1. BASIC SCIENCE

RESEARCH REPORT FOR JOINT PROJECT

  1. Title of Project:
    Biological and structural studies on non-covalent interactions between novel platinum anticancer drugs and bio-molecules
  2. Duration: April 1, 2004 — March 31, 2006
  3. Project Organization
    1. Japanese Principal Investigator (JPI)
      Dr. Akira Odani (Associate Professor, Research Center for Material Science, Nagoya University)
    2. U.S. Principal Investigator (USPI)
      Dr. Nicholas P. Farrell (Professor, Chemistry, Virginia Commonwealth University)
    3. Research Associate (Japanese / US)
      Seiji Komeda, Ph.D. (Osaka University of Pharmaceutical Sciences Pharmacy)
    4. List of Other Project Participants (except for PIs and RA)

      Japanese-side:
      Osamu Yamauchi (Professor, Engineering, Kansai University)
      Masahiko Chikuma (Professor, Pharmacy, Osaka University of Pharmaceutical Sciences)
      Yasuo Nakabayashi (Associate Professor, Engineering, Kanasai University)
      Takaji Sato (Assistant Professor, Pharmacy, Osaka University of Pharmaceutical Sciences)

      US-side:
      Nicholas P. Farrell (Professor, Chemistry, Virginia Commonwealth University)
      Loren D. Williams (Professor, Chemistry, Biochemistry, Georgia Institute of Technology)
      Yun Qu (Associate Professor, Chemistry, Virginia Commonwealth University)
      Qin Liu (PD, Chemistry, Virginia Commonwealth University)
      Genevieve Bulluss (PD, Chemistry, Virginia Commonwealth University)
      Atilio Anzellotti (Ph. D. Candidate, Chemistry, Virginia Commonwealth University)
  4. Activities of Research Associate (RA)
    1. Duration in US: April 14, 2005 ~March 26, 2006
    2. Institution Visited in US:
      1) Georgia Institute ofTechnology (GA Tech)
      Duration: April 14, 2005 - March 26, 2006
      Research Purposes: Crystallization of metal complex — DNA adducts and the X-ray crystal analysis
      2) Virginia Commonwealth University (VCU)
      Duration: February 7, 2006 - February 13, 2006
      Research Purposes: Report and discussion on the results obtained from this cooperative program
    3. Scientific Results/Achievements
      The purpose of RA’s study is to construct structure-function-activity relationships of Pt(II) complexes aimed at developing a Pt based anticancer drug with less potential side effects, using crystallography.
      At GA Tech, the RA performed crystallization of a double-stranded dodecamer DNA, [d(CGCGAATTCGCG)]2, in the presence of various series of anticancer-active Pt(II) complexes, which non-covalently interact with DNA or other bio-molecules. Single crystals obtained from the co-crystallization were processed to x-ray crystal analysis, by which more than 30 different high resolution crystal structures of different Pt(II) complex-DNA adducts were obtained.
      For instance, DNA binding modes of two different types of polynuclear Pt(II) complexes with anticancer activity, whose general formulas are [Pt(Am)3}2-µ-{trans-Pt(NH3)2(NH2(CH2)6NH2)2}]n+ (polyamine-bridged complex) and [{cis-Pt(Am)2}2(µ-OH)(µ-azolato)]2+ (azolato-bridged complex), were elucidated.
      In the DNA crystal structures with a series of polyamine-bridged complexes, they make many contacts with phosphate oxygens with hydrogen bonding and non-covalently (electrostatically) bind to DNA in two different modes named as "Backbone Tracking" and "Groove Spanning". For the former case, polyamine-bridged complexes bind to the phosphate backbone of one strand of DNA along the helix. For the latter case they interact with two phosphate groups that are juxtaposed across the minor groove. Both of these non-covalent interactions appear to make DNA distorted towards the major groove, compared to the control DNA structure that obtained in the absence of the Pt(II) complex.
