Sánchez Isabel, Reches Rosa, Caignard Daniel Henry, Renard Pierre, Pujol Maria Dolors
Laboratori de Química Farmacèutica (Unitat Associada al CSIC), Facultat de Farmàcia, Universitat de Barcelona, Spain.
Eur J Med Chem. 2006 Mar;41(3):340-52. doi: 10.1016/j.ejmech.2005.11.006. Epub 2006 Jan 18.
A series of new acridines has been prepared by cyclodehydration of N-(2,3-dihydro-1,4-benzodioxin-6-yl)anthranilic acid in acidic media following classical procedures. All these compounds have in common a dioxygenated ring fused to the acridine. The tetracyclic system possesses a linear or angular structure formed by intramolecular cyclisation. The last ring and the substituent of the system modify, in an interesting way, the antitumor activity of acridines. Several of the studied compounds displayed significant cytotoxic activity (inhibition of L1210 and HT-29 cell proliferation). The most cytotoxic compound 13a, shows more activity than m-AMSA in inhibiting L1210 and HT-29 cell proliferation and this compound has been selected as a development candidate for further evaluation. The activity results also indicate that the new 11-O-substituted compounds are of considerable interest with high levels of cytotoxic activity. The angular or non-linear dioxinoacridine 10 was equiactive with the linear structure 7. Pentacyclic analogues (14 and 15) were more cytotoxic than the tetracyclic compounds (up to twofold).
按照经典方法，通过在酸性介质中对N-(2,3-二氢-1,4-苯并二恶英-6-基)邻氨基苯甲酸进行环脱水反应，制备了一系列新的吖啶。所有这些化合物的共同特点是都有一个与吖啶稠合的二氧环。四环体系具有通过分子内环化形成的线性或角形结构。该体系的最后一个环和取代基以一种有趣的方式改变了吖啶的抗肿瘤活性。几种被研究的化合物表现出显著的细胞毒性活性（抑制L1210和HT-29细胞增殖）。细胞毒性最强的化合物13a在抑制L1210和HT-29细胞增殖方面比间胺苯磺酰胺表现出更强的活性，该化合物已被选为进一步评估的开发候选物。活性结果还表明，新的11-O-取代化合物具有相当高的细胞毒性活性，值得关注。角形或非线性二氧吖啶10与线性结构7具有同等活性。五环类似物（14和15）比四环化合物的细胞毒性更强（高达两倍）。
