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Aktywność biologiczna modyfikownych nukleozydów. Część 2

Szlenkier M.

Wiadomości Chemiczne

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2018

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[Z] 72, 5-6

245--264

EN

Part II of the review describes biological activities of nucleosides modified in the position 2’ and/or 3’ of a sugar moiety including 2’- and/or 3’-deoxy, 2’,3’-dideoxydidehydro and 2’-β-C-methylated derivatives. Analogues with a changed configuration in the sugar residue and others sugar modifications will be a subject of the part III of the review. Together with the part I it would be a short but possibly comprehensive review of nucleosides’ biological activities. In the group of analogues modified in the position 2’ and/or 3’ of the sugar moiety the following derivatives among others are listed: AZT (zidovudine) – one of the key nucleoside reverse transcriptase inhibitors (NRTI), which are the core of highly active antiretroviral therapy (HAART) against virus HIV; didanosine (ddI) – another potent NRTI with medical importance; stavudine – FDA approved NRTI; zalcitabine – historically important NRTI, however, because of a high mitochondrial toxicity is no longer in use; puromycin – a wide spectrum antibiotic which causes premature chain termination during translation, isolated from Streptomyces alboniger; gemcitabine – chemotherapy medication developed by Eli Lilly and Company and used to treat ovarian, breast, pancreas, bladder cancer and non-small cell lung carcinoma; cordycepin – the most intriguing analogue extracted from Cordyceps sp. known to traditional Chinese medicine (TCM) for centuries, possessing multi-activity against different cancer types; cladribine – used in the treatment of chronic lymphocytic leukemia, cutaneous T-cell lymphoma, hairy cell leukemia and non-Hodgkin’s lymphomas; valopicitabine – a prodrug form of 2’-C-methylcytidine, which was a promising HCV treatment agent, however, it was held during clinical trials and finally sofosbuvir developed by M.J. Sofia from Pharmasset Inc.– a ProTide prodrug form of 2’-deoxy-2’-fluoro-β-C-methyluridine 5’-monosphate, which revolutionized HCV infection therapy.

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Aktywność biologiczna modyfikownych nukleozydów. Część 1

Szlenkier M.

Wiadomości Chemiczne

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2018

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[Z] 72, 3-4

109--126

EN

Every year, hundreds of new nucleoside analogues are obtained in laboratories around the world. As early as in 1964, 3’-azidothymidine (AZT) was first synthesized, which turned out to be the main weapon in the fight against HIV viruses 20 years later. Part I of the review includes nucleosides possessing modifications in the base moiety or having other heterocyclic bases. Nucleosides modified in the sugar residue, because of a broad spectrum of examples, will be a subject of part II and III of the review. In the group of analogues modified in the base moiety the following derivatives among others are listed: 5-iodo-2’-deoxyuridine (IDU), E-5-(2- bromovinyl)-2’-deoxyuridine (BVDU), capecitabine – prodrug form of fluorouracil, 7-deazaadenosine, BCX4430 (immucillin-A) – 9-deazaadenosine derivative active against filoviruses such as Ebola virus (EBOV). In the group of nucleosides having a different heterocyclic base the following derivatives are listed: ribavirin (RBV) and its analogues – RBV triphosphate is an inhibitor of many viral enzymes involved in the replication cycle, mizoribine (MZB) – a naturally occurring nucleosidic immunosuppressor, 5-ethynyl-1-β-"-ribofuranosyl-imidazole-4-carboxamide (EICAR) which suppresses development of murine leukemia cell lines and has a broad spectrum of activity against RNA and DNA viruses. The C-nucleosides group includes e.g. oxazinomycin – a natural antibiotic with growth inhibitory properties against gram (+), gram (–) bacteria and sarcoma, and formycin A isolated from Streptomyces lavendulae, which has cytostatic and antiviral activity.

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Aktywność biologiczna modyfikowanych nukleozydów. Część 3

Szlenkier M.

Wiadomości Chemiczne

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2018

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[Z] 72, 9-10

767--787

EN

Part III of the review devoted to biological activities of nucleoside derivatives presents a further description of analogues modified in the sugar residue with particular focus on those with altered configuration in the 2’ or 3’ position, e.g. cytarabine – an old anticancer chemotherapy agent used to treat acute myeloid leukemia, acute lymphoblastic leukemia, and non-Hodgkin’s lymphomas; fludarabine – derivative of vidarabine used as a drug in the treatment of chronic lymphocytic leukemia, and non-Hodgkin lymphomas; clofarabine – approved by the FDA in 2004, a new-generation second-line drug for recurrent acute myeloid leukemia; and fialuridine – examined as a potential therapeutic for the treatment of HBV infection, however, clinical trials ended tragically. In the last section of the review derivatives with other modifications in the sugar moiety are described – carbocyclic and acyclic analogues, l-nucleosides and 5’-modified nucleosides. Among others, very important modified nucleosides are listed e.g. acyclovir, ganciclovir, DHPA, tenofovir, cyclopentenylcytosine, entecavir, carbovir, abacavir, lamivudine, telbivudine and sinefungin VA. All parts together make a possibly complete and concise review, including the latest reports, the most important groups of modified nucleosides, and should be considered as a whole. In the context of the activities description, there are references to the important molecular targets, mechanisms of action, pharmacodynamics, pharmacokinetics, toxicity, resistance, in vitro and in vivo tests or prodrug strategies, which can be a starting point for further study for chemists interested in medicinal chemistry.