Scalable synthesis of both diastereomers of rac-8-aminoindolizidines and their pyrazolyl-piperidinone hybrids with promising anticancer activity.

Piperidines are privileged scaffolds in medicinal chemistry because of their frequent occurrence in biologically active natural products and therapeutic agents. Construction of molecular hybrids combining natural-like pyrazolyl-piperidinone and 8-aminoindolizidine fragments with anticancer activity is a promising strategy for inventing novel anticancer remedies. To that end, modification of heterocyclic units via cyclopalladation can further enhance the potency of such hybrids. Herein, we report the synthesis of two bilateral pyrazolyl-piperidin-2-one palladacycles bearing the hydrophilic cage phosphine ligand 1,4,7-triaza-9-phosphatricyclo[5.3.2.1]tridecane (CAP), together with a scalable route to both diastereomeric rac-8-aminoindolizidines. The 8-aminoindolizidine fragments were conjugated with pyrazolyl-piperidinone scaffolds to generate a series of hybrid molecules. Among the synthesized derivatives, compound 18b showed the most favorable biological profile, with potent activity against A549 cells (IC50 = 22.46 ± 3.03 μM), comparable to cisplatin (IC50 = 22.06 ± 2.57 μM), while displaying lower toxicity toward HEK293 cells and a selectivity index of 2.78. Molecular docking predicted a favorable non-covalent binding pose of 18b within the DNA minor groove, providing hypothesis-generating structural information for further experimental investigation. These results identify pyrazolyl-piperidinone/8-aminoindolizidine hybrids as promising scaffolds for further development of selective anticancer agents and future palladium-containing drug candidates.