Synthesis, cytotoxic activity, and DNA binding properties of antitumor cis-1,2-dihydroxy-1,2-dihydrobenzo[b]acronycine cinnamoyl esters.
Monocinnamoyl esters at position 2 of (+/-)-cis-1,2-dihydroxy-6-methoxy-3,3,14-trimethyl-1,2,3,14-tetrahydro-7H-benzo[b]pyrano[3,2-h]acridin-7-one and their acetyl derivatives at position 1 were prepared as stabilized analogues of the anticancer alkylating agent S23906-1. Monocinnamoyl esters at position 2 were slower DNA alkylators than the reference 2-monoacetate. Mixed esters bearing an acetyl ester group at position 1 and a cinnamoyl ester group at position 2 alkylated DNA slower than S23906-1. A strong correlation was observed between cytotoxicity and DNA alkylation kinetics, with slower alkylators displaying more potent antiproliferative activities. The most cytotoxic compounds proved to be significantly active in vivo against murine C-38 adenocarcinoma implanted in mice, but less potent than S23906-1.
Do
Quyên
Q
Faculté des Sciences Pharmaceutiques et Biologiques, Laboratoire de Pharmacognosie de l'Université Paris Descartes, UMR/CNRS No 8638, Paris, France.
Tian
Wen
W
Yougnia
Rodrigue
R
Gaslonde
Thomas
T
Pfeiffer
Bruno
B
Pierré
Alain
A
Léonce
Stéphane
S
Kraus-Berthier
Laurence
L
David-Cordonnier
Marie-Hélène
MH
Depauw
Sabine
S
Lansiaux
Amélie
A
Mazinghien
Romain
R
Koch
Michel
M
Tillequin
François
F
Michel
Sylvie
S
Dufat
Hanh
H
D000175:Acronine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity*; D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity*; D045744:Cell Line, Tumor; D004247:DNA / Q000737:chemistry; D007700:Kinetics; D051379:Mice; D008810:Mice, Inbred C57BL; D014184:Transplantation, Homologous
D018906:Antineoplastic Agents, Alkylating; C436732:S 23906-1; D004247:DNA; D000175:Acronine