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

Customizable Porphyrin Platform Enables Folate Receptor PET Imaging Using Copper-64

“…Installation of a tether on folic acid can be achieved at either of the two carboxylic acid groups. Several selective conjugations of folic acid via stepwise reactions have been reported. ,− The method of synthesis of a folate bearing a PEG group at the γ-carboxylic acid reported by Willibald et al was adopted here (following considerable exploratory work) for use with a distinct azide-terminated PEG5 unit. Thus, glutamic acid bearing Fmoc and tert- butyl protection at the respective α-amino and α-carboxylic acid groups ( 7 ) was subjected to amidation with amino–PEG–azide 8 in the presence of standard coupling reagents HBTU and DIPEA to give 9 as shown in Scheme (right).…”

Folic acid functionalization for targeting self-assembled paclitaxel-based nanoparticles

“…We thus conceived a different retrosynthetic strategy that, even though complex, should have led us to target folic acid conjugate 2. 29 A stepwise assembly entailed at first to build folic acid from pteroic acid and l -glutamic acid (see also Fig. 1 ), proceeding through a sequential protection/activation cascade.…”

“…The first reaction attempts at rt were unsuccessful, as we only recovered starting material. To overcome poor solubility, following protocol published in literature, 29 we heated the reaction to 50 °C, observing gradual solubilization of 19 and darkening of the reaction mixture. TLC monitoring after 26 hours showed a reaction product together with unreacted pteroic acid 19, but work-up and purification of the crude was affected by the poor solubility of 19 which diffused through both manual and automated flash chromatography.…”

Synthesis and properties of covalently linked phenyl bridged 3-pyrrolyl BODIPY–BODIPY dyads

“…Prodigiosin derivatives have also shown anion recognition properties, which also inspired researchers to develop oligopyrrole based compounds. [4][5][6][7] Furthermore, it is also well established that the BF 2 complex of prodigiosin derivatives is a very useful dye for biological applications. 8,9 BF 2 complexes of dipyrrin (BODIPYs) and a-pyrrolyl dipyrrin (3-pyrrolyl BODIPYs) can act as precursors for the synthesis of innovative ligands such as dipyrrins and a-pyrrolyl dipyrrins by removing the BF 2 unit in the presence of Lewis acids 10 and such ligands can be used for metal coordination chemistry and also as building blocks or templates for the construction of advanced materials, including metal-organic frameworks (MOFs), 11 coordination polymers, 12 and molecular assemblies.…”