Ingrassia Laurent, Lefranc Florence, Kiss Robert, Mijatovic Tatjana
Unibioscreen SA, Brussels, Belgium.
Curr Med Chem. 2009;16(10):1192-213. doi: 10.2174/092986709787846659.
Naphthalimides, a class of compounds which bind to DNA by intercalation, have shown high anti-cancer activity against a variety of murine and more notably human cancer cell lines. Azonafide derivatives are also potential anti-tumor agents which are structurally related to the naphthalimides. Derivatives of azonafide have shown enhanced activity against various cancer models, especially leukemias, breast cancer and melanoma. Naphthalimides in general and amonafide in particular, are most probably the agents which have been involved in the greatest number of clinical trials without ever acceding to the market because of dose-limiting toxicity. This statement also reflects the immense interest that oncologists have paid to this class of compounds with respect to their anti-cancer potential. While the first generation of naphthalimides were mainly topoisomerse II poisons, some new compounds display novel mechanism of action. In contrast to the most widely used topo II poisons, including etoposide, adriamycin and their analogues, which often induce multi-drug resistance, several naphthalimide-related compounds have been reported not to be affected by this phenomenon. Multi-disciplinary approaches including medicinal chemistry, early toxicology and DMPK, in vivo activity assessment in diverse preclinical models and in-depth mechanism of action deciphering, along with the lessons learnt from previous and currently ongoing clinical trials, have resulted in the generation of a number of novel promising naphthalimide derivatives. It is thus reasonable to expect that members of this class of compounds will reach the oncology market in the near future.
萘二甲酰亚胺是一类通过嵌入作用与DNA结合的化合物，已显示出对多种小鼠尤其是人类癌细胞系具有高抗癌活性。偶氮萘酰胺衍生物也是与萘二甲酰亚胺结构相关的潜在抗肿瘤药物。偶氮萘酰胺的衍生物已显示出对各种癌症模型增强的活性，尤其是白血病、乳腺癌和黑色素瘤。一般来说，萘二甲酰亚胺尤其是氨萘非特，很可能是由于剂量限制毒性而参与了最多临床试验但从未进入市场的药物。这一说法也反映了肿瘤学家对这类化合物的抗癌潜力给予的极大关注。虽然第一代萘二甲酰亚胺主要是拓扑异构酶II毒药，但一些新化合物显示出新颖的作用机制。与最广泛使用的拓扑异构酶II毒药（包括依托泊苷、阿霉素及其类似物）不同，后者常常诱导多药耐药性，而一些与萘二甲酰亚胺相关的化合物已被报道不受此现象影响。包括药物化学、早期毒理学和药物代谢动力学、在多种临床前模型中的体内活性评估以及深入的作用机制解读在内的多学科方法，以及从以前和正在进行的临床试验中吸取的经验教训，已产生了一些有前景的新型萘二甲酰亚胺衍生物。因此，有理由期望这类化合物的成员在不久的将来进入肿瘤学市场。
