. Antibiotic Resistance during Therapy: Mechanisms and Means of Control (J. C. Rodr�guez, E. Pastor, M. Ruiz, E. Flores, and G. Royo): The continued evolution and dissemination of drug resistant bacteria is a major health care burden. The complex microbiological factors involved in the selection of resistance during antibiotic therapy are reviewed, along with approaches to minimize selection of resistance in the future....... 

Exploring DNA Topoisomerases as Targets of Novel Therapeutic Agents in the Treatment of Infectious Diseases by Y.-C. Tse-Dinh (pp. 3-9). 

DNA topoisomerases are ubiquitous enzymes needed to overcome topological problems encountered during DNA replication, transcription, recombination and maintenance of genomic stability. They have proved to be valuable targets for therapy, in part because some anti-topoisomerase agents act as poisons. Bacterial DNA gyrase and topoisomerase IV (type IIA topoisomerases) are targets of fluoroquinolones while human topoisomerase I (a type IB topoisomerase) and topoisomerase II are targets of various anticancer drugs. Bacterial type IA topoisomerase share little sequence homology to type IB or type IIA topoisomerases, but all topoisomerases have the potential of having the covalent phosphotyrosine DNA cleavage intermediate trapped by drug action. Recent studies have demonstrated that stabilization of the covalent complex formed by bacterial topoisomerase I and cleaved DNA can lead to bacterial cell death, supporting bacterial topoisomerase I as a promising target for the development of novel antibiotics. For current antibacterial therapy, the prevalence of fluoroquinolone-resistant bacterial pathogens has become a major public health concern, and efforts are directed towards identifying novel inhibitors of bacterial type IIA topoisomerases that are not affected by fluoroquinolone resistant mutations on the gyrase or topoisomerase IV genes. For anti-viral therapy, poxviruses encode their own type IB topoisomerases; these enzymes differ in drug sensitivity from human topoisomerase I. To confront potential threat of small pox as a weapon in terrorist attacks, vaccinia virus topoisomerase I has been targeted for discovery of anti-viral agents. These new developments of DNA topoisomerases as targets of novel therapeutic agents being reviewed here represent excellent opportunities for drug discovery in the treatment of infectious diseases. 

Novel Targets for the Development of Anti-Herpes Compounds by A. Greco, J-J. Diaz, D. Thouvenot, F. Morfin (pp. 11-18). 

Herpes simplex virus type 1 (HSV-1) and herpes simplex virus type 2 (HSV-2) are members of the Herpesviridae family. HSV infections have been known since ancient times and are one of the most common communicable diseases in humans. Although infections are often subclinical, HSV can cause mild to severe diseases, especially in immunocompromised patients. Herpes simplex viruses establish latency in the nuclei of neuronal cells and may reactivate, with or without symptoms, throughout the host's lifetime. Over one third of the world's population suffer from recurrent HSV infections several times a year and are thus capable of transmitting HSV by close personal contact. There are few drugs licensed for the treatment of HSV infections. Most target the viral DNA polymerase, and indeed acyclovir remains the reference treatment some thirty years after its discovery! Extensive clinical use of this drug has led to the emergence of resistant viral strains, mainly in immunocompromised patients. This highlights the crucial need for the development of new anti-herpes drugs that can inhibit infection by both wild-type viruses and drug-resistant strains. Over the last few years, significant efforts have been made to set up a range of strategies for the identification of potential new anti-viral drugs. One alternative is to develop drugs with different mechanisms of action. The present article reviews potential viral and cellular targets that are now known to be involved in HSV infection and for which specific inhibitors with anti-HSV activity, at least in cell culture, have been identified. 

Targeting Bacterial Secretion Systems: Benefits of Disarmament in the Microcosm by Christian Baron, Brian Coombes (pp. 19-27). 

