Design, synthesis and biological evaluation of novel steroidal spiro-oxindoles as potent antiproliferative agents

• Two series of novel steroidal spiro-oxindoles were efficiently synthesized.
• Most of these compounds exhibited broad-spectrum antiproliferative activities.
• Some of them were more potent than 5-Fu against four human cancer cell lines.
• Compound 3g showed good antiproliferative activity against SMMC-7721 (IC50 = 0.71 μM).
• Compound 3n showed cell cycle arrest at G2/M phase and induced early apoptosis.

Two series of novel steroidal spiro-pyrrolidinyl oxindoles 3a–t and 6a–c were designed and synthesized from dehydroepiandrosterone using the 1,3-dipolar cycloaddition as the key step and further evaluated for their antiproliferative activities for four human cancer cell lines (MGC-803, EC109, SMMC-7721 and MCF-7). This protocol achieved the formation of two CC bonds, one CN bond and the creation of one new five-membered pyrrolidine ring and three contiguous stereocenters in a single operation. Biological evaluation showed that these synthesized steroidal spiro-pyrrolidinyl oxindoles possessed moderate to good antiproliferative activities against the tested cell lines and some of them were more potent than 5-Fu. Particularly, compound 3g showed good antiproliferative activity against SMMC-7721 (IC50 = 0.71 μM). Steroid dimer 6b showed improved antiproliferative activities against SMMC-7721 and MCF-7 with the IC50 values of 4.30 and 2.06 μM, respectively. Flow cytometry analysis demonstrated that compound 3n caused the cellular early apoptosis and cell cycle arrest at G2/M phase in a concentration- and time-independent manner.

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