Our group studies structure-activity relationships on the antitumor activity of annonaceous acetogenins. Previously, we revealed that analog 1 with thiophene ring connected by amide bond in place of the γ-lactone ring of solamin, a natural acetogenin, shows potent antitumor activity against NCI-H23, human lung cancer cell, without toxicity. However, analog 1 has low water solubility due to two long alkyl chains. Therefore, we plan to synthesize analogs 2a-2b with a shorter side chain instead of the long one to improve water solubility and evaluate their cancer growth inhibition. First, the known THF fragment 3 was synthesized by our protocol. Next, the primary hydroxy group was converted to the leaving group, followed by basic treatment to give the epoxide. The epoxide was opened by Grignard reagent to introduce an alkyl side chain. Finally, two desired analogs 2a-2b were respectively synthesized by hydrogenation. Their growth inhibitory activities against 39 human cancer cells were evaluated. Analogs 2a-2b kept potent growth inhibitory activities against a few cancer cells (e.g., MKN-B and DMS114). However, it was found that the activities against all but those cells were weakened. These results revealed that the conversion to the shorter alkyl side chain significantly decreases their activity, and a certain length of the alkyl side chain was required for the activity. This presentation will show the detail of synthesis, biological activity, and prediction of the mode of action.

Divergent synthesis and biological activity evaluation of acetogenin thiophene analogs having shorter alkyl side chain

ACS Spring 2022

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