Dedication to Kyoichi A. Watanabe

This issue of Heterocyclic Communications is dedicated to Kyoichi A. ‘Kyo’ Watanabe (1935–2015), formerly of the Memorial Sloan Kettering Cancer Center (MSKCC), Codon Pharmaceuticals and Pharmasset, Inc. Kyo earned his PhD in the Mizuno lab at Hokkaido University. He was a member of the American Chemical Society, the Polish Academy of Sciences and a founding member of the International Society of Nucleosides, Nucleotides and Nucleic Acids (IS3NA). As the head of the Organic Chemistry Laboratory at MSKCC and Vice President for Research and Development at Pharmasset he was an eminent organic chemist who trained and influenced the careers of numerous scientists. Kyo’s impact has been recognized in five international awards, the most notable and recent being the Marie 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 University 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 MSKCC, left briefly for a fellowship in the Lemieux laboratory at the University of Alberta [1–3], and returned to Sloan-Kettering where he steadily advanced to become the head of the MSKCC laboratory of organic chemistry. While at Sloan-Kettering, Kyo held a professorship at Cornell University until his retirement from academia in 1996. After leaving MSKCC, Kyo joined Codon Pharmaceuticals as the Director of Chemistry. He joined Pharmasset in 1998 where he was the Vice President for Research and Development until he retired in 2003. Throughout his career Kyo was strongly influenced by pioneers in chemistry such as Liebig, Miescher, and Fischer [4]. The elucidation of the structures of the A- and B-form DNA helixes by Watson and Crick also had a profound influence [4].

Kyo was best known for synthesis of novel nucleosides, antivirals, anti-cancer agents, total synthesis of natural products, and carbohydrate ring transformations. He was the first to synthesize the natural products gougerotin and the blasticidins [5–8]. He was also the first to synthesize a 2-fluoro-2-deoxy-D-arabinose derivative from D-glucose [9].

The above arabinose was key in synthesis of F-ara-nucleosides that have anti-viral activity [10–13], anti-cancer activity [14–16] and are commercially available today. Important examples of these nucleosides include 1-(2′-deoxy-2′-fluoro-1-β-D-arabinofuranosyl)-5-methyluracil (FMAU) and 1-(2-deoxy-2-fluoro-1-β-D-arabinofuranosyl)-5-iodouracil (FIAU, fialuridine). FMAU advanced to clinical trials for cancer [17] and a radiolabeled FMAU has been used as an imaging agent [18]. FIAU reached clinical trials for hepatitis B but was withdrawn due to safety concerns [19]. However, the most notable example is probably 2′-F-ara-C. Radiolabeled versions are used in positron emission tomography imaging and for in vivo prediction of clinical response to gemcitabine [20].

While at Pharmasset, Kyo’s contribution to therapeutic nucleosides continued. Under his direction the potent anti-hepatitis C agent PSI-6130 [21, 22] was discovered [23]. Study of the pharmacokinetics of this drug led to discovery and successful clinical development of sofosbuvir by Pharmasset and Gilead. Sofosbuvir is a key component of the cornerstone HCV drug combination harvoni and has been marketed as monotherapy (sovaldi) for HCV [24, 25].

With around 300 publications the above are just a few salient examples of Kyo’s work that have significant impact. When asked about his career, Kyo would usually say that he was just ‘wandering through the wilderness of chemistry hoping to find something interesting and useful’. I am certain this attitude was heavily influenced by his experience during WWII. When Kyo was 8 years old, publications of Karl Marx were found in the office of his father, economist Yojiro Watanabe. As punishment the entire Watanabe family was exiled from Japan to Chilin, Manchuria. In 1946, after 3 years, the survivors returned to Japan. The journey home was a 400-mile ordeal covered entirely on foot from Chilin to the coast of China near Port Arthur. It was a brutal experience that took more than 5 months and claimed the lives of many (no child under 5 years old survived). That experience seemed to give Kyo an endurance and perseverance that was second to none.

The best example of Kyo’s perseverance is his first marathon in 1992. He had new shoes that fit poorly. After several miles the shoes hurt his feet so, rather than quitting, he removed his shoes and finished barefoot! Consistent with his first experience, Kyo finished every marathon he started.

Kyo also possessed a gentle spirit and preferred to lead by example. In the lab he was always approachable and when asked a question he would usually reply, ‘I don’t know,’ followed with, ‘Wait a moment!’ He would then search his large collection of literature, and pull out a paper that would help answer the question. More often than not he or someone he trained would be the corresponding author of that paper. Additionally, good relationships among his co-workers were always important to Kyo. He was the consummate peacemaker and when disagreements arose he would invite those involved to have a drink or two and solve the matter.

