Heterocycl. Commun. 2015; 21(5): 245–248

Guest Editorial Dedication to Kyoichi A. Watanabe

DOI 10.1515/hc-2015-0206 synthesize a 2-fluoro-2-deoxy-D-arabinose derivative from D-glucose [9]. This issue of Heterocyclic Communications is dedicated The above arabinose was key in synthesis of F-­ara- to Kyoichi A. ‘Kyo’ Watanabe (1935–2015), formerly of the nucleosides that have anti-viral activity [10–13], anti-cancer Memorial Sloan Kettering Cancer Center (MSKCC), Codon activity [14–16] and are commercially available today. Impor- Pharmaceuticals and Pharmasset, Inc. Kyo earned his PhD tant examples of these nucleosides include 1-(2′-deoxy-2′- in the Mizuno lab at Hokkaido University. He was a member fluoro-1-β-D-arabinofuranosyl)-5-methyluracil (FMAU) and of the American Chemical Society, the Polish Academy 1-(2-deoxy-2-fluoro-1-β-D-arabinofuranosyl)-5-iodouracil of Sciences and a founding member of the International (FIAU, fialuridine). FMAU advanced to clinical trials for Society of Nucleosides, Nucleotides and Nucleic Acids cancer [17] and a radiolabeled FMAU has been used as an (IS3NA). As the head of the Organic Chemistry Laboratory imaging agent [18]. FIAU reached clinical trials for hepatitis at MSKCC and Vice President for Research and Develop- B but was withdrawn due to safety concerns [19]. However, ment at Pharmasset he was an eminent organic chemist the most notable example is probably 2′-F-ara-C. Radiola- who trained and influenced the careers of numerous sci- beled versions are used in positron emission tomography entists. Kyo’s impact has been recognized in five interna- imaging and for in vivo prediction of clinical response to tional awards, the most notable and recent being the Marie gemcitabine [20]. Skłodowska-Curie medal (1993), the František Šorm medal (2003), and a Lifetime Achievement award from the IS3NA (2015). Obituaries were published by the IS3NA (http:// www.is3na.org/IS3NA_News_Details.asp?id=54) and The Atlanta Journal-Constitution, April 12, 2015. Kyo’s academic career began at Hokkaido Univer- sity in Japan where he earned his MS (1960). He then completed his PhD thesis in the Mizuno lab at Hokkaido in 3 years. From there Kyo joined Jack Fox’s group at While at Pharmasset, Kyo’s contribution to therapeu- MSKCC, left briefly for a fellowship in the Lemieux labo- tic nucleosides continued. Under his direction the potent ratory at the University of Alberta [1–3], and returned to anti-hepatitis C agent PSI-6130 [21, 22] was discovered [23]. Sloan-Kettering where he steadily advanced to become Study of the pharmacokinetics of this drug led to discov- the head of the MSKCC laboratory of organic chemistry. ery and successful clinical development of sofosbuvir by While at Sloan-Kettering, Kyo held a professorship at Pharmasset and Gilead. Sofosbuvir is a key component of Cornell University until his retirement from academia the cornerstone HCV drug combination harvoni and has in 1996. After leaving MSKCC, Kyo joined Codon Phar- been marketed as monotherapy (sovaldi) for HCV [24, 25]. maceuticals as the Director of Chemistry. He joined With around 300 publications the above are just a Pharmasset in 1998 where he was the Vice President few salient examples of Kyo’s work that have significant for Research and Development until he retired in 2003. impact. When asked about his career, Kyo would usually Throughout his career Kyo was strongly influenced by say that he was just ‘wandering through the wilderness pioneers in chemistry such as Liebig, Miescher, and of chemistry hoping to find something interesting and Fischer [4]. The elucidation of the structures of the A- useful’. I am certain this attitude was heavily influenced and B-form DNA helixes by Watson and Crick also had a by his experience during WWII. When Kyo was 8 years profound influence [4]. old, publications of Karl Marx were found in the office Kyo was best known for synthesis of novel nucleo- of his father, economist