Secretion systems are used by many bacterial pathogens for the delivery of virulence factors to the extracellular space or directly into host cells. They are attractive targets for the development of novel anti-virulence drugs as their inactivation would lead to pathogen attenuation or avirulence, followed by clearance of the bacteria by the immune system. This review will present the state of knowledge on the assembly and function of type II, type III and type IV secretion systems in Gram-negative bacteria focusing on insights provided by structural analyses of several key components. The suitability of transcription factors regulating the expression of secretion system components and of ATPases, lytic transglycosylases and protein assembly factors as drug targets will be discussed. Recent progress using innovative in vivo as well as in vitro screening strategies led to a first set of secretion system inhibitors with potential for further development as anti-infectives. The discovery of such inhibitors offers exciting and innovative opportunities to further develop these anti-virulence drugs into monotherapy or in combination with classical antibiotics. Bacterial growth per se would not be inhibited by such drugs so that the selection for mutations causing resistance could be reduced. Secretion system inhibitors may therefore avoid many of the problems associated with classical antibiotics and may constitute a valuable addition to our arsenal for the treatment of bacterial infections. 

Recent Developments in the Virology and Antiviral Research of Severe Acute Respiratory Syndrome Coronavirus by Kap-Sun Yeung, Nicholas Meanwell (pp. 29-41). 

This article summarizes the significant developments and new discoveries in both the virology and antiviral research associated with the severe acute respiratory syndrome coronavirus (SARS CoV) that were reported in 2005 and 2006. Areas reviewed include genomic studies and the identification of bat-SARS CoV, spike protein and host cell entry, nucleocapsid protein, accessory proteins, non-structural proteins of the replicase complex, viral proteases and their inhibitors, and clinical treatment of SARS with ribavirin. 

Antibiotic Resistance During Therapy: Mechanisms and Means of Control by J. Rodriguez, E. Pastor, M. Ruiz, E. Flores, G. Royo (pp. 43-45). 

Antibiotic resistance is a serious public health problem. The most effective way to control this phenomenon is to make rational use of antibiotics. However, antibiotic resistance is a complex process in which clinical, pharmacodynamic, pharmacokinetic and microbiological factors all play a part. Since antibiotic therapy is usually performed empirically, clinicians should follow guidelines that take all these factors into account together with the concepts of evidence based medicine. These guidelines may be elaborated using information technology tools that help to collect, analyze and weigh up all the information available on a certain pathogen. Therefore, the administration of antibiotics should be controlled with the help of multi-disciplinary working groups and in accordance with objective data collected following a thorough analysis of all the available information. 

Strategies to Design Inhibitors of Clostridium Botulinum Neurotoxins by S. Cai, B. Singh (pp. 47-57). 

Botulinum neurotoxins (BoNTs), produced by spore-forming anaerobic Clostridium botulinum, are the most toxic substances known. They cause the life-threatening disease botulism, characterized by flaccid muscle paralysis. While the natural cases of botulism are rare, due to their extreme toxicity and easy production, BoNTs have become potential biowarfare agents, and create maximum fear among populations concerned with bioterror agents. The only available antidote against BoNTs is equine antitoxin. Equine antitoxin can only target the toxins at extracellular level, and can not reverse the paralysis caused by botulism. In addition, equine antibody can cause severe hypersensitivity reactions, and is limited to be used for prophylaxis treatment. BoNTs are large proteins with three distinct domains, the binding domain, the translocation domain, and the enzymatic domain with highly specific endopeptidase activity to cleave the proteins involved the neurotransmitter release. Targeting any of these domains can inhibit the functions of BoNT. Humanized monoclonal antibodies, small peptides and peptide mimetics, receptor mimics, and small molecules targeting the endopeptidase activity have emerged as potential new inhibitors against BoNTs. With the structure of BoNT resolved, molecular modeling and rational design of potent antidotes against botulism is on the horizon. An area that has not been explored for designing the antidotes against botulism is aptamers, which have been successfully developed as therapeutics in several areas. This review will focus on some of these new strategies to design effective antidotes against botulism. The strategies reviewed in this article can be easily applied to design inhibitors for other bacterial toxins. 

Antiviral Strategies Against Human Coronaviruses by K. Pyrc, B. Berkhout, L. van der Hoek (pp. 59-66). 