Those of us who knew Kyo will remember him for all the above and perhaps most of all his sense of humor. I spoke with him 2 days before his passing and he was still able to make me laugh. After telling a couple jokes he said he only had a small problem and if he could overcome the problem he would be ‘fine’. I find it inspiring that he fought until the end and ironic that his life would be cut short by cancer, a disease he fought so hard to combat.

This dedication issue contains 11 publications authored by his friends.

Krzysztof ‘Kris’ Pankiewicz, who had a relationship with Kyo for about 30 years, has submitted a review describing inhibitors of the enzyme inosine monophosphate dehydrogenase (IMPDH). Kris’ association with Kyo began at MSKCC in the 1980s and their close working relationship continued even after Kris established his own program at MSKCC. With around 70 publications together, Kris was surely Kyo’s right hand man until Kyo’s retirement. Currently Kris is a Professor at The Center for Drug Design, The University of Minnesota. During his productive career Kris has made key contributions to fluorinated nucleoside synthesis, anti-cancer agents and the anti-HCV agent PSI-6130 that has entered clinical trials in prodrug form [21, 22, 26–32].

Przemysław Szafrański of Jagiellonian University in Kraków, Poland is corresponding author of a communication focused on synthesis and spectral characterization of a fluorescent triazole AZT analogue.

This issue also includes three contributions from researchers at the Engelhardt Institute for Molecular Biology (EIMB), The Russian Academy of Science. These include a communication from Anastasia Khandazhinskaya, and research articles from the labs of Marina Kukhanova and Liudmila Alexandrova. Kyo had a long association with the EIMB; he visited often and considered Marina, Liudmila and Anastasia among his best friends. Their bond was surely strengthened by their shared interest and considerable expertise in nucleosides and nucleotides.

Ibrahim Abdou of United Arab Emirates University presents a paper describing the synthesis and anti-proliferative activity (HL-60) of pyridine O-galactosides and related 2-(4′-fluorobenzyl)pyridine derivatives.

Barbara Nawrot was a postdoctoral associate with Kyo at MSKCC (1985–1986) where she made contributions to the synthesis of C-nucleosides and fluorinated nucleosides, notably FMAU [30–32]. She is now Professor and Head of the Department of Bioorganic Chemistry, Centre of Molecular and Macromolecular Studies of the Polish Academy of Sciences. She is corresponding author of a paper describing preparation of nucleobase functionalized tris-(hydroxymethyl)phosphine oxide derivatives. This paper is co-authorized by Professor Wojciech Stec who, before his recent retirement, was her boss at this institution. Professor Stec was Visiting Professor with Kyo.

Raymond Schinazi also had a long relationship with Kyo that dates back at least to the 1980s with their collaborative work in discovery of antiviral agents [12]. When Kyo joined Pharmasset he and Ray formed an even closer working and personal relationship that lasted until Kyo’s death. Ray is the Frances Winship Walters Professor of Pediatrics and Director of the Laboratory of Biochemical Pharmacology at Emory University. He serves as Senior Research Career Scientist at the Atlanta Department of Veterans Affairs and Director of the Scientific Working Group on Viral Eradication within the NIH-sponsored Emory University Center for AIDS Research (CFAR). He is probably best known for contributions to discovery and development of nucleoside anti-virals, for example: d4T (stavudine) [33], 3TC (lamivudine) [34, 35], FTC (emtriva) [36, 37], RCV (racivir) [38] and DAPD (amdoxovir) [39], drugs that are approved or in clinical development. Ray and co-workers have submitted a paper describing synthesis of novel 2′,3′-dideoxy-2′,3′-difluoro-D-arabino nucleosides and their HIV and HCV activities. No issue dedicated to Kyo Watanabe could be complete without inclusion of such a work on fluorinated nucleosides.

Snehal Chavan and colleagues have submitted a paper describing synthesis of some structurally interesting N-glucosylated dithiadiazepines. The key step in synthesis of the title compounds is reaction of N-tetra-O-acetyl-β-D-glucopyranosyl isocyanodichloride with a series of dithio-bis-ureas.

Grażyna Chłoń-Rzepa and colleagues at the Jagellonian University describe a series of purine substituted butanehydrazides and acetohydrazides that possess analgesic and anti-inflammatory properties. Four of the above are superior to acetyl salicylic acid.

Alfons Baumstark and co-workers at Georgia State University have submitted a paper describing a series of 3,5-diarylisoxazoles, and their reaction with N-bromosuccinimide to give corresponding 4-brominated isoxazoles. These products were analyzed by X-ray crystallography, molecular modelling and ¹³C NMR.