Yojiro Watanabe. As punish- sides, antivirals, anti-cancer agents, total synthesis of ment the entire Watanabe family was exiled from Japan natural products, and carbohydrate ring transformations. to Chilin, Manchuria. In 1946, after 3 years, the survivors He was the first to synthesize the natural products goug- returned to Japan. The journey home was a 400-mile erotin and the blasticidins [5–8]. He was also the first to ordeal covered entirely on foot from Chilin to the coast 246 Guest Editorial of China near Port Arthur. It was a brutal experience that This issue also includes three contributions from took more than 5 months and claimed the lives of many researchers at the Engelhardt Institute for Molecular (no child under 5 years old survived). That experience Biology (EIMB), The Russian Academy of Science. These seemed to give Kyo an endurance and perseverance that include a communication from Anastasia Khandazhin- was second to none. skaya, and research articles from the labs of Marina The best example of Kyo’s perseverance is his first Kukhanova and Liudmila Alexandrova. Kyo had a long marathon in 1992. He had new shoes that fit poorly. After association with the EIMB; he visited often and consid- several miles the shoes hurt his feet so, rather than quit- ered Marina, Liudmila and Anastasia among his best ting, he removed his shoes and finished barefoot! Consist- friends. Their bond was surely strengthened by their ent with his first experience, Kyo finished every marathon shared interest and considerable expertise in nucleosides he started. and nucleotides. Kyo also possessed a gentle spirit and preferred to Ibrahim Abdou of United Arab Emirates Univer- lead by example. In the lab he was always approach- sity presents a paper describing the synthesis and anti-­ able and when asked a question he would usually reply, proliferative activity (HL-60) of pyridine O-galactosides ‘I don’t know,’ followed with, ‘Wait a moment!’ He would and related 2-(4′-fluorobenzyl)pyridine derivatives. then search his large collection of literature, and pull out Barbara Nawrot was a postdoctoral associate with a paper that would help answer the question. More often Kyo at MSKCC (1985–1986) where she made contributions than not he or someone he trained would be the corre- to the synthesis of C-nucleosides and fluorinated nucleo- sponding author of that paper. Additionally, good rela- sides, notably FMAU [30–32]. She is now Professor and tionships among his co-workers were always important to Head of the Department of Bioorganic Chemistry, Centre Kyo. He was the consummate peacemaker and when dis­ of Molecular and Macromolecular Studies of the Polish agreements arose he would invite those involved to have a Academy of Sciences. She is corresponding author of a drink or two and solve the matter. paper describing preparation of nucleobase functional- Those of us who knew Kyo will remember him for all ized tris-(hydroxymethyl)phosphine oxide derivatives. the above and perhaps most of all his sense of humor. I This paper is co-authorized by Professor Wojciech Stec spoke with him 2 days before his passing and he was still who, before his recent retirement, was her boss at this able to make me laugh. After telling a couple jokes he said institution. Professor Stec was Visiting Professor with Kyo. he only had a small problem and if he could overcome Raymond Schinazi also had a long relationship with the problem he would be ‘fine’. I find it inspiring that he Kyo that dates back at least to the 1980s with their col- fought until the end and ironic that his life would be cut laborative work in discovery of antiviral agents [12]. When short by cancer, a disease he fought so hard to combat. Kyo joined Pharmasset he and Ray formed an even closer This dedication issue contains 11 publications authored working and personal relationship that lasted until Kyo’s by his friends. death. Ray is the Frances Winship Walters Professor