Nucleoside Chemistry at the Institute of Organic Chemistry and Biochemistry – Looking Back on History

The article is dedicated to the 70ᵗʰ anniversary of the founding of the Institute of Organic Chemistry and Biochemistry of the CAS in Prague

Abstract

Nucleoside chemistry has been developing at the Institute of Organic Chemistry and Biochemistry (IOCB) since 1957 thanks to the foresight of its first director František Šorm. This new area, targeted especially to oligonucleotide synthesis, earned soon an excellent reputation. At that time IOCB was one of only four institutions in the world successful in oligonucleotide synthesis. First successes in the field of chemically modified nucleosides were syntheses of 6-azauridine as antileukemic agent, 6‑azauridine triacetate investigated as antipsoriatic drug (Riboazauracil) and especially 5‑azacytosine nucleosides, i.e., 5-azacytidine and 2′-deoxy-5-azacytidine (decitabine) synthesized in early 1960s by Alois Pískala. Both compounds are antileukemic agents working on the epigenetic principle as inhibitors of DNA methylations. At present, they are clinically used for the treatment of myelodysplastic syndromes and other haematological malignancies, marketed under the names Vidaza^® (5-azacytidine, approved 2004) and Dacogen^® (5‑aza-2′-deoxycytidine, 2006). Remarkable synthetic achievements are connected with the personality of Antonín Holý including syntheses of ʟ-nucleosides or acyclic nucleoside analogues, compounds having a sugar furanose ring replaced by a (poly)hydroxylic carbon chain. Many of them were found effective antivirals. One of them, 9-(S)-[(2,3-dihydroxypropyl)]adenine entered to clinical practice as antiherpetic drug Duvira gel. However, it was the development of acyclic nucleoside phosphonates (ANPs), first reported by Holý and De Clercq in 1986, that became a real milestone. During next three decades a number of biologically active ANPs were identified as antivirals, cytostatics, immunomodulators and antiparasitics. Three of them reached the stage of clinical practice as successful antivirals: cidofovir for the treatment of cytomegalovirus retinitis in AIDS patients, tenofovir for the treatment and prevention of HIV (later approved also for the treatment of hepatitis B), and adefovir for the treatment of hepatitis B. Tenofovir in the form of prodrugs is mostly used as a part of several combined anti-HIV therapeutics containing various anti-HIV drugs in all-in-one pill and is currently the most successful anti-HIV drug available.