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Research Laboratories & Centers
Organic and Biocatalytic Chemistry
Human body is made of various types of optically active molecules and functions through their mutual interactions. Therefore, a majority of drug molecules have to be optically active and enantioselective synthesis is an essential tool in the research of new drug discovery, and sometimes, is vital.
Our research activity focuses on the synthesis of enantioselective molecules applicable as pharmaceuticals using both organic and enzymatic chemistry as two major research tools
Currently four topics are extensively studied;
1) Integrated chemo-enzymatic synthesis (three lab staffs)
Taking advantages of the combining application of enzyme-catalyzed enantiomeric resolution, asymmetric synthesis and other biotransformations, expeditious synthetic routes of oseltamivir derivatives, macrocyclic lactones, pharmaceutial targets & manufacting intermediates have been developed.
2) Total synthesis of bioactive natural products (Shoji, M.)
New stereo- and chemoselective reactions involving cycloaddition and organocatalyst-mediated functionalization were developed for total synthesis of batrachotoxin and epoxyquinols, carnosic acid, etc.
3) Synthetic and biological studies of aromatic bioactive materials (three lab staffs)
Regio- and stereoselective chemical and biochemical transformation were applied to provide new derivatives of phenolic substances, such as resveratrol, dephostatin and TBMB acids.
4) Enzyme-mediated synthesis of carbohydrates (Sugai, T.)
New pathways for the synthesis of various carbohydrates were developed using inexpensive and abundantly available compounds as starting materials, and by the application of chemo-enzymatic reactions. Carbohydrates so far synthesized are sugers (L-nucleosides, etc.), deoxyamino sugars and their derivatives (D-ManNAc, zanamivir-related sialic acids), and oligosaccharides, such as LeX.
Graduates of our laboratory will be fascinated by synthetic study through acquiring vast and deep knowledge and skill about organic and enzymatic chemistry.
They will have the potential to be medicinal and/or process chemists in pharmaceutical industry, and also be researchers and manufactures in chemical, petroleum and food industries, and in academic fields industries, and in academic fields.
Since the ancient ages, crude drugs and herbal medicines have played a great roll for relieving human from various diseases/disorders and for keeping human's healthy life. Even, at present, natural products as well as their semi-synthetic analogs derived from the natural resources play important role in pharmacotherapy and as health/functional foods.
Aiming at the better use of natural products for human health, our group focuses on the research of naturally derived bioactive materials, e.g., isolation and structure elucidation, synthesis and chemical modification of natural compounds.
Currently, our research activity concentrates in the following three areas;
- Exploration of biologically active compounds from various plant resources:
Biologically active substances contained in natural resources may be useful as leads for medicines with new mode of actions. The resources dealt with in our laboratory include crude drugs, herbal medicines, spices, and components of health food.
- Clarification of clinical efficacy of crude drugs on chemical basis
Although many biologically active substances have been isolated from crude drugs, therapeutic role of each component, especially in Kampo formulae, has not yet been fully clarified. One of our goals is to clarify the scientific bases of clinical efficacy of crude drugs, which will enable chemical evaluation of clinical efficacy of crude drugs.
- Synthesis of glycoconjugates from invertebrates and higher plants and clarification of their biological activities;
We have strong interest in the structure and the biological function of glycoconjugates found parasitic helminthes and higher plants, and are doing those chemical synthesis. The partially or totally synthesized substances may be developed as new conjugate vaccines and/or new diagnostics, especially effective against infections caused by parasites.
Some flowers of medicinal plants
Through participation in our research, students will be knowledgeable to herbal medicines, and acquire technical skills to handle natural products, such as purification, structure determination, chemical modification and biological evaluation. Let's enjoy nature through the eye of natural product chemistry!
Bioorganic and Medicinal Chemistry
Medicinal chemistry is a multidisciplinary specialty stemming from chemistry and intersecting with biology and physics. It involves discovery, designing and synthesis of chemical entities suitable for diagnostic and therapeutic use. Majority of compounds currently used as medicines are organic compounds with a variety of chemical entities. New chemical entities may have potentials to become novel medicines.
