Synthesis and Structural Characterization of Magnesium Drug Complexes: Efficient Initiators for Forming Polylactide–Drug Conjugates

Five novel magnesium alkoxides supported
by drug chelating agents pridinolum (PriOH = 1,1-diphenyl-3-(1-piperidinyl)-1-propanol)
and venlafaxinum (VenlOH = (RS)-1-[2-dimethylamino-1-(4-methoxyphenyl)-ethyl]­cyclohexanol)
were successfully synthesized and characterized. Direct reaction of
PriOH and VenlOH with MgBu2 (1:1) in toluene gives the
dimeric compounds [Mg­(μ,η2-OPri)nBu]2 (1) and [Mg­(μ,η2-VenlO)nBu]2 (2), respectively. Furthermore, the crystallization of an equimolar
mixture of 1 and 2 in toluene yields heteroleptic
magnesium complex [Mg­(μ,η2-OVenl)­(η1-OPri)]2 (3). Moreover, reactions
of 1 and 2 with 2 molar equivs of the corresponding
drug–ligands give the homoleptic magnesium bis-alkoxides [Mg­(μ,η2-OPri)­(η1-OPri)]2 (4) and [Mg­(μ,η2-OVenl)­(η1-OVenl)]2 (5). The treatment of compound 1 with 2 equivs of VenlOH or 2 with 2 equivs of PriOH
leads to the formation of 3. Complexes 1–5 were characterized by elemental analysis,
nuclear magnetic resonance, and single crystal X-ray diffraction (for 1–4). It was found that complexes 1–5 are efficient initiators of the ring-opening
polymerization of l-LA, yielding PLA-OPri and PLA-OVenl conjugates,
respectively. Moreover, the ring-opening polymerization of l-LA initiated by 3 led to the simultaneous generation
of a blend of poly-l-lactide conjugates with end-capped VenlO
and PriO groups.