Synthesis of conformationally North-locked pyrimidine nucleosides built on an oxabicyclo[3.1.0]hexane scaffold.
Beginning with a known 3-oxabicyclo[3.1.0]hexane scaffold (I), the relocation of the fused cyclopropane ring bond and the shifting of the oxygen atom to an alternative location engendered a new 2-oxabicyclo[3.1.0]hexane template (II) that mimics more closely the tetrahydrofuran ring of conventional nucleosides. The synthesis of this new class of locked nucleosides involved a novel approach that required the isocyanate II (B = NCO) with a hydroxyl-protected scaffold as a pivotal intermediate that was obtained in 11 steps from a known dihydrofuran precursor. The completion of the nucleobases was successfully achieved by quenching the isocyanate with the lithium salts of the corresponding acrylic amides that led to the uracil and thymidine precursors in a single step. Ring closure of these intermediates led to the target, locked nucleosides. The anti-HIV activity of 29 (uridine analogue), 31 (thymidine analogue), and 34 (cytidine analogue) was explored in human osteosarcoma (HOS) cells or modified HOS cells (HOS-313) expressing the herpes simplex virus 1 thymidine kinase (HSV-1 TK). Only the cytidine analogue showed moderate activity in HOS-313 cells, which means that the compounds are not good substrates for the cellular kinases.
Chemical Biology Laboratory, Center for Cancer Research, National Cancer Institute at Frederick, National Institutes of Health, Frederick, Maryland 21702, USA.
Olaf R
OR
Ludek
Victor E
VE
Marquez
D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor / Q000187:drug effects / Q000821:virology; D003562:Cytidine / Q000031:analogs & derivatives / Q000737:chemistry; D015195:Drug Design; D004353:Drug Evaluation, Preclinical / Q000379:methods; D018259:Herpesvirus 1, Human / Q000201:enzymology / Q000235:genetics; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008968:Molecular Conformation; D015394:Molecular Structure; D011741:Pyrimidine Nucleosides / Q000138:chemical synthesis* / Q000737:chemistry; D013237:Stereoisomerism; D013936:Thymidine / Q000031:analogs & derivatives / Q000737:chemistry; D013937:Thymidine Kinase / Q000235:genetics / Q000378:metabolism; D014529:Uridine / Q000031:analogs & derivatives / Q000737:chemistry
D019380:Anti-HIV Agents; D011741:Pyrimidine Nucleosides; D003562:Cytidine; D013937:Thymidine Kinase; D013936:Thymidine; D014529:Uridine