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

Abstract

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 γ-carboxylic acid and thus maintain the α-carboxylic site for folate receptor (FRα) recognition. Linkages via ethylenediamine, polyethylene glycol and glutathione are demonstrated.

Fig. 1. Naturally occurring prodigiosin, and SAR of prodigiosene analogues.

Fig. 2. Folic acid, or vitamin B9.

Fig. 3. Approach to targeted folate–prodigiosene conjugates.

Scheme 1. Synthesis of linker-prodigiosene adducts 2–4.

Fig. 4. Retrosynthetic approaches for the synthesis of folate–prodigiosene conjugates.

Scheme 2. Activation of folic acid with NHS and conjugation to linker-prodigiosenes 2a–c.

Scheme 3. Preparation of the activated Teoc-protected pteroic acid 13.

Scheme 4. Preparation of the protected glutamic acid derivative 16.

Scheme 5. Attempts to synthesise Teoc-protected folic acid-prodigiosene conjugates 20.

Scheme 6. Synthesis of folate–prodigiosene conjugates 27–28a–c and 29a–b.