Ojima, Iwao
Distinguished Professor
所属大学: Stony Brook University
所属学院: Department of Chemistry
个人简介
B.S., 1968, The University of Tokyo M.S., 1970, The University of Tokyo Ph.D. 1973, The University of Tokyo
研究领域
Synthetic Organic and Medicinal Chemistry at the Biomedical Interface Discovery and development of new and potent anticancer agents, antibacterial agents, anti-inflammatory agents, and various enzyme inhibitors are the major research interests in Dr. Ojima’s laboratory. Integration of all relevant chemistry and biological tools, including computational biology (docking, in silico screening, molecular dynamics), chemical biology (protein expression, enzyme assays, fluorescence labeling), cell biology (cell culture, cytotoxicity assay, fluorescent confocal microscopy, flow cytometry, transmission and scanning electron microscopy), has successfully been realized in this program. Naturally, this research program is promoted in close collaboration with cell biologists, oncologists, microbiologist, pharmacologists, hematologists, toxicologists, etc., as well as the Division of Laboratory Animals Resources for in vivo efficacy evaluations. Tumor-targeting chemotherapeutic agents. The drug discovery program includes tumor-specific drug delivery systems, “guided molecular missiles” in the fight against cancer. Despite the significant progress in the development of cancer detection, prevention, surgery and therapy, there is still no common cure for this disease. In addition, the long-standing problem of chemotherapy is the lack of tumor-specific treatments. Traditional chemotherapy relies on the premise that rapidly proliferating cancer cells are more likely to be killed by a cytotoxic agent. In reality, however, cytotoxic agents have very little or no specificity, which leads to systemic toxicity, causing undesirable severe side effects. Therefore, various “molecularly targeted cancer therapies” have been developed for use in specific cancers, including tumor-targeting drug delivery (TTDD). In general, a TTDD system consists of a tumor recognition moiety and a cytotoxic warhead connected through a “smart” linker to form a conjugate. When a multi-functionalized nanomaterial is used as the vehicle, a “Trojan Horse” approach becomes possible for mass delivery of cytotoxic warheads to maximize the efficacy. The Ojima Laboratory has been making an excellent progress in the novel molecular approaches to the design and discovery of “guided molecular missiles” for tumor-targeting chemotherapy.
Novel antibacterial agents targeting bacterial cell division. The program also includes novel antibacterial agents against drug-resistant tuberculosis, MRSA, VRE and other pathogens. Despite extensive research in the last 40 years, the drugs used to treat these infections are still limited to rather classical antibacterial drugs that target cell wall biosynthesis, nucleic acid synthesis, protein synthesis, etc. Furthermore, the widespread misuse of drugs and poor patient compliance have allowed bacteria to become resistant to drugs by means of their adaptive genetic machinery, leading to multi-drug resistant (MDR) strains of bacteria. Widespread bacterial resistance to existing therapeutics for bacterial infections mentioned above has been a key hurdle for the complete treatment. Therefore, in order to counter attack the adaptive genetic machinery of bacteria, there is a dire need for the identification of novel therapeutic targets. In this context, filamentous temperature sensitive protein Z (FtsZ), an essential bacterial cytokinesis protein, is a highly promising therapeutic target since the disruption of cell division would lead to the inhibition/arrest of bacterial infection. The Ojima Laboratory has discovered novel taxanes and benzimidazoles exhibit high potency against drug-sensitive and drug-resistant tuberculosis through efficient inhibition of FtsZ polymerization, which is crucial for bacterial cell division. The drug discovery efforts have been supported by design and synthesis of novel libraries of compounds and moderately high throughput (HTP) screening as well as rational optimization of the hit compounds.
New and efficient synthetic methodology development. The Ojima Laboratory has been exploring and developing new methodologies, especially based on catalytic organic transformations, including enantioselective processes, cyclohydrocarbonylations and higher order cycloadditions and carbocyclizations, which provide the basis for the efficient syntheses of biologically active substances of medicinal interest, such as those anticancer and antibacterial agents mentioned above. Mechanisms of these reactions are also studied based on spectroscopic methods including advanced NMR techniques, computer-assisted molecular modeling, and X-ray crystallography.