      On the other hand, in the DNA crystal structures with a series of azolato-bridged complexes, they preferentially bind to the DNA minor-groove in a non-covalent manner. No significant hydrogen bonding interaction was observed between the complex and DNA. Therefore, van der Waals interaction appears to contribute to this minor groove binding. No significant deformation was observed, compared to the control DNA.
      As described above, this study have clearly indicated that the different types of Pt(II) complexes interact with DNA each in a specific manner, and that these DNA binding modes and the resulting DNA deformations are related or involved in their anticancer mechanisms. Therefore, RA’s crystallographic approach would be a very powerful tool to construct structure-function-activity relationships of different types of Pt(II) complexes, leading to a development of a new Pt based anticancer drugs with less potential side effects.
  5. Number of Exchanges during Project Period
    1. from Japan to US
      Akira ODANI:
      2004.6.25-7.3 : Georgia Institute of Technology Michigan University
      2004.8.29-9.7: Garmisch-Partenkirchen, Szged University
      2005.7.30-8.9 : Georgia Institute of Technology, Michigan University
      2006.3.7-10: Georgia Institute of Technology
      Masahiko CHIKUMA:
      2004.8.27-9.2: Garmisch-Partenkirchen
      2005.7.30-8.6: Michigan University
      Yasuo NAKABAYASHI:
      2004.8.28-9.3: Garmisch-Partenkirchen
      Seiji Komeda:
      2004.8.27-9.4: Garmisch-Partenkirchen
    2. from US to Japan
      Nicholas P. FARRELL:
      2005.6.9-6.22: Nagoya University, Osaka University of Pharmaceutical Sciences
      Loren D. WILLIAMS:
      2005.6.8-6.17: Nagoya University, Osaka University of Pharmaceutical Sciences
      Yun QU:
      2005.6.7-6.12: Osaka University of Pharmaceutical Sciences
      Qin LIU:
      2005.6.9-6.15: Nagoya University, Osaka University of Pharmaceutical Sciences
      Genevieve BULLUSS:
      2005.6.9-6.15: Nagoya University, Osaka University of Pharmaceutical Sciences
      Atilio ANZELLOTTI:
      2005.6.9-6.15: Nagoya University, Osaka University of Pharmaceutical Sciences
      Tatsuya MAEHIGASHI:
      2005.6.9-6.30: Nagoya University, Osaka University of Pharmaceutical Sciences
  6. Purpose and Content of Project
    The objectives of this project are to develop cationic and anionic Pt(II) based anticancer drugs with potentially less side effects than currently used agents, in order to improve patient’s quality of life (QOL), and to elucidate a part of their anticancer mechanism. It is the foundation of this proposal that novel cellular uptake mechanisms as well as profiles of DNA binding by cationic platinum complexes differ significantly from that of neutral cisplatin and congeners. These differences can be used to develop new platinum-based drugs with a clinical profile complementary to cisplatin.
    Our goal is to elucidate anticancer mechanisms of cationic mono- and polynuclear platinum(II) complexes that interact with bio-molecules in a non-covalent manner, in order to develop a new metal-based anticancer drug with improved efficacy.
    The major drawbacks of the platinum based anticancer drug, cisplatin, are the serious side effects and acquired drug-resistance, which inevitably increases the drug dosage to patients. Accordingly, a new platinum based anticancer drug that circumvents these clinical inconveniences is strongly desired to improve patient’s quality of life (QOL). It is generally believed that cisplatin’s anticancer action is triggered by formation of 1,2-intrastrand crosslinks on DNA, resulting in a severe DNA distortion. Most of the structurally related cisplatin-analogues show cross-resistance to cisplatin, probably due to their similar biological consequences. Therefore, Farrell introduced a series of polyamine-bridged di- and trinuclear Pt(II) complexes which provide long range intra- and interstrand crosslinks, structurally very different from those formed by cisplatin. One drug from this work, BBR3464, entered clinical trials and exhibited remarkably high potency. The entry into clinical trials validates the concept of searching for new, structurally different platinum analogues. Chikuma and Reedijk also reported a series of azole-bridged dinuclear Pt(II) complexes which serve as 1,2-intrastrand crosslinks with minimal DNA distortion. They exhibited much higher in vitro cytotoxicity than cisplatin and overcame acquired resistance to cisplatin.
