Lignopurines: A new family of hybrids between cyclolignans and purines. Synthesis and biological evaluation

A new family of hybrids between cyclolignans related to podophyllic aldehyde, a non-lactonic cyclolignan, and purines were prepared and evaluated against several human tumour cell lines. Both fragments, cyclolignan and purine, were linked through aliphatic and aromatic chains. The influence on the cytotoxicity of the purine substitution and the nature of the linker is analyzed. The new family was slightly less cytotoxic than the parent podophyllic aldehyde, although the selectivity is maintained or even improved and among the linkers used, the presence of an aromatic ring gave the most potent and selective derivatives within the new series tested. Cell cycle and confocal studies demonstrate that these derivatives interfere with the tubulin polymerization and arrest cells at the G2/M phase, in the same way than the parent compounds podophyllotoxin and podophyllic aldehyde do.

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► A new family of hybrids, named lignopurines, were synthesized.
► Lignopurines are formed by the junction of cyclolignans and purines through aliphatic and aromatic chains.
► All new lignopurines were cytotoxic at the micromolar level or below.
► The most potent compounds, 20, 27 and 36, showed GI50 in the range 29–90 nM against HT-29 and A-549 cell lines.
► These derivatives interfere with the tubulin polymerization and arrest cells at the G2/M phase.