Projects currently pursued in our laboratory are;
1) Fullerene derivatives as novel bioactive compounds
Fullerene is a compound consisting of carbon and has a unique chemical structure. Since its discovery in 1985, modified derivatives have been synthesized and their properties were examined. Low water solubility has been a drawback of the molecule for applying to pharmaceuticals.
We synthesize water soluble fullerene derivatives and investigate their biological properties, with the hope to discover new lead for medicines, such as antioxidant, antibacterial, anti-HIV, and anti-HCV agents.
2) Molecular design of novel antioxidants and their synthesis
Reactive oxygen species (ROS) existing in our body are known to cause various disorders and sometimes to act as triggers of severe diseases. Some drugs are known to show their clinical efficacy through removal of ROS. There is still a room to explore new drugs with antioxidant activity as their mode of action. Our challenge is the discovery of novel antioxidants with novel chemical structure.
3) Metabolic pathways catalyzed by cytochrome P450
We investigate metabolic pathways of chemicals catalyzed by cytochrome P450. Discovery of novel metabolites may reveal the mechanism of toxicity of environmental
Students in our group will have a chemical insight into various biological phenomena and will brush up the creative mind for design of new drug. Students with strong background on organic chemistry are highly welcomed.
"Investigation of the molecular basis for prevention of lifestyle-related diseases through the food"
Prevention of lifestyle-related diseases such as obesity, hyperlipidemia, arteriosclerosis, diabetes, and hypertension is a urgent issue for the public health of our nation. Aiming at the prevention of lifestyle-related diseases through diet, we are carried out to research from various angles.
- Prevention of lifestyle-related diseases through effects of foods on the metabolism of steroids.
Steroid hormones such as estrogens and glucocorticoids, have a variety of physiological activity, and their activities are known to correlate with the risk of developing a variety of lifestyle-related diseases. On the other hand, it has been well recognized that diet has a significant impact on prevention and risk of developing lifestyle-related diseases. There are various reports which show correlation between the effects on prevention of lifestyle-related diseases and the effects on steroid metabolism by food ingredients. In recent years, epidemiological studies showed that coffee has preventive effect against a variety of lifestyle-related diseases, including cancer and diabetes. Then, we are evaluating the effect of coffee on the steroid hormone metabolism.
- Analysis of the molecular basis of the effects of probiotics on the lifestyle-related diseases.
Epidemiological studies indicate that there is a habitual intake effect of bifidobacteria and lactobacteria contained in yogurt to prevent lifestyle-related diseases, such as cancer and hyperlipidemia and inflammatory gastrointestinal disease. Using cultured cells derived from human gastrointestinal tract, we have analyzed the effects of probiotics on the immune system and cholesterol absorption within the digestive tracts.
In order to discover new drugs that control abnormal regulation in cells, our investigations focus on the identification of cellular signaling molecules in normal and tumor cells. Particular attentions have been paid on the mutation (including V617F or L611S) of Janus kinase 2 (JAK2) because of its demonstration in patients with polycythemia vera or acute leukemia. The reason why mutations of JAK2 are potently oncogenic, leading cytokine-independent growth of cells in vitro and tumorigenesis in vivo, has also been studied extensively. Consequently, we are interested in discovery of new JAK2 inhibitors for a potential targeted therapy against disorders related to the mutation(s) of JAK2. In addition, we are extensively investigating in vitro and in vivo several drugs and compounds that modulate immune responses, allergic and inflammatory responses. Students in our laboratory are requested to develop their expertise in immunological biochemistry and molecular biology-techniques in cell culture, flow cytometry, ELISA, Western blotting, RT-PCR, transfection etc. -so that highly reproducible experimental results should be obtained.
We are also interested in methionine metabolism because it is recently known to be involved in the regulation of various methylation reactions, accumulation of homocysteine (an independent risk factor for cardiovascular diseases), biosynthesis of major cysteine-derived antioxidants (glutathione and taurine/hypotaurine), and production of hydrogen sulfide (H2S, a gaseous bioactive mediator). Innate abnormality or dysregulation of the methionine metabolism pathway leads to various severe diseases such as thromboembolism, mental retardation, hepatic steatosis, osteoporosis, lens dislocation, skeletal abnormality, and anemia. We utilize genetically modified mice to reveal regulatory mechanisms leading to the onset of such diseases, and aim to contribute for the treatment/prevention of those diseases.
