SAR studies of chabrolonaphthoquinone B via rational design and synthesis of analogues - Cytotoxicity evaluation uncovers anticancer activity via mRNA splicing modulation.

A series of meroterpenoid cytotoxic natural product chabrolonaphthoquinone B (1) analogues were rationally designed. Key structural modifications of the parent compound were introduced to elucidate the features essential for optimal biological activity. Versatile and efficient synthetic strategies were employed to access the designed analogues. The SAR studies revealed that the quinone ring system in 1 is the key structural feature responsible for the observed cytotoxicity while other groups also contribute to the activity against a broad panel of cancer cell lines. Further evaluation of 1 and selected active analogues demonstrated their ability to modulate the mRNA splicing process in HeLa cells, a mode of cytotoxic activity that has only been sporadically attributed to the quinone moiety in previous studies.