Beyond Pseudo-natural Products: Sequential Ugi/Pictet-Spengler Reactions Leading to Steroidal Pyrazinoisoquinolines That Trigger Caspase-Independent Death in HepG2 Cells

GALILEA, AGUSTÍN; CABRERA, GABRIELA M.; RAMÍREZ, JAVIER A.; MAÑEZ, PAU ARROYO; OTERO, MARCELO; ALONSO, FERNANDO; ACEBEDO, SOFÍA L.; BARQUERO, ANDREA A.

CHEMMEDCHEM

WILEY-V C H VERLAG GMBH

Año: 2021 vol. 16 p. 1945 - 1955

1860-7179

In this work, we describe how stereochemically complex polycyclic compounds can be generated by applying a synthetic sequence comprising an intramolecular Ugi reaction followed by a Pictet-Spengler cyclization on steroid-derived scaffolds. The resulting compounds, which combine a fragment derived from a natural product and a scaffold not found in nature. are both structurally distinct and globally similar to natural products at the same time, and interrogate an alternative region of the chemical space. One of the new compounds showed significant antiproliferative activity on HepG2 cells through a caspase-independent cell-death mechanism, an appealing feature when new antitumor compounds are searched.