Duguetinine, an isoquinoline-derived alkaloid with an unprecedented skeleton from the bark of Duguetia surinamensis (Annonaceae)

Duguetia surinamensis (R.E. Fries) is a species of the Annonaceae family, unknown from both chemical and pharmacological points of view. It is endemic to the Amazon region found in Brazil, Colombia and Guianas. In this work, the phytochemical study through a bioactivity-guided approach was carried out by evaluating the in vitro cytotoxicity of D. surinamensis. By means of classical chromatography techniques, ten substances were isolated being eight alkaloids and two benzenoids. For the structural elucidations, mass spectrometry and nuclear magnetic resonance spectroscopy (1D/2D) were employed. The absolute stereochemistry was assigned by NOE NMR experiments, ECD spectroscopy, and theoretical calculations. The alkaloids were identified belonging to the subclasses: aporphine (duguetine-1, dicentrine-2, 7-hydroxynordicentrine-3, and duguetine-N-oxide-4), oxoaporphine (dicentrinone-5), tetrahydroprotoberberine, (tetrahydrojathrorrizine-6), and morphinan (pallidine-7). An alkaloid with an unprecedented isoquinoline skeleton, named duguetinine-8) was isolated. Benzenoids were identified as being 1,2,4-trimethoxybenzene-9 and a new natural product 1- (2,4,5-trimetoxyphenyl)-1,2-ethanediol-10, described only as synthetic product. Among them, tetrahydrojathrorrizine, duguetine, duguetine-N-oxide, and dicentrinone were previously reported in Duguetia. Pallidine was the first alkaloid of the subclass morphinan isolated in Duguetia, and 7-hydroxydicentrine was isolated for the first time in Annonaceae. The methanolic extract presented moderate cytotoxic activity against HepG2 (human-hepatocellular-carcinoma) and K562 (human-chronic-myelocytic-leukemia) cell lines with IC50 values equal to 46.86 and 35.58 μg/mL, respectively. The compounds 7-hydroxynordicentrine, dicentrine, duguetine, and duguetine-N-oxide alkaloids displayed promising cytotoxic activities against MCF7 (humanbreast- adenocarcinoma), HCT116 (human-colon-carcinoma), HepG2, and HL-60 (human-promyelocyticleukemia), with IC50 below 8.0 μg/mL for all cells tested, except for the duguetine-N-oxide against HepG2 cell line, which had an IC50 of 10.41 μg/mL. The results obtained in this reinforces the chemosystematics proposed for the Annonaceae family. Our findings also display D. surinamensis as a new reliable source of substances with potential cytotoxic activities.