Since the mid 60's the human coronaviruses (HCoV), represented by HCoV-OC43 and HCoV-229E, were generally considered relatively harmless viruses. This status changed dramatically with the emergence of SARS-CoV in 2002/2003. The SARSCoV pandemic took 774 lives around the globe and infected more than 8000 people in 29 countries. SARS-CoV is believed to be of zoonotic origin, transmitted from its natural reservoir in bats through several animal species (e.g., civet cats, raccoon dogs sold for human consumption in markets in southern China). The epidemic was halted in 2003 by a highly effective global public health response, and SARS-CoV is currently not circulating in humans. The outbreak of SARS-CoV and the danger of its re-introduction into the human population, as well as the danger of the emergence of other zoonotic coronaviral infections triggered an intense survey for an efficient treatment that resulted in the evaluation of several anticoronaviral compounds. HCoV-NL63 and HCoV-HKU1 were identified shortly after the SARS-CoV outbreak. The 4 human coronaviruses HCoV-229E, HCoVOC43, HCoV-NL63 and HCoV-HKU1 cause mild respiratory illnesses when compared to SARS, but these infections are involved in 10 - 20 % of hospitalizations of young children and immunocompromised adults with respiratory tract illness. Therefore, there is an urgent need for a successful therapy to prevent disease induction or a vaccine to prevent new infections. This review summarizes the current status of anticoronaviral strategies. 

Human Defensins: Turning Defense into Offense? by Erik de Leeuw, Wuyuan Lu (pp. 67-70). 

Defensins are a family of antimicrobial cationic peptides that act as a rapid response force against microbial invasion in a wide range of organisms, including plants, insects, animals and humans. In humans, defensins are produced predominantly by leukocytes and epithelial cells and are an important factor of innate immunity. In addition to their major role as natural antibiotics, defensins are increasingly recognized as signaling molecules in adaptive immunity and aberrant defensin expression has been associated with infectious diseases. In this review, we discuss the role of human defensins in relation to infectious disease and the possibility of novel defensin-based therapeutic approaches. 

3.

Anti-Cancer Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Anti-Cancer Agents) (v.12, #6)

Neutrophil Elastase as a Target in Lung Cancer by Gautier Moroy (pp. 565-579). 

Human neutrophil elastase (HNE), a main actor in the development of chronic obstructive pulmonary diseases, has been recently involved in non-small cell lung cancer progression. It can act at several levels (i) intracellularly, cleaving for instance the adaptor molecule insulin receptor substrate-1 (IRS-1) (ii) at the cell surface, hydrolyzing receptors as CD40 (iii) in the extracellular space, generating elastin fragments i.e. morphoelastokines which potently stimulate cancer cell invasiveness and angiogenesis. Since decades, researchers identified natural compounds and/or synthesized agents which antagonize HNE activity that will be described in this review article. Some of these compounds might be of value as therapeutic agents in lung cancer. However, it is now widely accepted that lung tumor invasion and metastasis involve proteolytic cascades. Accordingly, we will here mainly focus our attention to natural substances able to display a dual inhibitory capacity (i.e. lipids and derivatives, phenolics) towards HNE and matrix metalloproteinases (MMPs), particularly MMP-2. To that purpose, we recently synthesize substances named “LipoGalardin” (Moroy G. et al., Biochem. Pharmacol., 2011, 81(5), 626-635) exhibiting such inhibitory bifunctionality. At last, we will propose an original synthetic scheme for designing a potent biheaded HNE/MMP-2 inhibitor. 

Anticoagulant and Fibrinolytic Drugs – Possible Agents in Treatment of Lung Cancer? by Vladimir Bobek (pp. 580-588). 

The effect of anticoagulant adjuvant anti-tumor therapy depends on the cancer type and stage and on the type of the used anticoagulant drug. A striking response rate was described in experiments involving human patients with lung cancer. The aim of this study is to review anticoagulant and fibrinolytic drugs as antitumor agents with focus on their clinical use. The first part of the review evaluates the results of clinical studies. The results of early clinical research are promising and observations suggest novel approaches to the experimental therapy of lung cancer. The second part of the review shortly describes the problem of thrombosis in patients with lung cancer (incidence of thromboembolic disease and its pathogenesis). The third part briefly describes the antimetastatic and antitumor attributes of anticoagulants and fibrinolytics. 

