Design and synthesis of pironetin analogues with simplified structure and study of their interactions with microtubules

Synthesis and biological evaluation of truncated α-tubulin-binding pironetin analogues lacking alkyl pendants in the side chain or the dihydropyrone ring

“…It was found on the one hand that analogues I/II were cytotoxic in the low micromolar range, thus much less active than the parent molecule. 17 On the other hand, we also found that they behaved in the same way as pironetin in that they killed both sensitive and resistant cells with similar IC 50 values. This indicates that these compounds are not substrates for the P-glycoprotein 18 that resistant cells overexpress in order to pump out cytotoxic compounds, a feature expected for compounds which act through a covalent mechanism of action.…”

“…This is specially surprising in view of the fact that the pironetin analogue lacking the alkyl group at C-4 is also much more cytotoxic than 5 even though less than 6. 17 The comparatively high cytotoxicity of dihydropyrone 6 and conjugated ester (E)-57 are coherent with the fact that they are the compounds which cause an effect on the microtubule network more similar to pironetin (Fig. 5) and also a complete or extensive arrest of the cell cycle at the G2/M phase ( Fig.…”

“…This is that expected for a pironetin-like structure and has already been observed in previous pironetin analogues prepared by us. 17 The highest in vitro activities were shown, in this order, by compounds (Z)-57, 4, 6, 2 and (E)-57, followed by the remaining ligands. It is noteworthy that molecules without the dihydropyrone ring such as (Z)-57 and (E)-57 still retain a significant percentage of this microtubule-destabilizing activity.…”

“…Likewise, all eight stereoisomers exhibiting the general structure II, with a hydroxyl group at C-7, were synthesized. 17 The cytotoxic activity of these analogues and their interactions with tubulin were subsequently investigated. For the measurement of the cytotoxic activity, the ovarian carcinoma cell types A2780 (sensitive to chemotherapy) and A2780AD (resistant to chemotherapy) were used.…”

“…Furthermore, it is worth mentioning that variations in the configurations of the three stereocentres (C-5, C-7, C-9) did not translate into significant differences in the biological activity. 17 In continuation of this line of research, we have now investigated the importance of the alkyl pendants in the pironetin molecule for the biological properties of the natural compound. In line with this reasoning, we have prepared the six pironetin analogues 1-6 (Fig.…”