    Most of the researchers in platinum anticancer chemistry had been only focusing on geometries of covalently bound Pt-DNA adducts. However, a striking feature of the above mentioned polynuclear Pt(II) complexes is that they possess high positive charges (+2 to +6), whereas cisplatin is administered as a neutral molecule. The cisplatin and similar carboplatin and oxaliplatin drugs undergo hydrolysis immediately followed by a covalent interaction with DNA. Cationic Pt(II) complexes may experience an electrostatic pre-association before they covalently bind to negatively charged DNA. Given that this kind of non-covalent interaction also initiates anticancer effects, cationic Pt(II) complexes which have no covalent interaction with bio-molecules could reduce potential side effects without affecting, and indeed improving, therapeutic efficacies because cisplatin’s side effects are caused by the accumulation of its covalently bound species in organisms. The parameters affecting cytotoxicity of platinum compounds are cellular uptake, DNA interaction and metabolic deactivating reactions with sulfur-containing biomolecules such as Human Serum Albumin and glutathione. These latter interactions are also covalent and thus can be circumvented by the use of cationic non-covalent derivatives. To support this hypothesis, Odani and Farrell have recently found anticancer-active cationic mono- and polynuclear Pt(II) complexes which probably generate only non-covalent interaction upon bio-molecules.
    Therefore, we have initiated a project to elucidate the clinically most relevant properties of non-covalent interactions with bio-molecules such as DNA and related enzymes. A variety of new cationic mono- and polynuclear Pt(II) complexes are synthesized and biologically investigated at NU, OUPS, KU and VCU. A crystallographic study on DNA conformations in the presence of these drugs is performed at GA Tech. This study will open up a novel interpretation of anticancer mechanisms. These studies are expected to lead the development of new anticancer drug with less side effect which many cancer patients hope.
  7. Status Report of Project Implementation
    Each of the groups (NU, OUPS, KU and VCU) have independently developed different types of Pt(II) and related metal complexes, which are found to be highly active in preliminary in vitro cytotoxicity. Because of their positive charge, these derivatives may initially react in a non-covalent manner with biomolecules through hydrogen-bonding and electrostatic interactions. For a more sophisticated interpretation of their structure-activity relationships, we prepared new derivatives which were designed to only interact in a non-covalent manner with important biomolecules. Up to thirty derivatives of the cationic mono- and polynuclear Pt(II) complexes based on the structural formulas such as ternary [Pt(diimine)2]2+, cis-[Pt(Am)2(peptide)]2+, [{cis-Pt(Am)2}2(µ-azolate)(µ-hydroxo)]2+ (Am = amine), [{cis-Pt(Am)3}2(µ-polyamine)]4+, [{cis-Pt(Am)3}2{µ-Pt(polyamine)}2]6+, and related compounds were synthesized and characterized at NU, KU, OUPS, and VCU. The structure-activity dependence of the non-covalent interactions in Pt(II) complexes were studied at NU and KU. The comparison across different types were expected to allow the most important features contributing to antitumor activity to be identified and produce a profile of the most likely new drug candidate to emerge from this work, however, we do not get the common structural feature which is limited within related compounds.
    In order to choose biologically relevant Pt(II) complexes from those newly prepared by each group and to construct their structure-activity relationships, the cationic Pt(II) complexes are biologically assessed by performing in vitro cytotoxicity assay, in vitro apoptosis induction assay, cellular uptake and cell cycle analysis. OUPS and VCU are basically responsible for these biological evaluation assays. Selected derivatives were processed for in vivo anticancer activity in human xenograft models. New intellectual property stemming from the most promising selected cationic Pt(II) complexes were patented to ensure commercial interest for development.
