Labdane diterpenoids and highly methoxylated bibenzyls from the liverwort Frullania inouei

Seven labdane diterpenoids and four highly methoxylated bibenzyls were isolated from the liverwort Frullania inouei. Cytoxicity test showed bibenzyls were active to inhibit human tumor cells proliferation and had a reversal effect to MDR. Four undescribed labdane diterpenoids, 1,2-dehydro-3,7-dioxo-manoyl oxide ( 1), 1,2-dehydro-7 β-hydroxy-3-oxo-manoyl oxide ( 2), 3,7-dioxo-manoyl oxide ( 3), and 3 β-hydroxy-7-oxo-manoyl oxide ( 4) together with three known diterpenoids ( 5– 7) and four highly methoxylated bibenzyls ( 8– 11) were isolated from the liverwort Frullania inouei. The absolute structures of 1– 4 were established by combined analysis of NMR data, CD data coupled with TDDFT CD calculations, and single-crystal X-ray diffraction measurement. Cytotoxicity tests to human tumor KB, KB/VCR, K562 or K562/A02 cells showed bibenzyls 8– 11 inhibited cell proliferation with ID 50 values ranging from 11.3 to 49.6 μM and overcame the multidrug resistance (MDR) with the reversal fold (RF) values ranging from 3.19 to 10.91 (5 μM) for vincristine-resistant KB/VCR and RF values from 4.40 to 8.26 (5 μM) for adriamycin-resistant K562/A02 cells, respectively. However, none of the diterpenoids were found to be active (ID 50 > 50 μM).