This work represents the total synthesis of a small library of meso-substitued zinc(II) chlorin scaffolds whereby the number and relative position of conjugation functionality is completely controlled. The library consists of a series of related meso-phenyl 18,18-dimethyl substituted metallochlorin macrocycles that have been functionalized with either N-hydroxy succinimide ester or maleimide groups primed for efficient coupling to biomolecules through standard peptide and thioether bond forming reactions. The number and relative position of the functional groups is controlled using a modular synthetic approach inspired by the Eastern/Western half method for chlorin synthesis developed by Lindsey. The synthetic strategy is designed to minimize chromatographic steps and where possible reactions are carried out with minimal workup between steps. We have generated up to 200 mg of target scaffolds from simple commercially available starting materials. Select members of the library have been successfully coupled to PSMA (prostate specific membrane antigen) targeted phorsphoramidates. Current studies are underway to interrogate the binding of these conjugates to PSMA as well as cellular (prostate cancer) uptake and selectivity studies.

Modular and regioselective synthesis of a <i>meso</i>-phenyl zinc chlorin library with bioconjugation functionality

246th National Meeting (2013)

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Modular and regioselective synthesis of a meso-phenyl zinc chlorin library with bioconjugation functionality