C - Chemistry – Metallurgy – 07 – D
Patent
C - Chemistry, Metallurgy
07
D
C07D 221/18 (2006.01) A61K 31/473 (2006.01) A61P 35/00 (2006.01)
Patent
CA 2347100
A number of indenoisoquinolines were prepared and evaluated for cytotoxicity in human cancer cell cultures and for activity vs. topoisomerase I. The two most cytotoxic indenoisoquinolines proved to be cis-6-ethyl-5, 6, 12, 13-tetrahydro-2, 3-dimethoxy-8, 9(methylenedioxy)-5, 11-dioxo-11H-indeno[1,2-c] isoquinoline and cis-6-allyl- 5, 6, 12, 13-tetrahydro-2, 3-dimethoxy-8, 9-(methylene- dioxy)-5, 11-dioxo-(11H)indeno[1,2-c] isoquinoline. Two of the most potent topoisomerase I inhibitors were 6-(3-carboxy-1-propyl)-5, 6-dihydro-5, 1 Idioxo-11H-indeno[ 1,2-c] isoquinoline (26) and 6-ethyl-2, 3- dimethoxy-8, 9-(methylenedioxy)11H-indeno[ 1,2-c]isoquinolinium chloride (27). Two additional potent topoisomerase I inhibitors, 6-allyl-5, 6--dihydro-2, 3-dimethoxy-8, 9-(methylenedioxy)-5, 11-dioxo-11H-indeno[1,2-c] isoquinoline (13c) and 5, 6- dihydro-6-(4-hydroxybut-1-yl)-2, 3-dimethoxy-8, 9-methylenedioxy-5, 11 dioxo-(11H)indeno[1,2-c]isoquinoline (19a), did not unwind DNA and did not affect topoisomerase II.
L'invention concerne un certain nombre d'indéno-isoquinoléines que l'on a préparées en vue d'en évaluer la cytotoxicité dans des cultures de cellules cancéreuses humaines, ainsi que l'activité en fonction de la topoisomérase I. Il est apparu que les deux indéno-isoquinoléines les plus cytotoxiques étaient cis-6-éthyl-5,6,12,13-tétrahydro-2,3-diméthoxy-8,9(méthylènedioxy)-5,11-dioxo-11H-indéno[1,2-c]isoquinoline et cis-6-allyl-5,6,12,13-tétrahydro-2,3-diméthoxy-8,9-(méthylènedioxy)-5,11-dioxo-(11H)indéno[1,2-c]isoquinoline. Deux des inhibiteurs les plus puissants de topoisomérase I étaient 6-(3-carboxy-1-propyl)-5,6-dihydro-5,1 Idioxo-11H-indéno[1,2-c]isoquinoline (26) et 6-ethyl-2,3-diméthoxy-8,9-(méthylènedioxy)11H-indéno[1,2-c]chlorure d'isoquinoléinium (27). Deux autres inhibiteurs puissants de topoisomérase I, 6-allyl-5,6-dihydro-2,3-diméthoxy-8,9-(méthylènedioxy)-5,11-dioxo-11H-indéno[1,2-c]isoquinoléine (13c) et 5,6-dihydro-6-(4-hydroxybut-1-yl)-2,3-diméthoxy-8,9-méthylènedioxy-5,11-dioxo-(11H)indéno[1,2-c]isoquinoléine (19a), ne déroulaient pas l'ADN ni n'affectaient la topoisomérase II.
Cushman Mark S.
Jayaraman Muthusamy
Nagafuji Pamela M.
Pommier Yves G.
Purdue Research Foundation
R. William Wray & Associates
The Government Of The United States Of America
LandOfFree
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