Camptothecin-7-yl-methanthiole: Semisynthesis and Biological Evaluation

The introduction of a methylenthiol group at position 7 of camptothecin was carried out in four steps. This preparation also yielded the corresponding disulfide, which behaves as a prodrug due to its reactivity with glutathione. Assessment of their antiproliferative activities, investigations of their mechanism of action, and molecular modeling analysis indicated that the 7-modified camptothecin derivatives described herein maintain the biological activity and drug–target interactions of the parent compound. Biochemical characterization also indicated that ability of the 7-modified derivatives to induce DNA damage is similar to that of camptothecin. These observations support previous findings that position 7 is favorable for the safe introduction of suitable side chains without detrimental effects. These results are particularly significant with regard to camptothecins containing the methanthiole chain, which would allow linkage to other thiol-containing substituents suitable for targeting or delivery approaches, as evidenced by the activity of disulfide compound 6.