DNA-intercalating ligands as anti-cancer drugs: prospects for future design.

摘要: Interest in DNA-intercalating ligands as anti-cancer drugs has developed greatly since the clinical success of doxorubicin. However, despite a great deal 'rational design' synthetic DNA-intercalators, only few such compounds have proved clinically useful. This review briefly surveys history DNA-intercalators clinically-used drugs, summarizes known structure-experimental activity relationships and modes action, concludes that factor slow progress is much work on these been carried out by chemists, who were generally more interested ligand/DNA interactions than drug development. Future development class rests careful consideration biochemical reasons behind common limitations present drugs. The most important are: inherent resistance non-cycling cells, rapid (even cycling cells) expression both P-glycoprotein altered topoisomerase II, distribution to transport into tumours, low extravascular pH tumours cardiotoxic side-effects quinonoid chromophores. These considerations provide set constraints physicochemical properties which must be considered future design. within constraints, there are useful avenues for include: (i) production improved inhibitors (by drug/protein well drug/DNA interactions); (ii) reductively-activated chromophores hypoxia-selective agents; (iii) use DNA binding orientation 'carriers' delivery other reactive functionality specifically (sequence-, regio- site-specifically) DNA.