Current and Emerging Strategies in Bladder Cancer by Simone Carradori (pp. 589-603). 

Urothelial cell carcinoma is one of the most common malignancies of the urinary tract. The standard of care, intravesical chemo- and immunotherapy, while effective, is associated with a considerable side-effect profile and approximately 30% of patients either fail to respond to treatment or suffer recurrent disease within 5 years. In the setting of muscle-invasive urothelial carcinoma, use of neoadjuvant chemotherapy is associated with overall survival benefit. Muscle invasive bladder cancer is life threatening, showing modest chemosensitivity, and usually requires radical cystectomy. Although bladder cancer is fairly well-genetically characterized, clinical trials with molecularly targeted agents have, in comparison to other solid tumors, been few in number and largely unsuccessful. Hence, bladder cancer represents a considerable opportunity and challenge for alternative therapies. In this review, we will focus on promising global or pathway-based approaches (epigenetic modulators, kinase inhibitors, angiogenesis blockage, peroxisome proliferator-activated receptor γ agonists, apoptosis inductors, virus therapy) supported by a deeper understanding of molecular biology of urothelial carcinoma, which have been recently tested in clinical trials. 

Gallium Phthalocyanine Photosensitizers: Carboxylation Enhances the Cellular Uptake and Improves the Photodynamic Therapy of Cancers by Jin F. Zhao (pp. 604-610). 

The octacarboxyl gallium (GaPcC) and metal-free (H2PcC) phthalocyanines were prepared using the carboxyl as the peripheral substituent. The carboxylation improves the intracellular delivery of these two PcCs into KB and QGY cancer cells as compared to that of sulfonated aluminum phthalocyanines (AlPcS), a popularly used photosensitizer (PS). Moreover, GaPcC maintains high photoproduction of singlet oxygen. With a short incubation time of 3 hours, GaPcC accumulates sufficiently in both KB and QGY cells and improves photodynamic therapy (PDT) by effectively killing these cancer cells. AlPcS and H2PcC show much lower PDT effects under the same conditions, because AlPcS have a slow cellular uptake rate resulting in a low cellular amount and the ability of H2PcC to produce 1O2 is low. Carboxylation is a promising way to prepare water-soluble metal phthalocyanines (MPcCs) and facilitates the cellular uptake of MPcCs for PDT improvement. 

Anticancer Activity and Anti-inflammatory Studies of 5-Aryl-1,4-benzodiazepine Derivatives by Cortez-Maya Sandra (pp. 611-618). 

A series of 5-aryl-1,4-benzodiazepines with chloro- or fluoro-substituents in the second ring have been synthesized and their anti-inflammatory, myeloperoxidase and anticancer properties studied. The synthesized compounds showed potential anti-inflammatory and anticancer activities, which were enhanced in the presence of a chloro-substituent in the second ring of the 5-aryl-1,4- benzodiazepine. 

Cranberry as Promising Natural Source of Potential Anticancer Agents: Current Evidence and Future Perspectives by Athanasios Katsargyris (pp. 619-630). 

Background: Accumulating evidence suggest that dietary modification can lower the risk for several cancer types’ development. Cranberry in particular, has been shown to have anti-oxidative, -inflammatory and -proliferative properties in vitro. Objective: To present the latest knowledge regarding the role of cranberry extracts against human cancer several types. Methods: A review of the literature documenting both in vitro and in vivo anti-cancer effects of whole cranberry and/or its extracts is conducted. Conclusions: Current data provide evidence for several anti-cancer properties of either whole cranberry and/or its extracts. The discovery of the specific cranberry components and the appropriate concentrations that exert such beneficial effects along with verification of the preliminary in vitro results in in vivo settings could potentially lead to the invention of novel safer and efficient anti-cancer therapeutic agents. 

The Role of Cdc25A in the Regulation of Cell Proliferation and Apoptosis by Tao Shen (pp. 631-639). 