近期论文
"Targeted and armed oncolytic adenoviruses via chemoselective modification", P. S. Banerjee, E. S. Zuniga, I. Ojima and I. S. Carrico, Bioorg. Med. Chem. Lett. 21, 4985-4988 (2011). PMC3413283 [Special Issue for Carolyn Bertozzi] "Novel taxanes effectively suppress subcutaneous rat lymphoma: role of disposition, transport, metabolism, in vitro potency and expression of angiogenesis genes", B. Otová, I. Ojima, R. Václavíková, J. Hrdý, M. Ehrlichová, P. Souček, J. Vobořilová, V. Němcová, I. Zanardi, S. Horský, J. Kovář, and I. Gut, Invest. New Drugs 30, 991-1002 (2012). PMID: 21448670 "Synthesis, Chemical Reactivity as Michael Acceptors, and Biological Potency of Monocyclic Cyanoenones, Novel and Highly Potent Anti-inflammatory and Cytoprotective Agents", S. Zheng, S. Y. R. Laxmi, E. David, A. Dinkova-Kostova, K. Shiavoni, Y. Ren, Y. Zheng, I. Trevino, R. Bumeister, I. Ojima, W. Wigley, J. Bliska, D. Mierke and T. Honda, J. Med. Chem. 55, 4837−4846 (2012). PMID: 22533790 "Transport, metabolism, cytotoxicity and effects of novel taxanes on the cell cycle in MDA-MB-435 and NCI/ADR-RES cells", M. Ehrlichová, I. Ojima, R. Václavíková, V. Němcová-Fürstová, J. Vobořilová, P. Šimek, S. Horský, P. Souček, J. Kovář, and I. Gut, Naunyn-Schmiedeberg’s Arch. Pharmacol. 385, 1035-1048 (2012) [Epub ahead of print, 8/2/2012]. PMID: 22855252 "Synthesis and Biological Evaluation of Novel 3’-Difluorovinyl Taxoids", L. Kuznetsova, L. Sun, J. Chen, X. Zhao, J. Seitz, M. Das, Y. Li, J. M. Veith, P. Pera, R. J. Bernacki, S. Xia, S. B. Horwitz, and I. Ojima, J. Fluor. Chem. 143, 177-188 (2012). [Special Issue for ACS Award in Fluorine Chemistry: David O’Hagen]. PMC3489494 "Targeting Fatty Acid Binding Protein (FABP) Anandamide Transport - A Novel Therapy for the Management of Pain and Inflammation", W. T. Berger, B. P. Ralph, M. Kaczocha, J. Sun, T. E. Balius, R. C. Rizzo, S. Haj-Dahmane, I. Ojima, and D. G. Deutsch, PLOS ONE 7(12): e50968 (2012). PMC3517626 Microwave-assisted Diels-Alder reactions between Danishefsky's diene and derivatives of ethyl 2-(hydroxymethyl)-acrylate. Synthetic approach towards a biotinylated anti-inflammatory monocyclic cyanoenone", S. Zheng, A. Chowdhury, I. Ojima and T. Honda, Tetrahedron 69, 2052-2055 (2013). "Benzimidazole-Based Antibacterial Agents against F. tularensis", K. Kumar, D. Awasthi, S.-Y. Lee, J. E. Cummings, S. E. Knudson, R. A. Slayden and I. Ojima, Bioorg. Med. Chem. 21, 3318-3326 (2013). PMC3681959 "Pd-catalyzed Asymmetric Allylic Etherification Using Chiral Biphenol-based Diphosphonite Ligands and Its Application for The Formal Total Synthesis of (-)-Galanthamine", Y. Zang and I. Ojima, J. Org. Chem. 78, 4013-4018 (2013). PMID: 23472673 "Caspase-2 is involved in cell death induction by taxanes in breast cancer