Anti-tumoral activities of dioncoquinones B and C and related naphthoquinones gained from total synthesis or isolation from plants

Dioncoquinones belong to a family of natural naphthoquinone products of interest due to their promising anti-tumoral and anti-infective activities. In particular, dioncoquinones A (5) and B (6) have been shown to be highly active against Leishmania major and multiple myeloma cells without any significant toxicity toward normal blood cells. Their effective concentrations against multiple myeloma cell lines were similar to those of melphalan, a well known DNA-alkylating agent used in a standard therapy against B cell lymphoma and multiple myeloma. We report on the first total synthesis of the highly oxygenated anti-tumoral agent dioncoquinone B (6) and the isolation of its new, even higher-oxygenated analogs, dioncoquinones C (7), D (8), and E (9), from cell cultures of Triphyophyllum peltatum. In addition, several derivatives of these compounds were synthesized, including dioncoquinone C (7), and a small library of naphthoquinones was created. Furthermore, the first structure-activity relationship (SAR) study on this class of compounds was conducted, showing that each of the three hydroxy groups, at C-3, C-5, and C-6, is required for improved anti-tumoral activities and decreased cytotoxicities.

A number of naphthoquinones active against multiple myeloma (23 examples) were obtained for SAR studies, by synthesis or isolation, among them the highly active dioncoquinones B (6) and C (7).Figure optionsDownload as PowerPoint slideHighlights
► Dioncoquinones B (6) and C (7) were synthesized by a variety of approaches.
► Three new dioncoquinones C (7), D (8), and E (9) were isolated.
► A series of other naphthoquinones were synthesized or isolated.
► Preliminary SAR study resulted in the identification of the pharmacophore.
► Dioncoquinone C (7) and 35 showed high anti-tumoral activities.