Mitrephorines A–E and Other Cytotoxic Aporphinoids from the Bark of Mitrephora tomentosa

Abstract

Six previously undescribed alkaloids, including three dimeric aporphine alkaloids, mitrephorines A–C (1–3), two aristolactam–aporphine alkaloids, mitrephorines D and E (4 and 5), and one 4,5-dioxoaporphine alkaloid, 8-methoxycepharadione A (6), accompanied by 13 previously identified compounds, were isolated from the bark of Mitrephora tomentosa. Their structures were determined by the analysis of UV, IR, NMR, and HRMS, while absolute configurations were assigned by chiral HPLC, specific rotation values, and ECD spectral data. Known compounds (7–19) were identified by comparison with literature data. The structure of mitrephorine A was verified by the analysis of single-crystal X-ray diffraction. Alkaloid dimers were isolated as mixtures of enantiomers (1–3) and atropisomers (4 and 5). Several isolates were evaluated against HuCCA-1, MOLT-3, HeLa, HepG2, T47-D, MDA-MB-231, S102, H69AR, HL-60, and A549 cancer cell lines, as well as the MRC-5 normal cell line. Compound 11 was active against MOLT-3 and HeLa cancer cell lines with respective IC₅₀ values of 4.5 and 5.1 μM, while compound 12 exhibited cytotoxicity against HuCCA-1 and MOLT-3 cancer cell lines (IC₅₀ values of 10.0 and 7.9 μM, respectively). None of the isolates were toxic against the MRC-5 normal cell line, with doxorubicin hydrochloride serving as the positive control.