Enantioselective Synthesis, DFT Calculations, and Preliminary Antineoplastic Activity of Dibenzo 1‑Azaspiro[4.5]decanes on Drug-Resistant Leukemias

The
addition of 2-bromobenzylmagnesium bromide to chiral N-tert-butanesulfinyl imines derived from
tetralone-type ketones proceeds with high levels of diastereocontrol.
The resulting sulfinamide derivatives were transformed into dibenzoazaspiro
compounds after a palladium-catalyzed intramolecular N-arylation. DFT calculations have been performed to rationalize the
stereochemical course of the reaction. Similar results have been obtained
considering either diethyl ether or toluene as a solvent, in both
cases in an excellent agreement with experimental findings. NCI topological
calculations have also been used to evidence crucial noncovalent interactions.
In addition, the azaspiro compounds reduced the viability of chronic
myeloid leukemia cells in the micromolar range. Notably, both the
halogen-substituted (R)- and (S)-8g and -8h as well as (R)-8j were at least two times
more effective on a multidrug-resistant derivative than on the parental
cell line, exerting a collateral sensitivity effect.