Cell division cycle 25 A (Cdc25A), a dual-specificity protein phosphatase, is one of the most crucial cell cycle regulators, which removes the inhibitory phosphorylation in cyclin-dependent kinases (CDKs), such as CDK2, CDK4, and CDK6, and positively regulates the activities of CDKs that lead to cell cycle progression. In addition, Cdc25A also acts as a regulator of apoptosis. Overexpression of Cdc25A promotes tumorigenesis, and is frequently observed in various types of cancer. Here we briefly summarize current understanding of the role of Cdc25A in cell proliferation and apoptosis, as well as the impact of overexpression of Cdc25A on tumorigenesis. 

Effects of Bioactive Compounds from Carrots (Daucus carota L.), Polyacetylenes, Beta-Carotene and Lutein on Human Lymphoid Leukaemia Cells by Rana G. Zaini (pp. 640-652). 

New therapies for leukaemia are urgently needed. Carrots have been suggested as a potential treatment for leukaemia in traditional medicine and have previously been studied in other contexts as potential sources of anticancer agents. Indicating that carrots may contain bioactive compounds, which may show potential in leukaemia therapies. This study investigated the effects of five fractions from carrot juice extract (CJE) on human lymphoid leukaemia cell lines, together with five purified bioactive compounds found in Daucus carota L, including: three polyacetylenes (falcarinol, falcarindiol and falcarindiol-3-acetate) and two carotenoids (beta-carotene and lutein). Their effects on induction of apoptosis using Annexin V/PI and Caspase 3 activity assays analysed via flow cytometry and inhibition of cellular proliferation using Cell Titer Glo assay and cell cycle analysis were investigated. Treatment of all three lymphoid leukaemia cell lines with the fraction from carrot extracts which contained polyacetylenes and carotenoids was significantly more cytotoxic than the 4 other fractions. Treatments with purified polyacetylenes also induced apoptosis in a dose and time responsive manner. Moreover, falcarinol and falcarindiol-3-acetate isolated from Daucus carota L were more cytotoxic than falcarindiol. In contrast, the carotenoids showed no significant effect on either apoptosis or cell proliferation in any of the cells investigated. This suggests that polyacetylenes rather than beta-carotene or lutein are the bioactive components found in Daucus carota L and could be useful in the development of new leukemic therapies. Here, for the first time, the cytotoxic effects of polyacetylenes have been shown to be exerted via induction of apoptosis and arrest of cell cycle. 

A New 4-phenyl-1,8-naphthyridine Derivative Affects Carcinoma Cell Proliferation by Impairing Cell Cycle Progression and Inducing Apoptosis by Antonella Capozzi (pp. 653-662). 

In targeted cancer therapy the search for novel molecules led to the discovery of a plethora of small organic molecules inhibiting cancer cell proliferation. Among these, quinazoline and derivatives, such as quinolines and naphthyridines, have been considered as of particular interest. One of these, the naphthyridine derivative 4-phenyl-2,7-di(piperazin-1-yl)-1,8-naphthyridine, has been analyzed in detail in the present work. We found that this compound elicited a powerful anti-proliferative activity on carcinoma cells, with IC50 values comparable with paradigmatic microtubule-deranging drugs. The mechanisms underlying this effect were seemingly due to a framework of cellular alterations that include peculiar alterations of mitochondria, i.e. an increase of mitochondrial membrane potential (MMP), followed by the typical MMP loss leading to the release of apoptogenic factors, and cell death by apoptosis. Furthermore, the analysis of cell cycle revealed that a significant percentage of treated cells was in G2/M phase. This block was seemingly due to a target effect of the naphthyridine derivative on microtubular network dynamic instability, which impaired mitotic spindle formation, possibly leading to mitotic catastrophy. Since the dual effects of naphthyridine derivative on cell cycle and mitotic spindle were obtained at very low concentrations, i.e. micromolar concentrations, we hypothesize that this compound could represent a new promising tool in the control of cancer cell proliferation. 

Anticancer Effects of the Organosilicon Multidrug Resistance Modulator SILA 421 by Ulrike Olszewski (pp. 663-671). 