    In parallel with the cytotoxicity and in vivo assays, investigations about the influence of cationic complexes on relevant bio-molecules were expedited at NU, OUPS, KU and VCU, respectively, to find out insights of their anticancer mechanisms, since we believe the significant roles of the cationic Pt(II) complexes lie in their non-covalent interactions with DNA and/or specific enzymes. To elucidate the minimal DNA binding affinity required for meaningful anticancer activity of non-covalent compounds, the significant DNA conformational changes induced by their non-covalent association were investigated using NMR and CD spectroscopy. Using spectroscopy experiments revealed to clarify their preferred DNA binding site. To examine other possible targets besides DNA, a specific enzyme-inhibition assay were performed on selected probable target molecules such as DNA dependent protein kinase. Correlations between their biological activities and non-covalent DNA binding properties were discussed comprehensively.
    A crystallographic study on small fragments of double-stranded DNA co-crystallized with each of the selected Pt(II) complexes was scheduled at GA Tech. The purpose for this study is to unambiguously find out their specific DNA-binding positions of the selected Pt(II) complexes and the resulting DNA conformations.
    The results obtained from the above-mentioned studies bring us considerable information on biological activities and biochemical functions against bio-molecules such as specific DNA binding modes and significant structural changes. Accordingly, we are able to elucidate the decisive factors needed to trigger cell death and acquire a novel interpretation of anticancer mechanisms.
  8. Seminar
    1. Title: "Biological and structural studies on non-covalent interactions between novel platinum anticancer drugs and bio-molecules"
    2. Period: 2006.6.10-11
    3. Site: Senri Life Science Center (Osaka)
    4. Participants: Total 50 (Japan side 43 , US side 7 , Other country 0 )
    5. Agenda, Topics and Scientific Achievements
      Akira Odani (Nagoya University)
      Anticancer Effects of Pt(II) Complexes through Non-covalent Interactions
      Takao Yamori (Japanese Foundation for Cancer Research)
      Anticancer Drug Discovery and Target Prediction by Cancer Cell Informatics
      Osamu Yamauchi (Kansai University)
      Metal Complex-Biomolecule Interactions and Their Effects
      Qin Liu (VCU)
      A Membrane Interaction Mechanism for Polynuclear Platinum Complex Uptake in Cells
      Yun Qu (VCU)
      Solution NMR Studies on DNA Conformational Changes of Non-covalent Polynuclear Platinum Complexes
      Atilio I. Anzellotti (VCU)
      Study of covalent and non-covalent interactions in [Pd(dien)nucleobase]2+/
      l-tryptophan(N-Acetyl-tryptophan) systems: Formation of metal-tryptophan species by nucleobase substitution under biologically relevant condition
      Genevieve BULLUSS (VCU) Structural Studies on a Series of Polynuclear Platinum Complexes
      Yasuo NAKABAYASHI (Kansai University)
      DNA Binding by Dinuclear Ruthenium(II) Complexes Containing Flexible Bridging Ligands Diamines
      Takaji Sato (Osaka University of Pharmaceutical Sciences)
      Non-covalent interactions of pyrazole-bridged dinuclear platinum(II) complex with DNA
      Rei Komaki (Osaka University of Pharmaceutical Sciences)
      Induction of apoptosis in human ovarian tumor cell lines by novel binuclear platinum (II) complexes
      Aoi Makino (Osaka University of Pharmaceutical Sciences)
      Antioxidative effects of Glycyl-L-histidyl-L-lysine (GHK) and GHK-Cu(II) complex
      Hiroshi Takayama (Nagoya University)
      Anticancer Property for Ternary Bipyridine- Aromatic Ring Containing Ethylenediamine Metal Complexes (M = Pt(II), Pd(II))
      Kazuyuki Tanabe (Nagoya University)
      Synthesis and Anticancer Effect for cisplatin Like Pt(II) Complexes Involving New Leaving Group
      Akihito Kiguchiya (Nagoya University)
      Synthesis and Anticancer Effect of Phytate Containing Pt(II) Complexes
      Loren D. Williams (Georgia Institute of Technology)
      DNA-Drug Interactions
      Fumio Hanaoka (Osaka University / SORST, JST / RIKEN)
      Our recent studies on nucleotide excision repair and translesion synthesis
      Kimitoshi Kohno (University of Occupational and Environmental Health)
      Transcription factors and cisplatin resistance
