Novel 3',6'-anhydro and N12,N13-bridged glycosylated fluoroindolo[2,3-a]carbazoles as topoisomerase I inhibitors. Fluorine as a leaving group from sp3 carbon.
[reaction: see text] Both 6'- and 4'-fluoro-glycosylated indolo[2,3-a]carbazoles are substrates for base-induced loss of fluorine as a leaving group from sp3 carbon. In the case of alpha-N-glycosylated substrate 3, loss of fluorine from the 6'-position leads to 3,6-anhydroglucose analogue 1. A novel N12,N13-bridged sugar analogue 2 results from loss of 4'-fluorine from beta-N-glycosylated analogue 4. Both analogues 1 and 2 display topo I inhibitory potencies similar to camptothecin.
Saulnier
Mark G
MG
Discovery Chemistry, Bristol-Myers Squibb Pharmaceutical Research Institute, 5 Research Parkway, Wallingford, Connecticut 06492, USA. mark.saulnier@bms.com
Langley
David R
DR
Frennesson
David B
DB
Long
Byron H
BH
Huang
Stella
S
Gao
Qi
Q
Wu
Dedong
D
Fairchild
Craig R
CR
Ruediger
Edward
E
Zimmermann
Kurt
K
St Laurent
Denis R
DR
Balasubramanian
Balu N
BN
Vyas
Dolatrai M
DM
D000818:Animals; D002227:Carbazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D002244:Carbon / Q000737:chemistry*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D005461:Fluorine / Q000737:chemistry*; D006027:Glycosides / Q000138:chemical synthesis* / Q000494:pharmacology; D006572:Heterocyclic Compounds, Bridged-Ring / Q000138:chemical synthesis* / Q000494:pharmacology; D006845:Hydrocarbons, Fluorinated / Q000138:chemical synthesis* / Q000737:chemistry; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry; D007941:Leukemia P388; D008968:Molecular Conformation; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D059004:Topoisomerase I Inhibitors
D002227:Carbazoles; D004791:Enzyme Inhibitors; D006027:Glycosides; D006572:Heterocyclic Compounds, Bridged-Ring; D006845:Hydrocarbons, Fluorinated; D007211:Indoles; D059004:Topoisomerase I Inhibitors; D005461:Fluorine; D002244:Carbon