Physics for Life Functions
Our research objectives are: (1) to reveal structural mechanisms of proteins critical for life functions at atomic level, (2) to establish novel strategies for drug developments based on the mechanisms, and (3) to create compounds to regulate the life functions. Proteins playing important roles physiological processes are analyzed at an atomic resolution by nuclear magnetic resonance (NMR) spectroscopy and X-ray crystallography.
The major focus of this laboratory is a disease-oriented basic neuroscience research. Although recent progress in the neuroscience field begins to shed light on complicated interactions between genetic and epi-genetic (environmental) control in the nervous system, fundamental brain functions such as learning/memory, attention, sleep, movement control are largely still enigmatic. Neurodegenerative diseases are adult-onset and slowly progressive disorders affecting the central and peripheral nervous system. One of the major causes of the diseases is known to be aging. With the growth of elderly population, risks of suffering from these diseases are rapidly increasing and making them heavy social burden.
The main goals of our research are to elucidate physiological and pathological roles of cholinergic neurons in neurologic/psychiatric diseases such as Alzheimer's, Parkinson's, amyotrophic lateral sclerosis (ALS) and schizophrenia, and ultimately develop better pharmacological interventions to these devastating conditions.
We are looking forward to working with motivated students who have high interest in basic research for uncovering hidden mysteries of brain functions and their disorders.
Physiological Chemistry and Metabolism
Recent advance in molecular biology of cancer has provided the rationale for the control of cancer. Our research is focused on molecular target therapy of cancer, anticancer drug resistance, gene therapy and regenerative medicine. Particularly, we have been studying functional interactions between the ABC transporter proteins, molecular-target drugs and genetic polymorphisms to contribute to the understanding of the molecular basis of the pharmacokinetics of currently used anticancer drugs and to provide valuable information to optimize the effectiveness of novel chemotherapeutics. We are also investigating molecular basis of cancer malignancy to identify novel molecular targets for anticancer agents. Collaborative studies between our laboratory and major pharmaceutical companies are ongoing for the development of new anticancer agents. All laboratory members actively conduct the forefront research of cancer treatment.
Pharmaceutical Physical Chemistry
Physicochemical property of biological and bioactive molecules has great influences on their pharmacodynamic and pharmacokinetic behaviors, and vice-versa, biological behavior of a molecule can be controlled by modification of its physicochemical properties.
The objective of our laboratory is to explore new functional materials which can be applicable in pharmaceuticals area. We design and synthesize functional polymers, and apply them to bio-separations, drug delivery, and as molecular probes of cellular imaging.
Our current research subjects are;
- Temperature-responsive Chromatography; We developed a novel chromatographic system consisting of temperature-responsive polymers. Advantages of the system are, to separate solutes without using organic solvents, avoidance of loss of bio-activity in separation process, environmental protection, and cost saving, especially of reagents for mobile-phase.
- Drug delivery system utilizing functional polymer We are developing a drug delivery system made of functional nanoparticles. We expect that the system may control the release and affinity to cells of bioactive molecules. Synthetic chemical molecules, peptides and genes are our targeted bioactive molecules.
- Environmentally sensitive fluorescent molecular probe for cellular imaging A dual temperature- and pH-responsive fluorescent probe is being designed using a functional polymer. The reversibly control of fluorescence intensity with external stimuli may lead to new molecular diagnostics, tools for lab assays, biosensor and bio-imaging.
- Studies on Physiological Functions of Natural Radical Scavengers such as Tocopherols and Polyphenols. We have developed analytical methods for measuring antioxidants and their oxidative products, and also oxidative damage that might be indicative of specific alterations in brain redox chemistry
uptaken by cells
Pharmaceutics is a discipline to pursue the optimal delivery of drug substance to target site of patient's body through the best scientific knowledge and technology, so that patients are released from diseases and disorders. The ultimate goal of our research is "Individualized Pharmaceutical Care".
For realizing such an object, two projects are currently carried out ;
- Molecular mechanisms of drug transport across the blood-placental barrier
The transport process across the blood-placental barrier is a key determinant of fetal drug disposition. The elucidation of placental transport mechanism will provide molecular basis for the individual optimization of drug administration to expectant mothers in more-successful and strategic manner. The blood-placental barrier is formed by syncytiotrophoblasts. Conditionally immortalized syncytiotrophoblast cell lines, TR-TBTs were established in our laboratory. We have elucidated mechanisms of placental transport of several drugs, such as zidovudine and didanosine. These nucleoside analog reverse transcriptase inhibitors (NRTIs) are used for preventing the transmission of HIV from infected pregnant mothers to their fetuses.
