Polyoxygenated (9β-H)-Pimarane Derivatives from Leaves of Icacina oliviformis and Their Anti-tumor Activities

Abstract

Thirteen novel polyoxygenated (9β-H)-pimarane derivatives, icacinolides A–G (1–7), oliviformislactones C–H (8–13), and two known analogs (14 and 15), were isolated from the leaves of Icacina oliviformis. Their structures were constructed by spectroscopic analysis, chemical method, 13C NMR-DP4+ analysis, ECD calculation, and single-crystal X-ray diffraction technology. Among them, compounds 1, 5, and 7 were the first three examples bearing a novel rearranged 3-epi-17-nor-(9β-H)-pimarane carbon skeleton with a unique (11S)-carboxyl-9-oxatricyclo[5.3.1.02,7]dodecane motif with contiguous stereogenic centers, whereas their C-3 epimers, compounds 2–4 and 6 were the first four rearranged 17-nor-(9β-H)-pimaranes possessing a unique 19,20-epoxy bridge. Additionally, compound 8 represented the first example of 16-nor-(9β-H)-pimarane in the Icacina genus, and its absolute configuration was constructed by the X-ray diffraction method of its 4-nitro-benzenesulfonamide derivative. In cytotoxicity bioassay, compound 14 showed broad-spectrum anti-tumor activity against HepG2, HT-29, and MIA PaCa-2 cell lines with IC50 values of 11.62, 9.77, and 4.91 μM, respectively. In particular, 2 showed significant cytotoxicity against HT-29 with IC50 values of 7.88 μM, which was stronger than the positive control drug 5-fluorouracil. Meanwhile, a preliminary structure-activity relationship suggested that 3,20-epoxy, 6,19-lactone, 2-OH, 7-OH, and 8-OH, in 9β-H)-pimarane derivatives might be active groups, whereas ring C aromatization may decrease the anti-tumor activity.