      Takenori Tomohiro (Toyama Medical and Pharmaceutical University)
      Detection and purification of CDDP-DNA binding proteins
      Shuichi Kishimoto (Kobe Gakuin University)
      Lipophilic platinum compound for liver cancer
      Shin Aoki, Kazusa Sakurama, Eiichi Kimura* (Hiroshima University)
      Zinc Probe, DNA, and Apoptosis
      Shigenobu Yano (Nara Women’s University)
      Synthesis, Structural Characterization, and Antitumor Activity of Platinum(II) and Palladium(II) Complexes Containing a Sugar Unit
      Keiichi Tsukahara (Nara Women’s University)
      DNA-Binding Properties of New Platinum(II) Complexes—Construction of a DNA-Hemoprotein Complex
      Hitoshi Yamamoto (Osaka University)
      Inhibition of Thermus thermophilus HB8 thioredoxin activity by Pt(II) complex
      Masahide Noji (Suzuka University of Medical Science)
      The development of the third generation platinum complex, Oxaliplatin

      Ryoichi Kizu (Doshisha Womens' College of Liberal Arts)
      Significance of HMG1 in Cisplatin-induced Apoptosis in HeLa Cells
      Masahiko Chikuma (Osaka University of Pharmaceutical Sciences)
      Chemical and biological properties of antitumor dinuclear platinum(II) cation complexes binding covalently and non-covalently with DNA.
      Seiji Komeda (Osaka University of Pharmaceutical Sciences)
      Crystal Structure of [d(CGCGAATTCGCG)2 Co-crystalized with Polynuclear Platinum(II) Complexes
      Nicholas P. Farrell (Virginia Commonwealth University)
      Non-covalent (Electrostatic and Hydrogen Bonding) Effects on the interactions of Polynuclear Platinum Compounds and biomolecules.
  9. Research Results of Project
    Our goal is to elucidate anticancer mechanisms of cationic mono- and polynuclear platinum(II) complexes that interact with bio-molecules in a non-covalent manner, in order to develop a new metal-based anticancer drug with improved efficacy.
    Firstly we prepared new derivatives which were designed to only interact in a non-covalent manner with important biomolecules, and observed that such Pt(II) compounds revealed anticancer effect trough the non-covalent interaction. One of the compounds revealed same bio-activity against cis-platin resistance cancer cell. This confirmed our approach to new anticancer drug through non-covalent interaction. However, the activity were usually lower than the corresponding compound with covalent interaction with DNA and we considered the non-covalent mode is important for adding the drug interaction mode. As we did not get the common structural feature in vitro cytotoxicity assay and observed various type of the structure-activity relations in Pt(II) complexes involving with non-covalent interaction manner, the relation indicated one possible explanation that amount of Pt(II) in the cancer cell may decide the rough bio-activity of the Pt(II) compounds because the amount of Pt(II) is responded with various factors.
    The significant roles of the Pt(II) complexes have been believed to lie in their non-covalent interactions with DNA, however, the non-covalent touch is possible for other bio-molecule. To examine other possible targets besides DNA, a specific enzyme-inhibition assay were performed on selected probable target molecules such as a protein kinase, topoisomerase activity etc. The result showed weak inhibitions on some Pt(II) compounds, however, the inhibition effects were not enough for the explanation of the cytotoxicity for the compound. These effects on the proteins may help the anti-cancer effects of Pt(II) compounds.
    A crystallographic study on small fragments of double-stranded DNA co-crystallized with each of the selected Pt(II) complexes was scheduled at GA Tech for many Pt(II) compounds. The crystals were prepared after searching the crystallization conditions and measured in the USA radiation center. At the present we do not finish the analysis of the measured data, however, at least two Pt(II) compound-oligo DNA adducts were revealed the non-covalent interactions between DNA and the Pt(II) compound. Surprisingly the Pt(II) center do not interact with DNA, but Pt(II) coordinated ligand interacted with the phosphate and/or the groove of the DNA. The groove binding was also confirmed in aqueous solution by NMR. As these Pt(II) compounds high cytotoxicity, the fixtation at specific DNA site through many non-covalent interactions indicated to be important.