of Krzysztof ‘Kris’ Pankiewicz, who had a relation- Pediatrics and Director of the Laboratory of Biochemical ship with Kyo for about 30 years, has submitted a review Pharmacology at Emory University. He serves as Senior describing inhibitors of the enzyme inosine monophos- Research Career Scientist at the Atlanta Department of phate dehydrogenase (IMPDH). Kris’ association with Veterans Affairs and Director of the Scientific Working Kyo began at MSKCC in the 1980s and their close working Group on Viral Eradication within the NIH-sponsored relationship continued even after Kris established his own Emory University Center for AIDS Research (CFAR). He is program at MSKCC. With around 70 publications together, probably best known for contributions to discovery and Kris was surely Kyo’s right hand man until Kyo’s retire- development of nucleoside anti-virals, for example: d4T ment. Currently Kris is a Professor at The Center for Drug (stavudine) [33], 3TC (lamivudine) [34, 35], FTC (emtriva) Design, The University of Minnesota. During his produc- [36, 37], RCV (racivir) [38] and DAPD (amdoxovir) [39], tive career Kris has made key contributions to fluorinated drugs that are approved or in clinical development. Ray nucleoside synthesis, anti-cancer agents and the anti-HCV and co-workers have submitted a paper describing synthe- agent PSI-6130 that has entered clinical trials in prodrug sis of novel 2′,3′-dideoxy-2′,3′-difluoro-D-arabino nucleo- form [21, 22, 26–32]. sides and their HIV and HCV activities. No issue dedicated Przemysław Szafrański of Jagiellonian University in to Kyo Watanabe could be complete without inclusion of Kraków, Poland is corresponding author of a communica- such a work on fluorinated nucleosides. tion focused on synthesis and spectral characterization of Snehal Chavan and colleagues have submitted a paper a fluorescent triazole AZT analogue. describing synthesis of some structurally interesting Guest Editorial 247

N-glucosylated dithiadiazepines. The key step in synthe- [11] Watanabe, K. A.; Su, T. L.; Klein, R. S.; Chu, C. K.; Matsuda, A.; sis of the title compounds is reaction of N-tetra-O-acetyl- Chun, M. W.; Lopez, C.; Fox, J. J. Nucleosides. 123. Synthesis of antiviral nucleosides: 5-substituted 1-(2-deoxy-2-halog- β-D-glucopyranosyl isocyanodichloride with a series of eno-beta-D-arabinofuranosyl)cytosines and -uracils. Some dithio-bis-ureas. structure activity relationaships. J. Med. Chem. 1983, 26, Grażyna Chłoń-Rzepa and colleagues at the Jagel- 152–156. lonian University describe a series of purine substituted [12] Perlman, M. E.; Watanabe, K. A.; Schinazi, R. F.; Fox, J. J. butanehydrazides and acetohydrazides that possess anal- ­Nucleosides. 133. Synthesis of 5-alkenyl-1-(2-deoxy- gesic and anti-inflammatory properties. Four of the above 2-fluoro-beta-D-arabinofuranosyl)cytosines and related ­pyrimidine nucleosides as potential antiviral agents. J. Med. are superior to acetyl salicylic acid. Chem. 1985, 28, 741–748. Alfons Baumstark and co-workers at Georgia State [13] Watanabe, K. A.; Harada, K.; Zeidler, J.; Matulic-Adamic, J.; University have submitted a paper describing a series of Takahashi, K.; Ren, W. -Y.; Cheng, L. -C.; Fox, J. J.; Chou, T. -C.; 3,5-diarylisoxazoles, and their reaction with N-bromosuc- Zhu, Q. -Y.; et al. Synthesis and anti-HIV-1 activity of 2′- cinimide to give corresponding 4-brominated isoxazoles. “up” -fluoro analogues of active anti-AIDS nucleosides 3′-azido-3′-deoxythymidine (AZT) and 2′,3′-dideoxycytidine These products were analyzed by X-ray crystallography, (DDC). J. Med. Chem. 1990, 33, 2145–2150. 13 molecular modelling and C NMR. [14] Grant, A. J.; Feinberg, A.; Chou, T. -C.; Watanabe, K. A.; Fox, J. J.; Philips, F. S. Incorporation of metabolites of 2′-fluoro-5-iodo- 1-beta-D-arabinofuranosylcytosine into deoxyribonucleic acid of neoplastic an normal mammalian tissues. Biochem. 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