The naturally-occurring lignan nordihydroguaiaretic acid (NDGA) has found use as a traditional medicine in creosote bush-based remedies, but recently chronic use of NDGA has been associated with hepatotoxicity in humans. Previously we showed that oxidative cyclization of NDGA (a di-catechol) at physiological pH forms a dibenzocyclooctadiene that may have therapeutic benefits whilst oxidation to ortho-quinone likely causes its toxicological properties.  Curiously, NDGA does not appear to form the expected para-quinone methide, which we initially attributed to steric hindrance preventing isomerisation.  Attempts at direct oxidation of NDGA to a para-quinone methide with silver oxide were unsuccessful but resulted in some dibenzocyclooctadiene formation.  To better understand NDGA oxidation, we have synthesised a series of NDGA analogues to determine whether NDGA lignans can form para-quinone methides and the contribution of ortho- and para-quinones to dibenzocyclooctadiene formation.  We modified literature procedures to prepare the lignan analogues via a multi-step synthesis and successfully prepared six analogues.  We have determined that NDGA autoxidation at pH 7.4 is dependent on substituents and/or substitution pattern on the two aromatic rings. In particular, mono-catechol and phenolic NDGA analogues were stable and did not cyclize at pH 7.4. The catechol analogues could be oxidized to ortho-quinones and were trapped as glutathione conjugates; however they did not form para-quinone methides even after oxidation with silver oxide.  In contrast the phenol lignans were oxidized with silver oxide to para-quinone methides which were trapped as glutathione conjugates. Spontaneous intramolecular cyclization to a dibenzocyclooctadiene seems to require a di-catechol lignan, raising the possibility that quinone formation may not be necessary for cyclization to occur.

Nordihydroguaiaretic acid (NDGA) analogs: Quinone formation vs. intramolecular cyclization to benzocyclooctadienes

246th National Meeting (2013)

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