Photooxidative Molecular Rearrangement of Vouacapane Diterpenes Generates Proapoptotic Spirocaesalmins

Abstract

The photooxidative reactivity of vouacapane derivatives and their potential as apoptotic inducers are explored in the present research. We report the obtention of the new diastereomeric spiroepoxylactones (+)-(5S,6R,8S,9S,10R,13S,14R,15R,16S)-15,16-epoxy-6-hydroxy-13-spirocassan-12,16-olide (2a), (−)-(5S,6R,8S,9S,10R,13R,14R,15S,16R)-15,16-epoxy-6-hydroxy-13-spirocassan-12,16-olide (2b), (+)-(5S,8S,9S,10R,13S,14R,15R,16S)-15,16-epoxy-6-oxo-13-spirocassan-12,16-olide (3a), (−)-(5S,8S,9S,10R,13R,14R,15S,16R)-15,16-epoxy-6-oxo-13-spirocassan-12,16-olide (3b), (+)-(5R,6R,7R,8S,9S,10R,13S,14R,15R,16S)-6-benzoyloxy-15,16-epoxy-5,7-dihydroxy-13-spirocassan-12,16-olide (4a), and (−)-(5R,6R,7R,8S,9S,10R,13R,14R,15S,16R)-6-benzoyloxy-15,16-epoxy-5,7-dihydroxy-13-spirocassan-12,16-olide (4b) by photooxidation of 6β-hydroxyvouacapane (2), 6-oxovouacapane (3), and isovouacapenol C (4), respectively. Known spirolactones (+)-(5S,6R,8S,9S,10R,13S,14R,15R,16S)-6-acetoxy-15,16-epoxy-13-spirocassan-12,16-olide (1a) and (−)-(5S,6R,8S,9S,10R,13R,14R,15S,16R)-6-acetoxy-15,16-epoxy-13-spirocassan-12,16-olide (1b) were also obtained from 6β-acetoxyvouacapane (1). All compounds were characterized by their physical and spectroscopic properties, while their absolute configurations were established by single-crystal X-ray analysis of 2a and 3a, and computational calculations of their specific rotation values. The cytotoxicity and apoptosis induction potential of the compounds were determined in vitro using HeLa and MDA-MB-231 human cancer cell lines, in comparison with CCD-18Co normal cell lines. The results showed that rearranged compounds 1b, 2a, and 4a had the highest cytotoxic activity against HeLa cells, while for MDA-MB-231 cells, the best results were obtained with derivatives 1b, 2a, and 3b.