1,3-dimethyl-1,3-bis(4-fluorophenyl)-1,3-bis{3-[1(4-butylpiperazinyl)]-propyl}-disiloxan-tetrahydrochlorid (SILA 421) is a compound that was developed as modulator of the ABC cassette transporter P-glycoprotein. Furthermore, it exerted antimicrobial toxicity, vascular effects, downregulation of chaperone induction and plasmid curing in bacterial cells. Here, this drug was found to possess cytotoxic activity against a panel of human cancer cell lines that do not overexpress P-gp, with 50% inhibitory concentrations ranging between 1.75±0.38 μM for GLC14 small cell lung cancer and 34.00±4.75 μM for PC-3 prostate cancer cells. HL-60 leukemia and MDA-MB-435 breast cancer cells exhibited cell cycle arrest and apoptotic cell death in response to SILA 421. Assessment of global gene expression of SILA 421-treated HL-60 cells was employed to identify cellular pathways affected by the compound and revealed disturbance of DNA replication, transcription and production of apparently misfolded proteins. Endoplasmatic reticulum stress and downregulation of cell cycle, cellular repair mechanisms and growth factor-related signaling cascades eventually resulted in induction of apoptosis in this cell line. In addition to the well established P-gp inhibitory effect of SILA compounds, reversal of resistance to taxanes, which had been reported for SILA 421 and the related molecule SILA 409, may be linked to downregulation of gene expression of kinesins. Interference with DNA replication and transcription seems to be the common denominator of antimicrobial activity and plasmid curing, as well as anticancer toxicity in human cell lines. Thus, in consideration of the full range of putative cellular targets found in the present work, the application of these SILA compounds for treatment of tumors should be further evaluated. 

Triple-negative Breast Cancer and Poly(ADP-ribose) Polymerase Inhibitors by Youngjin Park (pp. 672-677). 

Recent gene profiling studies have identified at least 5 major subtypes of breast cancer, including normal type, luminal A type, luminal B type, human epidermal growth factor receptor (HER)-2 positive type, and basal-like type. Triple-negative breast cancer (TNBC), showing no or low expressions of estrogen receptor (ER), progesterone receptor (PgR), and HER2, considered important clinical biomarkers, accounts for 10% to 20% of all breast cancers. Hormonal therapy and molecular targeted therapy are not indicated for the management of TNBC, resulting in poor outcomes. Because TNBC lacks clear-cut therapeutic targets, effective treatment strategies remain to be established. However, TNBC is known to share similar biologic characteristics with basal-like type breast cancer and is often accompanied by loss of functional BRCA, a gene-modifying enzyme. Breast cancer with BRCA1 or BRCA2 mutations is accompanied by activation of the enzyme poly(ADP-ribose) polymerase (PARP). PARP, a DNA base-excision repair enzyme, is known to play a central role in gene repair, along with BRCA. Because some breast cancers with BRCA1 or BRCA2 mutations are TNBC, the suppression of PARP has attracted attention as a new treatment strategy for TNBC. In this article, we review the clinical characteristics of TNBC, discuss problems in treatment, and briefly summarize the international development status of PARP inhibitors. 

Chemoinformatics in Multi-target Drug Discovery for Anti-cancer Therapy: In Silico Design of Potent and Versatile Anti-brain Tumor Agentsby Alejandro Speck-Planche (pp. 678-685). 

A brain tumor (BT) constitutes a neoplasm located in the brain or the central spinal canal. The number of new diagnosed cases with BT increases with the pass of the time. Understanding the biology of BT is essential for the development of novel therapeutic strategies, in order to prevent or deal with this disease. An active area for the search of new anti-BT therapies is the use of Chemoinformatics and/or Bioinformatics toward the design of new and potent anti-BT agents. The principal limitation of all these approaches is that they consider small series of structurally related compounds and/or the studies are realized for only one target like protein. The present work is an effort to overcome this problem. We introduce here the first Chemoinformatics multi-target approach for the in silico design and prediction of anti-BT agents against several cell lines. Here, a fragment-based QSAR model was developed. The model correctly classified 89.63% and 90.93% of active and inactive compounds respectively, in training series. The validation of the model was carried out by using prediction series which showed 88.00% of correct classification for active and 88.59% for inactive compounds. Some fragments were extracted from the molecules and their contributions to anti-BT activity were calculated. Several fragments were identified as potential substructural features responsible of anti-BT activity and new molecular entities designed from fragments with positive contributions were suggested as possible anti-BT agents.