Synthesis and cytotoxic and antitumor activity of benzo[b]pyrano[3, 2-h]acridin-7-one analogues of acronycine.
Benzo¿băcronycine (6-methoxy-3,3,14-trimethyl-3, 14-dihydro-7H-benzo¿bpyrano¿3,2-hăcridin-7-one, 4), an acronycine analogue with an additional aromatic ring linearly fused on the natural alkaloid basic skeleton, was synthesized in three steps, starting from 3-amino-2-naphthalenecarboxylic acid (5). Eight 1, 2-dihydroxy-1,2-dihydrobenzo¿băcronycine esters and diesters (17-24) were obtained by catalytic osmic oxidation, followed by acylation. All these compounds were significantly more cytotoxic than acronycine, when tested against L1210 leukemia cells in vitro. The potency of the cyclic carbonate 24 was in the range of the most active drugs currently used in cancer chemotherapy. Two selected diesters (17 and 24) were evaluated in vivo against P388 leukemia and colon 38 adenocarcinoma implanted in mice. Both compounds were markedly active at doses 16-fold lower than the dose of acronycine itself. Against colon 38 adenocarcinoma, compounds 17 and 24 were highly efficient, inhibiting tumor growth by more than 80%. Diacetate 17 was the most active, inhibiting tumor growth by 96% at 6.25 mg/kg, with two of seven mice being tumor-free on day 43.
Costes
N
N
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.
Le Deit
H
H
Michel
S
S
Tillequin
F
F
Koch
M
M
Pfeiffer
B
B
Renard
P
P
Léonce
S
S
Guilbaud
N
N
Kraus-Berthier
L
L
Pierré
A
A
Atassi
G
G
D000166:Acridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000175:Acronine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001578:Benzopyrans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004273:DNA, Neoplasm; D004354:Drug Screening Assays, Antitumor; D051379:Mice; D009368:Neoplasm Transplantation; D013329:Structure-Activity Relationship
C410939:1,2-di-O-carbonyl-1,2-dihydroxy-6-methoxy-3,3,14-trimethyl-1,2,3,14-tetrahydro-7H-benzo(b)pyrano(3,2-h)acridin-7-one; C410938:1,2-diacetoxy-6-methoxy-3,3,14-trimethyl-1,2,3,14-tetrahydro-7H-benzo(b)pyrano(3,2-h)acridin-7-one; D000166:Acridines; D000970:Antineoplastic Agents; D001578:Benzopyrans; D004273:DNA, Neoplasm; D000175:Acronine