A step-wise synthetic approach is necessary to access gamma-conjugates of folate: folate-conjugated prodigiosenes

Despite the vast literature that describes reacting folic acid with a pharmacophore, this route is ineffective in providing the correct regioisomer of the resulting conjugate. We herein present a step-wise route to the preparation of nine folate conjugates of the tripyrrolic prodigiosene skeleton. The strict requirement for step-wise construction of the folate core is demonstrated, so as to achieve conjugation at only the desired gamma-carboxylic acid and thus maintain the alpha-carboxylic site for folate receptor (FR alpha) recognition. Linkages via ethylenediamine, polyethylene glycol and glutathione are demonstrated.