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

摘要

Five novel magnesium alkoxides supported by drug chelating agents pridinolum (PriOH = 1,1-dipheny1-3-(1-piperidinyl)-1-propanol) and venlafaxinurn (VenlOH = (RS)-1-[2-dimethylamino-1-(4-methoxyphenyl)-ethyl] cydohexanol) were successfully synthesized and characterized. Direct reaction of PriOH and VenlOH with MgBu, (1:1) in toluene gives the dimeric compounds [Mg(mu,eta(2)-OPri)Bu-n](2) (1) and [Mg(mu,eta(2-)VenlO)Bu-n](2) (2), respectively. Furthermore, the crystallization of an equimolar mixture of 1 and 2 in toluene yields heteroleptic magnesium complex [Mg(mu,eta(2)-OVenl) (eta(1)-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(mu,eta(2)-OPri)(eta(1)-OPri)](2) (4) and [Mg(mu,eta(2)-OVenl)(eta(1)-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 Xray 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.