Doan Thi Mai Huong, Gaslonde Thomas, Michel Sylvie, Koch Michel, Tillequin François, Pfeiffer Bruno, Renard Pierre, Kraus-Berthier Laurence, Léonce Stéphane, Pierré Alain
Laboratoire de Pharmacognosie de l'Université René Descartes, UMR/CNRS n degrees 8638, Faculté des Sciences Pharmaceutiques et Biologiques, Paris, France.
Chem Pharm Bull (Tokyo). 2004 Mar;52(3):293-7. doi: 10.1248/cpb.52.293.
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.
通过顺式-1,2-二羟基-6-甲氧基-3,3,14-三甲基-1,2,3,14-四氢-7H-苯并[b]吡喃并[3,2-h]吖啶-7-酮的酰化反应制备了一系列顺式-1,2-二羟基-1,2-二氢苯并[b]吖啶二羧酸半酯和二氨基甲酸酯。二氨基甲酸酯的细胞毒性取决于1位和2位酯化基团的空间位阻。二酸半酯表现出显著的体外细胞毒性活性，并诱导细胞周期紊乱，类似于目前处于临床前开发阶段的顺式-1,2-二乙酰氧基-1,2-二氢苯并[b]吖啶（S23906-1）所产生的细胞周期紊乱。顺式-1-乙酰氧基-2-半谷氨酰氧基-1,2-二氢苯并[b]吖啶是该系列中最有前景的化合物，在对植入小鼠的C38结肠腺癌进行测试时，可诱导肿瘤生长完全受到抑制。
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