- Development of various tools for best utilization of drug information, especially, those of OTC therapy. We have developed a manual and an e-learning system of OTC (Over-the-Counter) medicines. These products are now available to public and are used at community pharmacies for guidance to patients.
Students to be welcomed are those who have interest in pharmaceutics and its clinical application. During the stay at our laboratory, students will acquire a vast knowledge of pharmaceutics and its meaningfulness for better clinical drug use. Through collaboration with other research units, students will have the opportunity to brush up their skills of international communication.
Clinical Physiology and Therapeutics
Our laboratory is aiming at conquest of therapy-resistant cancer by means of translational research. For example, multiple myeloma which is a incurable and fatal hematological malignancy despite of application of stem cell transplantation or novel therapy including thalidomide, its derivatives and bortezomib, a dipeptide boronic acid analogue showing inhibition of 26S proteasome. Thus, we are challenging to develop more effective and much safer pharmacotherapy than current ones to overcome refractory cases by designing new drugs under elaboration of our original biological techniques and by conducting clinical trials. We also are trying to identify the targeting molecule of those novel drugs by unique molecular cloning system. Glycobiology, is another important theme in our laboratory. For example, M-proteins produced by myeloma cells revealed a different glycosylation pattern from normal immunoglobulin. It is expected that glycosylation of M-protein will be a novel biomarker for this disease indicating disease control. Future direction is to accumulate preclinical data for conducting clinical trial of the drugs. To accomplish these project, we are conducting a collaborative research with departments of Faculty of Science & Technology and School of Medicine, Keio University, and also some other Universities and academic institutions outside of Keio University. We are also trying to develop the effective immunotherapy using peptides derived from tumor antigens. We are now investigating immunogenesity of novel tumor antigens, which we have identified from leukemia cells and melanoma cells. Our goal is to apply these antigens to peptide vaccination for cancer patients.
Our research targets are mainly on metabolic diseases necessary for keeping our homeostasis, especially on the diseases of gastroenterology, liver, muscle, adipose tissues and also cancers. Recently, we focus on epigenetics and microRNAs in the understanding of mechanism in these diseases. Our goal is to develop new therapeutic strategies for these diseases and we always think about the bench-to-bed utility. Our laboratory is always open to everyone who has a high motivation to create a new concept of pharmacotherapeutics. If you have interested in our department, why not join us?
The educational target of our laboratory is to turn out researchers and pharmacists who have wide range of pharmaceutical view and knowledge, and is able to solve various clinical problems in pharmaceutical care. We consider that a good practitioner should be able to systematically organize a wide range of pharmaceutical knowledge and such ability can be acquired during pharmaceutical research.
Therefore, our research field is clinical pharmacy based on a variety of fields such as pharmacokinetics, pharmacodynamics, cell biology, information technology, and others. Especially, we aim to solve clinical problems, as mentioned below, for marketed drugs to create pharmaceutical evidences for proper and effective use of medicines.
- Study on drug metabolism and drug interactions to promote personalized pharmacotherapy.
- Quantitative prediction and IVIVE (in vitro-to-in vivo extrapolation) of drug interactions in drug absorption process.
- In vivo PK/PD study for dosage optimization to reduce adverse reactions.
- Optimization of pharmacotherapy by using the information technology and pharmacometrics
Drug information based on sciences and reliable clinical evidences is required for proper use of drugs. On the other hands, there is a tendency of "information overflow", even on a single drug, in different style, quality and quantity.
The objective of our laboratory is to explore the mean and way for rational and proper use of drug information so that medical professionals can give patients evidence-based, safe, and effective drug therapy. The areas of our research covered are information retrieval, critical appraisal, effective provision, and the application of information, etc.
Following research projects are currently ongoing;
- Methodology for the proper and effective provision of OTC drug information,
- Systematic reviews and network meta-analysis of pharmacotherapy and dietary supplements,
- Pharmacoecomics study, e.g., cost-effective analysis of switch OTCs and lifestyle-related diseases, comsumer's perception on payment, etc.
