Design and synthesis of a fluoroindolocarbazole series as selective topoisomerase I active agents. Discovery of water-soluble 3,9-difluoro-12,13-dihydro-13-[6-amino-beta-D-glucopyranosyl]-5H,13H-benzo[b]- thienyl[2,3-a]pyrrolo[3,4-c]carbazole- 5,7(6H)-dione (BMS-251873) with curative antitumor activity against prostate carcinoma xenograft tumor model.
A series of fluoroindolocarbazoles were studied with respect to their topoisomerase I activity, cytotoxicity, selectivity, and in vivo antitumor activity. Emerging from this series was BMS-251873, a potential clinical candidate possessing a robust pharmacological profile including curative antitumor activity against prostate carcinoma.
Balasubramanian
Balu N
BN
The Bristol-Myers Squibb Pharmaceutical Research Institute, 5 Research Parkway, Wallingford Connecticut 06492, USA. balu@bms.com
St  Laurent
Denis R
DR
Saulnier
Mark G
MG
Long
Byron H
BH
Bachand
Carol
C
Beaulieu
Francis
F
Clarke
Wendy
W
Deshpande
Milind
M
Eummer
Jeffrey
J
Fairchild
Craig R
CR
Frennesson
David B
DB
Kramer
Robert
R
Lee
Frank Y
FY
Mahler
Mikael
M
Martel
Alain
A
Naidu
B Narasimhulu
BN
Rose
William C
WC
Russell
John
J
Ruediger
Edward
E
Solomon
Carola
C
Stoffan
Karen M
KM
Wong
Henry
H
Wright
John J
JJ
Zimmermann
Kurt
K
Vyas
Dolatrai M
DM
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002227:Carbazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D005960:Glucosides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008297:Male; D051379:Mice; D009368:Neoplasm Transplantation; D011471:Prostatic Neoplasms / Q000188:drug therapy*; D012995:Solubility; D013329:Structure-Activity Relationship; D059004:Topoisomerase I Inhibitors; D014867:Water; D023041:Xenograft Model Antitumor Assays
C484861:3,9-difluoro-12,13-dihydro-13-(6-aminoglucopyranosyl)-5H,13H-benzo(b)thienyl(2,3-a)pyrrolo(3,4-c)carbazole-5,7(6H)-dione; D000970:Antineoplastic Agents; D002227:Carbazoles; D005960:Glucosides; D059004:Topoisomerase I Inhibitors; D014867:Water