Synthesis and biological properties of 5-o-carboranyl-1-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)uracil.
A novel 5-o-carboranyl-containing nucleoside, 5-o-carboranyl-1-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)uracil (6, CFAU), was synthesized as a potential intracellular neutron capture agent. This compound was prepared in five steps starting from 5-iodo-1-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)uracil (1). The desired carboranyl derivative was obtained by addition of decaborane [as the bis(propionitrile) adduct] to the protected acetylenic nucleoside precursor followed by debenzoylation. The synthesis of CFAU was also performed by glycosylation of the suitably protected 5-o-carboranyluracil with the appropriate 2-fluoroarabinosyl derivative. This compound was evaluated for its cytotoxicity in human lymphocytes, monkey cells, and rat and human gliomas cells, as well as for antiviral activity against human immunodeficiency virus and herpes simplex virus type 1. Its biological activity was compared to 5-o-carboranyl-1-(2-deoxyribofuranosyl)uracil in these cell culture systems, human bone marrow cells, and mice. The results obtained to date suggest that CFAU has suitable characteristics as a sensitizer for boron neutron capture therapy.
Fulcrand-el Kattan
G
G
Veterans Affairs Medical Center (Atlanta), Decatur, Georgia 30033.
Goudgaon
N M
NM
Ilksoy
N
N
Huang
J T
JT
Watanabe
K A
KA
Sommadossi
J P
JP
Schinazi
R F
RF
D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001086:Arabinofuranosyluracil / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology / Q000633:toxicity; D001853:Bone Marrow / Q000187:drug effects; D001896:Boron Compounds / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D016754:Boron Neutron Capture Therapy; D002470:Cell Survival / Q000187:drug effects; D005260:Female; D005910:Glioma / Q000473:pathology; D006031:Glycosylation; D015497:HIV-1 / Q000187:drug effects; D018259:Herpesvirus 1, Human / Q000187:drug effects; D006801:Humans; D008214:Lymphocytes / Q000187:drug effects; D051379:Mice; D011838:Radiation-Sensitizing Agents / Q000138:chemical synthesis*; D051381:Rats; D014407:Tumor Cells, Cultured
D000998:Antiviral Agents; D001896:Boron Compounds; D011838:Radiation-Sensitizing Agents; C088809:5-o-carboranyl-1-(2-deoxy-2-fluoro-arabinofuranosyl)uracil; D001086:Arabinofuranosyluracil