    After correlations between their biological activities and non-covalent DNA binding properties were discussed comprehensively, we concluded the Pt compounds with the non-covalent interaction mode are very useful for the development of new anticancer drug.
  10. Papers and Publications (Project-related papers that have or will be published)
    Komeda, S.; Moulaei, T.; Woods, K. K.; Chikuma, M.; Farrell, N.; Williams, L. D.
    Phosphate Clamps: A Novel Mode of DNA Interaction by a Polynuclear Platinum(II) Complex"
    J. Am. Chem. Soc. 2006, to be submitted.
    Komeda, S.; Moulaei, T.; Woods, K. K.; Farrell, N.; Chikuma, M.; Williams, L. D.
    Crystal structure of DNA with pyrazolato-bridged dinuclear Pt(II) complex.
    Biochemistry 2006, to be submitted.
    Komeda, S.; Chikuma, M.; Farrell, N.; Williams, L. D.
    Crystal structure of DNA with non-covalent trinuclear Pt(II) complex.
    J. Am. Chem. Soc. 2006, to be submitted.
    Komeda, S.; Chikuma, M.; Farrell, N.; Williams, L. D.
    Crystal structure of DNA in the presence of a polyamine-bridged trinuclear Pt(II) complex : a spermine molecule observed in the minor-groove.   Manuscript in preparation
    Komeda, S.; Chikuma, M.; Williams, L. D.
    Covalent and non-covalent interactions between DNA and azolato-bridged dinuclear Pt(II) complex observed in a crystal structure.   Manuscript in preparation
    Komeda, S.; Heroux, A.; Odani, A.; Chikuma, M.; Farrell, N.; Williams, L. D.
    Distribution of cisplatin and transplatin on DNA surface. Manuscript in preparation
    Komeda, S.; Chikuma, M.; Farrell, N.; Williams, L. D.
    Crystal structure of DNA with a potential anticancer drug, BBR3464. Manuscript in preparation
    Komeda, S.; Hsiao, C.-L.; Chikuma, M.; Farrell, N.; Williams, L. D.
    Crystal structure of a DNA interacting with a spermine-bridged dinuclear Pt(II) complex. Manuscript in preparation
    Y. Nakabayashi, Y. Watanabe, T. Nakao, and O. Yamauchi, Interactions of Mixed Ligand Ruthenium(II) Complexes Containing an Amino Acid and 1,10-Phenanthroline with DNA, Inorg. Chim. Acta, 357, 2553-2560(2004). (Apr., 2004).
    F. Zhang, Y.-Z. Li, X. Gao, H.-L. Chen, Q.-T. Liu, A. Odani, and O. Yamauchi, Aromatic Iodine Assisted Self-Assembly of a Cobalt(II) Complex of Ferron (Ferron = 7-iodo-8-hydroxyquinoline-5-sulfonate), Chem. Lett., 33(5), 556-557(2004).(May, 2004)
    T. Motoyama, Y. Shimazaki, T. Yajima, Y. Nakabayashi, Y. Naruta, and O. Yamauchi, Reactivity of Indole Ring in Palladium(II) Complexes of 2N1O-Donor Ligands: Cyclopalladation and π-Cation Radical Formation, J. Am. Chem. Soc., 126(23), 7378-7385(2004).(June 16, 2004).
