Among my recent work on the syntheses of complex natural products based on the development of a novel synthetic method for the heteroaromatic skeleton, this article primarily deals with the total syntheses of (+)-CC-1065, isobatzeline A/B, and batzeline A. These syntheses were accomplished via a novel indole synthesis utilizing a ring expansion reaction of benzocyclobutenone oxime sulfonate as the key step. The 1,2-dihydro-3H-pyrrolo[3,2-e]indole segments of (+)-CC-1065 were rapidly constructed via a two-directional double-ring expansion strategy. Highly substituted pyrrolidine-fused common 5-chloro-2-methylthioindoles of isobatzeline A/B and batzeline A were constructed using a ring expansion reaction of benzocyclobutenone oxime sulfonate with NaSMe and a benzyne-mediated cyclization/functionalization reaction.
I have been active as a professional basketball player at Hiroshima Dragonflies, which belongs to B.LEAGUE until 2018. At the beginning of my professional career, I started by balancing a pharmaceutical student and a professional life. I also obtained a pharmacist license during the B. LEAGUE season and was certified as a sports pharmacist to be involved in the team's anti-doping efforts. From my own experience of being subject to doping tests, I strongly felt that “athletes also need the cooperation of pharmacists”, and many people recognized the need. I have a strong desire to change the status quo. Nowadays, young athletes are also connected to the Internet, and it has become easier to learn about efficient training methods, supplements and medicines. Furthermore, from marketing activities centered on advertising by companies, communication between consumers such as word-of-mouth influences decision-making. Under these circumstances, it is important to understand how athletes make decisions, engage in consultation services, and actively work with pharmacists. Athletes consult with us about “whether or not they can take supplements and medicines” is one of the athletes' wants (means). I think it is important to understand the needs (purposes) behind it. We do not think that it is our job to decide whether or not to take supplements and medicines, but we want to be a person who can be close to athletes. By understanding the hidden needs, various approaches become possible.
With the hosting of the Tokyo Olympics, interest in anti-doping (AD) has increased, and at the same time, sports pharmacists (SPs) are expected to play active roles. However, despite the fact that it has been more than 10 years since the SP certification system was launched, the existence and roles of SPs are not well recognized by sports officials, and many SPs feel that there is no place or way for them to contribute. In my case, as a staff member of the federation, I have supported competitions as a referee and secretariat, so I have had opportunities to conduct AD activities such as seminars for athletes and coaches, and to respond to inquiries. Also, in my work as a hospital pharmacist, I have had opportunities to respond to informal inquiries about AD measures from hospital staff. In both cases, I think it was very important to first make people aware of the existence of SPs.The current problem is that it is sometimes difficult for the federation's staff to respond promptly, which puts a burden on their normal work. Therefore, it is important to have pharmacists who are close to the athletes and can provide health consultations on a daily basis in order to share correct information, educate them about AD measures, and help manage their health.
Anti-doping (AD) education for athletes is mainly one-way and through passively attended lectures. As such, learning about prohibited substances and highly technical doping rules is often difficult for athletes. Therefore, having athletes passively attending lectures is not enough to prevent unintentional doping violations caused by medicines and supplements. Therefore, it is important for athletes to acquire knowledge about individual prohibited substances as well as active learning and practical knowledge about AD measures. “Doping Guardian” is an educational card game that has been developed to help prevent unintentional doping violations. Participants (pharmacists) of this game can learn how to use medicines and supplements from an AD perspective while simulating the life of an athlete. This presentation will provide an overview of this card game and how it has been used to date.
In this study, we conducted a survey and interviews of young athletes to clarify the actual conditions of medication use and nutritional management (supplement use, etc.) with the aim of enhancing their health support. In addition, a second questionnaire was conducted for pharmacists working at medical institutions to clarify the actual situation of anti-doping (AD) activities by pharmacists, and examined the issues they face to support the health of athletes in the future. The results of the athletes' surveys revealed that the roles of pharmacists in AD activities was not recognized by athletes. In particular, the dissemination of AD education by pharmacists is considered to be critical. In future AD education, it will be necessary not only to provide knowledge of prohibited drugs, but also to provide self-medication support tailored to the individual needs of athletes, such as knowledge of nutrition and health. The results of the pharmacist survey revealed that athletes are treated by pharmacists on a daily basis, but for pharmacists, there are difficulties regarding how to provide information on AD, and it is necessary to enhance AD education at schools of pharmacy as well as in lifelong education seminars. Considering the pharmacists' AD activities as part of health support for athletes, it is considered more effective to collaborate with other health professionals such as sports doctors or nutritionists because it requires a wide range of knowledge such as nutrition.
