Original paperSynthesis and antineoplastic activity of alanyl-2-glycyl peptide derivatives of nocodazoleSynthèse et activité antinéoplastique de dérivés alanyl-2-glycyl peptide de nocodazole

To provide the antineoplastic agent nocodazole, 1, with improved solubility and drug-transport properties, The (S)-alanyl-2-glycyl moiety was introduced as a benzimidazole-nitrogen-substituent which would be expected to be enzymatically cleaved in vivo to regenerate 1 and achieve enhanced antineoplastic effectiveness. Synthesis produced 2 pairs of diastereo-isomers (2a–d) which were separated and purified by solubility and chromatography. Site of substitution (N1 vs. N3) and chirality were established by 1H NMR nOe difference spectra and CD spectra on 2a–d and derivatives. The compounds were evaluated in cytotoxicity, leukemia, and solid tumor models and as inhibitors of tubulin binding. These test results indicated that these compounds were not functioning as prodrugs for 1. However, the solid tumor model study showed that 2 compounds had equivalent to enhanced antitumor effectiveness over 1 itself.