Discovery and SAR studies of a novel class of cytotoxic 1,4-disubstituted piperidines via Ugi reaction

• A novel class of 1,4-disubstituted piperidines were prepared as potential anticancer agents.
• Efficient synthesis of a diverse library through an Ugi four-component reaction.
• Structure–activity relationship is discussed.
• Broad spectrum cytostatic activity in the low micromolar range.
• One selected compound was included in the NCI-60 cancer panel screen at five doses.

Herein we report a novel class of 1,4-disubstituted piperidines as potential anticancer agents. One-step and efficient synthesis of a structurally diverse library of piperidine-based analogs with five points of diversity has been developed using the Ugi four-component reaction. A structure–activity relationship (SAR) study showed that the presence of a benzyl or a Boc group at the N-1 position together with two or three aromatic groups at the C-4 position of the piperidine ring are important for optimal cytostatic properties. Compounds 20, 22, 27 and 29 were found to be the most potent with a 50% inhibitory concentration (IC50) ranging between 3 and 9.5 μM in the cancer cell lines evaluated. The NCI60 screen confirmed this 50% cytostatic concentration range for compound 20, irrespective of the nature of the tumor cell lines evaluated. The NCI COMPARE algorithm did not show any significant correlation between the growth inhibition profile of compound 20 with the NCI database compound profiles suggesting a potential novel mechanism of action.

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