Almost all conventional drug discovery research has been based on hydrocarbon-based frameworks and common chemical elements such as nitrogen, oxygen, sulfur, and the halogens. However, triggered by the approval of bortezomib, a boronic acid-containing pharmaceutical agent, the incorporation of functionalities that are not native in biological systems has been intensively investigated. Several other boron-containing pharmaceuticals have also been marketed. Therefore, the inclusion of various elements is one of the most promising strategies for the development of novel and distinctive drug candidates. In this symposium review, the author focused on the ‘elements chemistry’ approaches for the structural development of biologically active compounds, particularly those involving silicon and phosphorus. The isosteric exchange of Si and C (Si/C-exchange) is one of the most-investigated forms of substituting elements. We revealed the detailed physicochemical impact of Si/C-exchange, and we proposed several applications of silyl functionalities other than the simple Si/C-exchange. Regarding phosphorus, we recently revealed that the P-B substructure can function as the isostere of C-C or Si-C substructures. In addition to these isosteric exchanges, the development of biologically active compounds bearing unique substructures such as carboranes, hydrophobic boron clusters, and ferrocene is introduced. These novel strategies provide several options for structural development, offering great potential for expanding the chemical space of medicinal chemistry.
Deuterium (2H, D) is a stable isotope of hydrogen (1H). Deuterium-incorporated (labelled) compounds are widely utilized in various scientific fields such as mechanistic studies of organic reactions, elucidation of drug metabolism, application as tracers for microanalysis. Recently, development of heavy drugs and molecular imaging using techniques such as neutron scattering and Raman spectroscopy are spotlighted. We have developed various deuterium-incorporated compounds using D2O as an inexpensive deuterium source to construct novel functional materials. The use of platinum group metals on carbon as catalysts could result in the multi-deuteration of compounds in the mixed solvents of 2-propanol and D2O, and site-selectively deuterated compounds can be synthesized by organocatalytic methods. In this review, the latter deuteration methods using organocatalysts and their applications are summarized. Terminal alkynes smoothly underwent deuterium incorporation by using triethylamine as an organic base or a solid resin possessing the tertiary amine moiety in the same molecule to give mono-deuterated alkynes. These compounds were partially reduced over our prepared specific palladium catalyst under atmospheric D2 gas to produce tri-deuterated alkenes. Achiral or chiral di-deuterated β-nitro alcohols were also prepared by the organic-base-catalyzed deuteration of nitromethane, followed by nitroaldol reactions in a one pot manner. The mono-deuteration of aromatic aldehyde could be effectively catalyzed by N-heterocyclic carbene. Furthermore, the α-deuteration of aliphatic aldehydes using a basic resin catalyst and the subsequent Knoevenagel condensation with malononitrile could provide γ-deuterium-incorporated α,β-unsaturated nitrile derivatives. The deuterated compounds thus obtained can be important synthetic precursors to construct the deuterium-incorporated target functional materials.
The first medicine containing the boron element, bortezomib, was approved for clinical use just 18 years ago. The boronic acid substructure in bortezomib serves as an electrophilic functionality with high affinity for hydroxy groups, which are frequently found in catalytic sites of proteolytic enzymes, to create reversible covalent bonds with a slow dissociation rate. Today, boronic acid is considered an important molecule in the medicinal chemistry toolbox, which was promoted by the success of bortezomib and pioneering approaches to use boronic acid in the molecular design of serine protease inhibitors in the 1980s. In this review article, we first provide an overview of the development of bortezomib, and then summarize our achievements to construct boronic acid analogs of tyropeptin A, a naturally occurring proteasome inhibitor, with potent in vivo efficacy. Representative stereoselective synthetic methods of α-aminoboronic acid are also showcased.
Boron neutron capture therapy (BNCT) is a type of radiation therapy and a new modality for cancer treatment. The radiation used in BNCT is a very low energy neutron called a “thermal neutron”, and unlike other radiation, it has no effect on treating cancer on its own. However, when this neutron collides with boron-10 (10B), which is a stable isotope of boron, fission occurs into a high-energy helium nucleus (α-particle) and a lithium nucleus. Moreover, the effect of this fission reaction is limited to a range of about 10 μm, which corresponds to the approximate size of one cell. Therefore, the basic principle of BNCT is “cell-selective” radiation therapy that only damages cells that have taken up 10B present in the area irradiated with thermal neutrons. For the practical application of BNCT, it is indispensable to generate a boron drug capable of selectively accumulating 10B in cancer cells. We have successfully developed a boron drug for BNCT targeting amino acid transporters. We have obtained manufacturing and marketing approval for the world's first boron drug for BNCT, Steboronine® intravenous drip bag 9000 mg/300 mL (March 25, 2020), for indications of locally unresectable recurrent or advanced unresectable head and neck cancer. This uses Borofalan (10B), which is 10B introduced into l-phenylalanine, as a drug substance. This review describes the progress of drug development and future prospects of boron drugs for BNCT.
