Synthesis of novel anticancer agents through opening of spiroacetal ring of diosgenin

• Diosgenin has been modified to furostene derivatives after opening spiroketal moiety.
• An aldehyde at C26 unexpectedly transformed to a ketone at C25.
• Compound 7 showed potent cytotoxicity (IC50 = 7.5 μM & 10.9 μM) induces cell cycle arrest and apoptosis.
• Compound 7 is non-toxic up to 1000 mg/kg dose.

Diosgenin has been modified to furostane derivatives after opening the F-spiroacetal ring. The aldehyde group at C26 in derivative 8 was unexpectedly transformed to the ketone 9. The structure of ketone 9 was confirmed by spectroscopy and finally by X-ray crystallography. Five of the diosgenin derivatives showed significant anticancer activity against human cancer cell lines. The most potent molecule of this series i.e. compound 7, inhibited cellular growth by arresting the population at G0/G1 phase of cell division cycle. Cells undergo apoptosis after exposure to the derivative 7 which was evident by increase in sub G0 population in cell cycle analysis. Docking experiments showed caspase-3 and caspase-9 as possible molecular targets for these compounds. This was further validated by cleavage of PARP, a caspase target in apoptotic pathway. Compound 7 was found non-toxic up to 1000 mg/kg dose in acute oral toxicity in Swiss albino mice.

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