- Pharmacoepidemiology study, e.g., development of a reporting system of spontaneous adverse events by patients and consumers
- Pharmacogenetics/genomics of methotrexate and warfarin, etc.
Students joining to our research group are expected to acquire the research oriented way of thinking and proper insight on quality information of drugs. We expect that students will be able to play an active role in clinical fields, the pharmaceutical industry, and the government and the related organization after graduation.
Students to be welcomed are, such as, those with interest in proper and effective usage of drugs in clinical phase.
"Establishment of New Pharmacotherapy Options Based on Drug Efficacy Evaluation and Adverse Event Analysis"
The Division of Pharmacodynamics conducts research, aiming to establish new pharmacotherapy options by evaluating drug efficacy or the therapeutic and adverse effects of drugs.
To maximize their effectiveness while avoiding related adverse events as much as possible, the division analyses influencing factors, and clarifies optimal drug options and administration methods for each patient.
It also establishes new treatment methods by identifying new drug activities and developing new dosage forms. Furthermore, with a view to obtaining evidence that is useful for medical services, it identifies issues to be addressed (such as drug-drug interactions), and expands clinical and basic research.
The division aims to nurture clinical pharmacists to truly contribute to medical services and researchers with the ability to develop drugs needed in such services through research activities.
Figure. Voriconazole (VRCZ) trough concentration and logistic regression model for hepatotoxicity.
The estimated probability of hepatotoxicity at VRCZ trough concentrations of 2mg/L and 4mg/L was 1.6% and 21.6%, respectively
Figure. Relationships for Acinetobacter baumannii ATCC 19606 between the log10CFU/thigh at 24 h and the pharmacokinetic/pharmacodynamic indices.
Sulbactam showed time-dependent bactericidal activity, and was sufficiently bactericidal when an fT>MIC of >60% against A. baumannii thigh infection was achieved.
Drug Development and Regulatory Science
Every pharmaceutical product is subject to be registered and regulated under appropriate legislation because of its possible serious effects on human lives.
Then, question becomes what kind of data is required, why and when. How to collect such data and how to adequately evaluate are also essential factors to be clarified before starting of drug development process or, even whole life span of a drug.
Establishment of adequate and safe use of the drug in our real world is also crucial point to meet the expectation of patients and medical professions.
All the above issues consist of regulatory sciences and this laboratory is concentrating in clarifying and responding on these questions in accordance with scientific approach and international manner.
Our goal is not easy to be met particularly in the days of such a rapid progress in the human life science can be seen but therefore it is absolutely needed for regulatory sciences to catch up with it.
Students here will be exposed and gain such sciences through study and learning.
Education Research Center for Pharmaceutical Sciences
The responsibility of our group is to give undergraduate students the training of fundamental chemistry or biology for pharmaceuticals and pharmacy, such as analytical chemistry, pharmacology, biochemistry, hygiene chemistry and organic chemistry, so that students in Faculty of Pharmacy can have the ability to comprehend the modern and progressing life sciences. We are also responsible for managing the introductory and fundamental laboratory training at our Faculty of Pharmacy. We develop the program for laboratory experiment and execute it for undergraduate students during their second and third year.
In parallel, our group is active in conducting research within the above premise. Our current research subjects are;
- analysis of reactive oxygen species
- explore novel diagnostic and therapeutic approach for intractable neuronal diseases, cardiovascular diseases and inflammation
- discover novel substances for therapeutic use for these diseases/disorders
- regulation of drug metabolizing enzymes
- Application of effective e-learning in pharmacy education
- development of effective interprofessional education for pharmaceutical students in Japan
- biochemical analysis of pathogenic mechanism in allergic inflammation
Center for Social Pharmacy and Pharmaceutical Care Sciences
Director: NAKAMURA Tomonori
Division of Pharmaceutical Care Sciences
Division of Social Pharmacy
In 2001, Center for Pharmacy Practice was established with the purpose of excellence in medical pharmacy education and nurturing pharmacists who can contribute to the medical front. The early exposure program in a hospital and a community pharmacy run shortly after admission, the four-week practical training in a hospital and the two-week in a pharmacy were made compulsory ahead of other universities. These practical programs have made contribution to improving the motivation pharmacy students should have and keeping it up. The center also plays a central role in the "6-year education program in pharmacy" launched in 2006 with cooperating with many other medical facilities. In addition to enriching the early on-site training, the early pharmacy practical training in the second year focusing on dispensing, the lectures preparing for following practical training in the fourth year, and hands-on clinical session at full scale of hospitals and pharmacies for 11 weeks each are smoothly offered in Center for Pharmacy Practice.
