Bachur N R, Steele M, Meriwether W D, Hildebrand R C
J Med Chem. 1976 May;19(5):651-4. doi: 10.1021/jm00227a015.
Alterations in the C-9 side chain of the anthracycline antibiotics, adriamycin and daunorubicin, have a profound effect on antibiotic uptake and accumulation by cultured L1210 cells. The degree of inhibition of DNA and RNA biosynthesis in the L1210 cells is directly related to the cellular uptake and accumulation of the drug analogues. Polar drug metabolites, daunorubicinol and adriamycinol, retain inhibitory activity against nucleic acid metabolism but have a decreased membrane binding and permeability. Cellular uptake and accumulation of the C-9 analogues are inversely related to drug polarity. We propose that the polarity of the anthracycline analogues contributes heavily to the differences in therapeutic index and in vivo activity through fundamental effects on membrane permeability, metabolism, and macromolecular binding.
蒽环类抗生素阿霉素和柔红霉素C-9侧链的改变，对培养的L1210细胞摄取和积累抗生素有深远影响。L1210细胞中DNA和RNA生物合成的抑制程度与药物类似物的细胞摄取和积累直接相关。极性药物代谢产物柔红霉醇和阿霉素醇保留了对核酸代谢的抑制活性，但膜结合和通透性降低。C-9类似物的细胞摄取和积累与药物极性呈负相关。我们认为，蒽环类类似物的极性通过对膜通透性、代谢和大分子结合的基本影响，在很大程度上导致了治疗指数和体内活性的差异。
