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.
Laboratoire de Pharmacognosie de l'Université René Descartes, UMR/CNRS n degrees 8638, Faculté des Sciences Pharmaceutiques et Biologiques, Paris, France.
Huong
H
Doan Thi Mai
Thomas
T
Gaslonde
Sylvie
S
Michel
Michel
M
Koch
François
F
Tillequin
Bruno
B
Pfeiffer
Pierre
P
Renard
Laurence
L
Kraus-Berthier
Stéphane
S
Léonce
Alain
A
Pierré
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