Synthesis and cytotoxic and antitumor activity of 1,2-dihydroxy-1,2-dihydrobenzo[b]acronycine diacid hemiesters and carbamates.
A series of cis-1,2-dihydroxy-1,2-dihydrobenzo[b]acronycine diacid hemiesters and dicarbamates were prepared by acylation 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. The cytotoxicity of the dicarbamates depended on the steric hindrance of the esterifying groups at positions 1 and 2. Diacid hemiesters displayed significant in vitro cytotoxic activities and induced cell cycle perturbations similar to those obtained with cis-1,2-diacetoxy-1,2-dihydrobenzo[b]acronycine (S23906-1) currently under preclinical development. cis-1-Acetoxy-2-hemiglutaryloxy-1,2-dihydrobenzo[b]acronycine was the most promizing compound of the series, inducing complete inhibition of tumor growth when tested against C38 colon adenocarcinoma implanted in mice.
Doan Thi Mai
Huong
H
Laboratoire de Pharmacognosie de l'Université René Descartes, UMR/CNRS n degrees 8638, Faculté des Sciences Pharmaceutiques et Biologiques, Paris, France.
Gaslonde
Thomas
T
Michel
Sylvie
S
Koch
Michel
M
Tillequin
François
F
Pfeiffer
Bruno
B
Renard
Pierre
P
Kraus-Berthier
Laurence
L
Léonce
Stéphane
S
Pierré
Alain
A
D000175:Acronine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D002219:Carbamates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D003110:Colonic Neoplasms; D004354:Drug Screening Assays, Antitumor; D066298:In Vitro Techniques; D051379:Mice; D015394:Molecular Structure; D009368:Neoplasm Transplantation; D027821:Rutaceae / Q000737:chemistry; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D000972:Antineoplastic Agents, Phytogenic; D002219:Carbamates; C436732:S 23906-1; D000175:Acronine