22-epi-hippuristanol and hippuristanol

An efficient synthesis of hippuristanol (1), a marine-derived highly potent antiproliferative steroidal natural product, and nine closely related analogues has been accomplished from the commercially available hydrocortisone utilizing Hg(II)-catalyzed spiroketalization of 3-alkyne-1,7-diol motif as a key strategy. This practical synthetic sequence furnished 1 in 11% overall yield from hydrocortisone in 15 linear steps. Modifications to the parent molecule 1 encompassed changing the functional groups on rings A and E. Each analogue was screened for their effects on inhibition of cap-dependent translation, and the assay results were used to establish structure-activity relationships. These results suggest that the stereochemistry and all substituents of spiroketal portion (rings E and F) and C3-α and C11-β hydroxyl functional groups on rings A and C, respectively, are critical for the inhibitory activity of natural product 1.

Topics: Animals; Catalysis; Cell Line, Tumor; Cell Proliferation; DNA-Directed RNA Polymerases; Humans; Hydrocortisone; Magnetic Resonance Spectroscopy; Mercury; Stereoisomerism; Sterols; Structure-Activity Relationship

A new cephalostatin/ritterazine analogue was prepared from the commercially available hecogenin acetate and the natural cytotoxic steroid 22-epi-hippuristanol. The method involved the reductive dimerization of enaminoketones (condensation of alpha-aminoketones) and condensation between an enaminoketone and an alpha-hydroxyketone. The new analogue showed higher cytotoxic activity than the cytotoxic 22-epi-hippuristanol against MDA-MB-231, A-549 and HT-29 cultured tumor cell lines.

Topics: Antineoplastic Agents; Breast Neoplasms; Carcinoma; Cell Line, Tumor; Cell Proliferation; Colorectal Neoplasms; Cytotoxins; Female; Humans; Inhibitory Concentration 50; Lung Neoplasms; Phenazines; Sapogenins; Spiro Compounds; Steroids; Sterols