Salarin C is known to oxidatively rearrange in the presence of oxygen through a Wasserman rearrangement involving the oxazole and singlet oxygen. While salarin C is a potent cytotoxin, its oxidized analogues show little to no biological activity, thus hampering the elucidation of salarin C’s biological target(s). We hypothesized that this reactivity is due to two factors: the extended conjugation surrounding the oxazole and the strained macrocycle which includes the oxazole ring. Through the synthesis of a simplified macrocycle bearing the oxazole, we have confirmed that salarin C analogs become reactive with ambient singlet oxygen once the macrolactone is formed. The synthesis of a thiazole-containing version of the same simplified macrocycle demonstrated that these thiazole variants undergo Wasserman rearrangement over 7 times slower than their oxazole counterparts. This increased stability could lead to the development of oxygen-stable bioactive analogs of salarin C that will facilitate mode of action studies of this highly potent cytotoxic agent.

Aerobic reactivity of the sponge macrolide salarin C: Synthesis of a stable macrocyclic analog

ACS Spring 2022

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