Ent-Atisane and 3,4-seco-atisane diterpenoids from Croton crocodilorum roots and their antiproliferative effect on human colorectal cancer cells.

Five previously undescribed diterpenoids (1-5) along with four known ones (6-9) were isolated from the roots of Croton crocodilorum. Most notably, the four ent-3,4-seco-atisane diterpenoids (2-5) biosynthesized from the ent-atisane diterpenoid (1) were crotogoudin derivatives. Their structures were elucidated by spectroscopic data including HRESIMS and extensive 1D and 2D NMR investigations. The absolute configuration of compounds (-)-1, (-)-3 and (-)-6 was determined by vibrational circular dichroism (VCD) and Raman optical activity (ROA) spectroscopies along with density functional theory calculations. Their plausible biosynthetic pathway was proposed. All isolated diterpenoids were evaluated for their antiproliferative activity against sensitive and resistant human colorectal cancer cells (HCT116 and HT-29). Compounds 3, 5, 6 and 7 displayed more potent activities than the two positive controls (5 FU and irinotecan) against the two cancer cell lines.