    Y. Shimazaki, S. Huth, S. Karasawa, S. Hirota, Y. Naruta, and O. Yamauchi, Nickel(II)-Phenoxyl Radical Complexes: Structure—Radical Stability Relationship, Inorg. Chem., 43(24), 7816-7822(2004).(Nov. 29, 2004)
    F. Zhang, T. Yajima, Y.-Z. Li, G.-Z. Xu, H.-L. Chen, Q.-T. Liu, and O. Yamauchi, Iodine-Assisted Assembly of Helical Coordination Polymers of Cucurbituril and Asymmetric Copper(II) Complexes, Angew. Chem. Int. Ed., 44(22), 3402-3407(2005).(June 2, 2005)
    Y. Shimazaki, M. Tashiro, T. Motoyama, S. Iwatsuki, T. Yajima, Y. Nakabayashi, Y. Naruta, and O. Yamauchi, Cyclopalladation of the Indole Ring in Palladium(II) Complexes of 2N1O-Donor Ligands and Its Dependence on the O-Donor Properties, Inorg. Chem., 44(17) 6044-6051(2005).(Aug. 22, 2005)
    Y. Nakabayashi, Y. Hirosaki, and O. Yamauchi, Dipolar Ruthenium(II) Ammine Complexes as Electron Transfer Mediators of Amperometric Glucose Sensors, Bioelectrochemistry, in press.
    M. Takani, T. Takeda, T. Yajima, and O. Yamauchi, Indole Rings in Palladium(II) Complexes. Dual Mode of Metal Binding and Aromatic Ring Stacking Causing syn-anti Isomerism, submitted.
    Y. Nakabayashi, N. Iwamoto, H. Inada, and O. Yamauchi, DNA-binding Properties of Flexible Diamine Bridged Dinuclear Ruthenium(II)-2,2’-bipyridine Complexes, submitted.
    Y. Nakabayashi, A. Erxleben, U. Létinois, G. Pratviel, B. Meunier, and B. Lippert, Spontaneous Reduction of Mixed 2,2’-Bipyridine/Methylamine/Chloro Complexes of PtIV in Water in the Presence of Light is Accompanied by Complex Isomerization and Loss of Methylamine, submitted.
    T. Yajima, R. Takamido, Y. Shimazaki, A. Odani, Y. Nakabayashi, and O. Yamauchi, π-π Stacking Assisted Binding of Aromatic Amino Acids by Copper(II)-Aromatic Diimine Complexes. Effects of Ring Substituents on Ternary Complex Stability, to be submitted.
    Hanaki, Akira; Funahashi, Yasuhiro; Odani, Akira
    Ternary Cu(II) complexes, Cu(H-1L)(ACys-) and Cu(H-2L)(ACys-); L=peptides, ACys- = N-acetyl-cysteinate. Analogous complexes to the intermediates in the transport of Cu(II) from Cu(H-2L) to cysteine.
    J. Inorg. Biochem., 100, 305-315 (2006).
    Nakajima, H.: Saita, M: Watanabe, Y.: Odani, A.
    New anticancer Pt(II)-bisphosphonate complex and its Properties submitted
    Synthesis and Anticancer Effect for 4N Pt(II) and Pd(II) Complexes through Non-covalent Interaction
    Akira Odani, Hiroshi Takayama, Masahiro Kato, Takao Yamori to be submitted
    Seiji Komeda, S. Hirotoshi Yamane, Masahiko Chikuma, Jan Reedijk
    A kinetic study on the reactions of azole-bridged dinuclear platinum(II) complexes with guanosine 5’-monophosphate.
    Eur. J. Inorg. Chem., 24, 4828-4835(2004).
    Takaji Sato, Yoshihiko Onishi, Yoshihiro Saito, Seiji Komeda, and Masahiko Chikuma
    Preparation and antitumor activity of azole-bridged dinuclear platinum(II) complexes.    in preparation.
    Masahiko. Chikuma, Takaji. Sato, Souichi Ueda, and Seiji. Komeda Proton-assisted substitution reaction of a hydroxo-bridged dinuclear platinum(II) complex capable of circumventing cisplatin-resistance.   in preparation
    Takaji Sato, Sachie Wada, Ryuhei Wada, Yoshihiro Saito, Seiji Komeda, and Masahiko Chikuma
    Non-covaent interactions of pyrazole-bridged dinuclear platinum(II) complexes with DNA   in preparation
  11. Any Comments
    I appreciate that we have a nice experiment of Japan-US research collaboration because we get the valuable information about the anticancer drug development through this joint program. This should lead the exploration of new anticancer drug and the rescue of many cancer patients. However, now this program remains shut down. I hope this program opens again soon.