cells", M. Jelínek, K. Balušíková, J. Fidlerová, V. Němcová-Fürstová, D. Kopperová, J. Šrámek, I. Zanardi, I. Ojima and J. Kovář, Cancer Cell Int. 13(1):42 (2013). [Epub ahead of print: 5/15/2013] PMID: 23672670 "Synthesis and biological evaluation of biotin conjugates of (±)-(4bS,8aR,10aS)-10a-ethynyl-4b,8,8-trimethyl-3,7-dioxo-3,4b,7,8,8a,9,10,10a-octahydro-phenanthrene-2,6-dicarbonitrile, an activator of the Keap1/Nrf2/ARE pathway, for the isolation of its protein targets", A. Saito, M. Higgins, S. Zheng, W. Li, I. Ojima, A. T. Dinkova-Kostova, and T. Honda, Bioorg. Med. Chem. Lett. 23, 5540-5543 (2013). PMID: 24018193 "Prostate cancer stem cell-targeted efficacy of a new generation taxoid, SBT-1214 and novel polyenolic zinc binding curcuminoid, CMC2.24", G. I. Botchkina, E. S. Zuniga, R. Park, R. H. Rowehl, R. Bhalla, A. B. Bialkowska, Y. Zhang, F. Johnson, L. M. Golub, I. Ojima and K. R. Shroyer, PLoS ONE 8, e69884: 1-15 (2013). PMC3782470 "An Improved Synthesis of a Hydroxymethyl Tricyclic Ketone from Cyclohexanone, the Key Processes for the Synthesis of a Highly Potent Anti-inflammatory and Cytoprotective Agent", A. Saito, S. Zheng, M. Takahashi, W. Li, I. Ojima, and T. Honda, Synthesis, 45, 3251-3254 (2013). "SAR Studies on Trisubstituted Benzimidazoles as Inhibitors of Mtb FtsZ for the Development of Novel Antitubercular Agents", D. Awasthi, K. Kumar, S. E. Knudson, R. A. Slayden and I. Ojima, J. Med. Chem. 56, 9756-9770 (2013). NIHMS544122 "Crystallographic Study of FABP5 as an Intracellular Endocannabinoid Transporter", B. Sanson, T. Wang, J. Sun, M. Kaczocha, I. Ojima, D. G. Deutsch, and H. Li, Acta Cryst., Section D (Biological Crystallography), 70, 290-298 (2014). PMC3976407 "Inexpensive chemical method for preparation of enantiomerically pure phenylalanine", H. Moriwaki, D. Resch, H. Li, I. Ojima, R. Takeda, J. L. Aceña and V. Soloshonok, Amino Acids. 46, 945-952 (2014). PMID: 24385244 "Synthesis and stereochemical assignments of diastereomeric Ni(II) complexes of glycine Schiff base with (R)-2-(N-{2-[N-alkyl-N-(1-phenylethyl)amino]acetyl}amino)benzophenone; a case of configurationally stable stereogenic nitrogen", H. Moriwaki, D. Resch, H. Li, I. Ojima, R. Takeda, J. L. Aceña, V. A. Soloshonok, Beilstein J. Org. Chem. 10, 442–448 (2014). PMC3943998 "A Trisubstituted benzimidazole cell division inhibitor with efficacy against Mycobacteria tuberculosis", S. E. Knudson, D. Awasthi, K. Kumar, A. Carreau, L. Goullieux, S. Lagrange, H. Vermet, I. Ojima, and R. A. Slayden, PLoS ONE 9(4):e93953 (2014). PMC3988029
"Inhibition of Fatty Acid Binding Proteins Elevateds Brain Anandamide Levels and Produces Analgesia", M. Kaczocha; M. J. Rebecchi, B. P Ralph, Y.-H. Gary Teng, W. T. Berger, W. Galbavy, M. W. Elmes, S. T. Glaser; L. Wang; R. C. Rizzo, D/ G. Deutsch and I. Ojima, PLoS ONE 9(4), e94200 (2014). PMC3976407