Fullerene (C60) and fullerene derivatives are attractive novel compounds not only for carbon materials of nanotechnology but also for medical fields because of its unique chemical and physical properties. We intend to develop fullerene derivatives as novel lead compounds for drug discovery. At first, we synthesized many types of water-soluble fullerene derivatives to investigate their biological activities because of their poor solubility in water. We found that anionic fullerene derivatives possess anti-oxidant activities, whereas di-cationic fullerene derivatives exhibited antiproliferative activities against various cancer cell lines including drug-resistant cells. Proline-type fullerene derivatives showed inhibitory activities against human immunodeficiency virus (HIV) reverse transcriptase, HIV protease, hepatitis C virus (HCV) NS5B RNA polymerase, and HCV NS3/4A protease. These activities may strongly inhibit virus replication via a synergistic effect and fullerene derivatives may be used as novel multi-target drugs for the treatment of AIDS and hepatitis C in the future.
The author has an interest in unique chemical and physical properties of fullerene (C60) and fullerene derivatives, and has studied bio-active fullerene derivatives to develop novel lead compounds for drug discovery. He showed that anionic fullerene derivatives possess anti-oxidant activities, di-cationic fullerene derivatives exhibited antiproliferative activities against various cancer cell lines including drug-resistant cells, and proline-type fullerene derivatives showed anti-virus activities. The process of the studies is also written in this report.
Providing medication information according to a patient's health literacy and communication ability is needed for safe and effective healthcare. Communication barriers due to hearing loss prevent pharmacists from providing medication information to patients with hearing loss. A questionnaire about the difficulty in understanding medication information and the feeling of inconvenience during medication education was conducted from September to October 2020 with 84 people with prelingual hearing loss and 346 pharmacists. The 84 hearing loss participants were divided into low- and high-scoring groups based on their understanding of medication use. Pharmacists did not realize that low-scoring group participants did not understand items with homonyms, abstract expressions about medication use and medical terminology. Pharmacists were also unaware that the low-scoring group felt the inconvenience in medication education because of the difficulty to communicate, inform not understanding medication information and consult about medication use with a pharmacist. Prior learning about hearing loss led to higher responses in recognition of the aforementioned issues. However, even pharmacists with prior experience of learning did not fully recognize that speaking out loud is not useful for effective communication and that hearing loss patients need contact methods other than the phone. This indicates the need to learn about hearing loss to improve provision of medication information and effective communication in medication education to people with hearing loss.
We report a rare case of suppurative thrombophlebitis of the posterior neck caused by Streptococcus constellatus. A 69-year-old female patient was admitted to the hospital with neck pain and fever, which had persisted for 16 days prior to hospitalization. On day 1 (day of admission), blood cultures (later identifying S. constellatus) were performed, and ceftriaxone (CTRX) IV (2 g SID) was started. On day 3, suppurative thrombophlebitis of the posterior neck was diagnosed by CT scan. The antimicrobials were changed from CTRX to ampicillin/sulbactam IV (12 g QID) to guard against the possibility of complicated infection with Fusobacterium spp. or Prevotella spp. On day 17, a CT scan revealed that the thrombus remained. Therefore, oral edoxaban (30 mg SID) was started. On day 27, the patient was discharged after her medication was changed to oral amoxicillin/clavulanate (1500 mg/375 mg TID). On day 33, the amoxicillin/clavulanate was changed to oral cefaclor (1500 mg TID) and edoxaban was discontinued due to itching. On day 45, the course of cefaclor was completed. The patient went on to follow an uneventful course with no relapses or complications for two years since the conclusion of treatment. These results suggest that when a patient presents with persistent neck pain accompanied by fever, suppurative thrombophlebitis of the posterior neck should be considered. In antimicrobial therapy, the treatment could be switched from intravenous to oral. In addition, direct-acting oral anticoagulants may be an alternative to other forms of anticoagulants.