Structure-activity relationships and mechanism of action of antitumor benzo[b]pyrano[3,2-h]acridin-7-one acronycine analogues.
The cytotoxic and antitumor activities of cis-1,2-diacyloxy-6-methoxy-3,3,14-trimethyl-1,2,3,14-tetrahydro-7H-benzo[b]pyrano[3,2-h]acridin-7-one derivatives 3, 6-9 were strongly correlated with their ability to give covalent adducts with purified, as well as genomic, DNA. Such adducts involve reaction between the exocyclic N-2 amino group of guanines exposed in the minor groove of double helical DNA and the leaving ester group at the benzylic position 1 of the drug. A transesterification process of the ester group from position 2 to position 1 in aqueous medium accounted for the intense activity of the cis-1-hydroxy-2-acyloxy-6-methoxy-3,3,14-trimethyl-1,2,3,14-tetrahydro-7H-benzo[b]pyrano[3,2-h]acridin-7-one derivatives 10-13. Compounds without acyloxy or hydroxy group at position 1, such as 15, 17, 18, and 22, were inert with respect to DNA and almost devoid of significant cytotoxic activity. Condensation of 5-amino-2,2-dimethyl-2H-chromene (26) with 3-bromo-2-naphthoic acid (27), followed by cyclization, gave access to 6-demethoxy analogues. Diacetate 32 and cyclic carbonate 33, both belonging to the latter series, were less reactive toward DNA and less cytotoxic than their 6-methoxy counterparts 3 and 34. DNA alkylation appears thus to play an important role in the antitumor properties of benzo[b]pyrano[3,2-h]acridin-7-one derivatives.
Thi Mai
Huong Doan
HD
Laboratoire de Pharmacognosie de l'Université René Descartes, UMR/CNRS No 8638, Faculté des Sciences Pharmaceutiques et Biologiques, 4 Avenue de l'Observatoire, 75006 Paris, France.
Gaslonde
Thomas
T
Michel
Sylvie
S
Tillequin
François
F
Koch
Michel
M
Bongui
Jean-Bernard
JB
Elomri
Abdelhakim
A
Seguin
Elisabeth
E
Pfeiffer
Bruno
B
Renard
Pierre
P
David-Cordonnier
Marie-Hélène
MH
Laine
William
W
Bailly
Christian
C
Kraus-Berthier
Laurence
L
Léonce
Stéphane
S
Hickman
John A
JA
Pierré
Alain
A
D000166:Acridines / Q000737:chemistry* / Q000494:pharmacology; D000175:Acronine / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000494:pharmacology; D000478:Alkylation; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D001578:Benzopyrans / Q000737:chemistry* / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D004247:DNA / Q000737:chemistry / Q000378:metabolism; D018736:DNA Adducts / Q000737:chemistry / Q000378:metabolism; D004354:Drug Screening Assays, Antitumor; D004952:Esters; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D009368:Neoplasm Transplantation; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D000166:Acridines; D000970:Antineoplastic Agents; D001578:Benzopyrans; D018736:DNA Adducts; D004952:Esters; D004247:DNA; D000175:Acronine