Basic Education in Arts and Sciences
Our group is responsible for a general education curriculum necessary for professionals in human sciences and pharmaceuticals. Each professor covers the disciplinary area which he himself majors in. Students have chances to take the training either by attending a course or joint academic work with each professor.
Each professor is in charge of the following academic activities;
- One of my cultural activities is writing critical essays and reviews for several theater magazines and newspapers. In recent years, I am concerned with
interprofessional education (IPE) and participated in establishing the Japan Association for Interprofessional Education. (Y. E.) ;
- I am most interested in immigration and its history and literature, especially in Japanese-Americans. Field work is also contained in my activities. I have published six translations in the past three years. 1. Shigeo Shimada, A Stone Cried Out, 2. James Walvin, The Trader, The Owner, and The Slave, 3. Gordon S. Wood, The Americanization of Benjamin Franklin, 4. Emmy E. Werner, A Conspiracy of Decency-Danish Jews during WWII, 5. Joan Didion, The Year of Magical Thinking, 6. Joan Didion, Blue Nights
- I am a physicist, and I have devised physical and mathematical model of radioactive decay, and of chemical kinetics and pharmacokinetics; for example, hypothetical and actual hydrodynamic models about the kinetics. (S. S.).
- I study about the ergodicity of some measure preserving transformations.
I studied the ergodicities of "piecewise rotations", "interval exchanges" and "zippered rectangles", and try to clarify these relations now.
Laboratory for Radiopharmaceutical Chemistry
Development of methods for determining the environmental radionuclides, and study evaluating the effect of environmental radiation on the human body.
In the environment, not only natural radionuclides such as radon, but also trace amounts of radionuclides resulting from nuclear testing in the past are present. On the other hand, radiation has been used in medical treatment. Furthermore, small amount of radiation is emitted from some product containing minerals.
To date, we have developed accurate methods for measuring radon and applied successfully to the determination of the radon activity in natural water and indoor air, and presented the resultant distribution of radon in natural water and indoor air. Further work to establish the suitable system for measuring the radionuclide in the outdoors is in progress. Based on the modified measuring system, we measure the radionuclide in various kinds of food and products, and estimate the absorbed dose due to the environmental radionuclide, and the effect of environmental radiation on the human body.
Hospital Pharmacy Science
Hospital Pharmacy Science is close to clinical work.
Faculty members of our lab are active pharmacists holding the posts and duties of the hospital pharmacy. Keio University hospital and the department of pharmacy are the main fields of our activities.
Our mission is to train future leaders of pharmacists.
We aim at the training of future leaders of pharmacists who can play an active part in the healthcare setting. The future leaders of pharmacists need to have research abilities to produce evidence by oneself as well as advanced clinical skills. We nurture these abilities through research activities. The experience in clinical work and clinical research at Keio University Hospitals is useful not only for hospitals and pharmacies but also for pharmaceutical companies.
The clinical sites are full of the research theme.
In order to improve a pharmacotherapy and offer more effective and safer medical care to the patient, we develop the clinical studies that cooperated with the hospital pharmacy and clinical departments.The findings of research provided by pharmacoepidemiology and clinical pharmacology are returned to patients.
Our research themes are ...
- To build the evidence of pharmacist's work. ・ The impact of the patient compliance instruction by a pharmacist to the therapeutic effect. ・ Establishment of the countermeasure against an exposition of anticancer agent at the time of preparation and administration.
- Pharmacoepidemiology. ・ Epidemiological study on the cost effectiveness of expensive drugs. ・ Benefit risk evaluation by using data bases
- Individualization of pharmacotherapy. ・ Analysis of risk factors of adverse drug reactions using electronic medical recods. ・ Factorial analysis of the individual difference about the clinical response of antirheumatic agents.
Research Center for Drug Discovery