Current Drug Discovery Technologies

ISSN: 1570-1638

Current Drug Discovery Technologies
Volume 4, Number 2, August 2007

Contents


A Novel Candidate Compound with Urethane Structure for Anticancer Drug Development Pp. 69-76
Atsuko Matsuoka, Kazuo Isama, Susumu Tanimura, Michiaki Kohno and Takao Yamori
[Abstract]


SMILES in QSPR/QSAR Modeling: Results and Perspectives Pp. 77-116
Andrey A. Toropov and Emilio Benfenati
[Abstract]


Prediction of MHC Binding Peptides and Epitopes from Alfalfa mosaic virus Pp. 117-125
Virendra S. Gomase, Karbhari V. Kale, Nandkishor J. Chikhale and Smruti S. Changbhale
[Abstract]


In Vivo ¹⁹F MR Studies of Fluorine Labeled Photosensitizers in a Murine Tumor Model Pp. 126-132
Subbaraya Ramaprasad, Elzbieta Ripp, Joseph Missert and Ravindra K. Pandey
[Abstract]


Current Treatment Strategies for Non-Alcoholic Fatty Liver Disease (NAFLD) Pp. 133-140
Poonam Mishra and Zobair M. Younossi
[Abstract]




Abstracts


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A Novel Candidate Compound with Urethane Structure for Anticancer Drug Development
Atsuko Matsuoka, Kazuo Isama, Susumu Tanimura, Michiaki Kohno and Takao Yamori

Diethyl-4,4’-methylenebis(N-phenylcarbamate) (MDU) is a urethane compound that we originally synthesized, along with three other compounds, to investigate how polyurethane is hydrolysed. We tested the four compounds for cytotoxicity in two Chinese hamster cell lines (CHL and V79) and a human cancer cell line (HeLa S3). MDU showed the strongest cytotoxicity in all the cell lines with an IC₅₀ of around 0.1 μg/ml. We further investigated MDU for its ability to induce chromosome aberrations (CAs) and micronuclei (MN) in CHL cells. MDU induced around 100% polyploid cells at 0.5 μg/ml after 24- and 48-h treatment in the CA test and a significantly increased frequency of micronuclei, polynuclear cells, and mitotic cells in the MN test, suggesting that it may induce numerical CAs. MDU’s ability to cause mitotic arrest in CHL cells was greater than that of taxol and colchicine. Based on a COMPARE analysis using JFCR39, a panel of cancer cell lines, we predicted MDU to be a tubulin inhibitor. We confirmed this possibility in nerve growth factor-stimulated PC12 cells as well as in HT1080 cells, in which MDU exhibited the activity to inhibit tubulin polymerization. MDU is simpler in structure than existing anticancer drugs taxol and vincristine and can be synthesized relatively easily. Here we offer MDU as a potential new type of anticancer drug, stable even at room temperature, and inexpensive.


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SMILES in QSPR/QSAR Modeling: Results and Perspectives
Andrey A. Toropov and Emilio Benfenati

The technique of constructing optimal descriptors calculated with the Simplified molecular input line entry system (SMILES) is described. SMILES based optimal descriptors and descriptors calculated with molecular graphs (hydrogen filled graphs and graph of atomic orbitals) are compared in modeling done by means of quantitative structure – property/activity relationships (QSPR/QSAR). QSPR/QSAR models for normal boiling points of organic compounds, mutagenicity of heteroaromatic amines, toxicity, and anti-HIV-1 potentials of TIBO and HEPT derivatives are described in details. Possible ways to improve the SMILES based concept of QSPR/QSAR analyses are discussed.


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Prediction of MHC Binding Peptides and Epitopes from Alfalfa mosaic virus
Virendra S. Gomase, Karbhari V. Kale, Nandkishor J. Chikhale and Smruti S. Changbhale

Peptide fragments from alfalfa mosaic virus involved multiple antigenic components directing and empowering the immune system to protect the host from infection. MHC molecules are cell surface proteins, which take active part in host immune reactions and involvement of MHC class-I & II in response to almost all antigens. Coat protein of alfalfa mosaic virus contains 221 aa residues. Analysis found five MHC ligands in coat protein as 64-LSSFNGLGV-72; 86- RILEEDLIY-94; 96-MVFSITPSY-104; 100- ITPSYAGTF-108; 110- LTDDVTTED-118; having rescaled binding affinity and c-terminal cleavage affinity more than 0.5. The predicted binding affinity is normalized by the 1% fractil. The MHC peptide binding is predicted using neural networks trained on c-terminals of known epitopes. In analysis predicted MHC/peptide binding is a log transformed value related to the IC50 values in nM units. Total numbers of peptides found are 213. Predicted MHC binding regions act like red flags for antigen specific and generate immune response against the parent antigen. So a small fragment of antigen can induce immune response against whole antigen. This theme is implemented in designing subunit and synthetic peptide vaccines. The sequence analysis method allows potential drug targets to identify active sites against plant diseases. The method integrates prediction of peptide MHC class I binding; proteosomal c-terminal cleavage and TAP transport efficiency.


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In Vivo ¹⁹F MR Studies of Fluorine Labeled Photosensitizers in a Murine Tumor Model
Subbaraya Ramaprasad, Elzbieta Ripp, Joseph Missert and Ravindra K. Pandey

The main focus of this report is the MR spectroscopy of the changes in the concentration of fluorine labeled photosensitizer that occur following the IP administration. This process is studied by ¹⁹F in vivo MR methodology in a murine tumor model. The animal model used in these studies was mice bearing radiation induced fibrosarcoma (RIF) tumor on the foot dorsum. The mice were injected with a solution of ~ 100 micro-moles of the fluorinated photosensitizer and the ¹⁹F MR examination of the photosensitizer in the tumor or the muscle was performed. The pharmacokinetic (PK) profile for each labeled compound was generated using the ¹⁹F MR data at various time points post photosensitizer administration. The pharmacokinetic parameters were analyzed and the relationship of these results to photodynamic therapy is discussed.

The ¹⁹F MR methods clearly demonstrate utility in measuring the pharmacokinetic profiles and provide a new approach in the evaluation of appropriate photosensitizers for use in preclinical mammalian systems.


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Current Treatment Strategies for Non-Alcoholic Fatty Liver Disease (NAFLD)
Poonam Mishra and Zobair M. Younossi

Nonalcoholic fatty liver disease (NAFLD) is recognized as the most common cause of chronic liver disease worldwide. NAFLD is a clinicopathologic syndrome ranging from simple steatosis, which is relatively benign, to the more severe form known as nonalcoholic steatohepatitis (NASH), which may progress to cirrhosis, liver failure, and hepatocellular carcinoma. NAFLD is associated with significant liver related morbidity and mortality, and its underlying patho-physiology is thought to result from a multiple hit process. The initial insult is the accumulation of hepatic fat secondary to insulin resistance. In the setting of hepatic steatosis, the second hit can be caused by reactive oxygen species, inflammatory cytokines, and adipokines. Several therapeutic modalities that target these mechanisms are under investigation, but no proven treatment has yet emerged. Insulin sensitizers such as thiazolidinediones and metformin show promise, and several studies have explored the role of lipid lowering agents, antioxidants, and cytoprotective agents. Novel agents such as anti-obesity drugs, selective cannabinoid-1 receptor blockers, and dual PPAR alpha and gamma agonists are also under investigation. Unfortunately, data on the long-term safety and efficacy of these agents and their impact on liver related histologic outcomes are currently lacking. NAFLD treatment currently focuses on reducing metabolic risk factors, with the mainstay of therapy focusing on life-style modifications such as gradual weight loss through diet and regular exercise.