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

Abstract

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 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.

1,2-Additions on Chiral N-Sulfinylketimines: An Easy Access to Chiral α-Tertiary Amines

“…In a more recent paper Foubelo, Buarque, and co-workers performed DFT calculations (B3LYP-d3bj/def2svp level) specifically for the addition reaction of 2-bromobenzylmagnesium bromide to tetralone-derived sulfinylketimine. 12 These calculations were in good agreement with the experimental results, evidencing that the reaction is under kinetic control. In all considered transition states, two competitive transition structures were found to have the correct geometry and lower energy, leading to the two observed diastereomers: the favored one resulting from Si attack to the E isomer, and the other re-…”

“…As discussed in the introduction, Foubelo, Buarque, and co-workers investigated the addition of 2-bromobenzylmagnesium bromide to a variety of tetralone-derived Nsulfinylketimines (Scheme 23). 12 The product was then transformed into spiro compounds by a sequential deprotection and intramolecular N-arylation.…”

Assessment of Thiosemicarbazone‐Containing Compounds as Potential Antileukemia Agents against P‐gp Overexpressing Drug Resistant K562/A02 Cells

“…Moreover, we also examined their inhibitory effect on the proliferation of parental sensitive leukemic K562 cells to investigate the ability of the target compounds to induce collateral sensitivity (CS) against P‐gp. According to literature methods, [17,18] CS can be quantitatively assessed by calculating the relative resistance (RR) index, which means the ration of IC 50 values of a compound against resistant and corresponding parental sensitive cells.…”

Chiral N‐tert‐Butylsulfinyl Imines: New Discoveries

“…The reaction of imines 151 with o ‐bromobenzylmagnesium bromide 152 led to the formation of the expected compounds 153 (Scheme 65). [85] Desulfinylation of 153 yielded compound 154 , which were cyclized under a Pd‐catalyzed process, giving compounds 155 . The same reactions were performed with imines ent ‐ 151 , so after the whole process, compounds ent ‐ 155 were obtained.…”