The synthesis, stability and biological activity of bis-intercalating bis-daunomycin hydrazones.

Drug design and delivery Pub Date : 1990-03-01
D R Phillips, B C Baguley, R T Brownlee, P Cacioli, C J Chandler, I Kyratzis, J A Reiss, P A Scourides
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Abstract

The synthesis of a series of bis-daunomycin hydrazones (5a-g)--all moderately stable at 37 degrees C, pH 6.8, with a half-life of approximately 30 h--is reported. Under a pulse exposure of 2 h they exhibited growth inhibition of mouse L1210 cells, and were 2-3 fold more active than daunomycin. Under continuous exposure growth inhibition conditions with human colon cell lines (HT-29 and HCT-8) they hydrolysed to daunomycin and a partially hydrolysed mono-derivative of daunomycin, and there was no apparent increase in activity over that of the parent anthracycline. Their rate of hydrolysis was observed to increase rapidly with decreasing pH.

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双插层双道霉素腙的合成、稳定性和生物活性。
报道了一系列双道诺霉素腙(5a-g)的合成,这些腙在37℃、pH 6.8下都是中等稳定的,半衰期约为30小时。在脉冲暴露2小时下,它们表现出对小鼠L1210细胞的生长抑制作用,活性比道诺霉素高2-3倍。在持续暴露于人类结肠细胞系(HT-29和HCT-8)生长抑制条件下,它们水解为道诺霉素和部分水解的道诺霉素单衍生物,与母体蒽环类药物相比,活性没有明显增加。它们的水解速率随着pH的降低而迅速增加。
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