Efficient Syntheses of Pyrofolic Acid and Pteroyl Azide, Reagents for the Production of Carboxyl-Differentiated Derivatives of Folic Acid

Abstract

Reaction of folic acid (1) with excess trifluoroacetic anhydride provides access to both the previously unknown N 10-(trifluoroacetyl)pyrofolic acid (8) and pyrofolic acid (9). Reaction of either of these materials with hydrazine selectively affords pteroyl hydrazide (13), which may be oxidized to pteroyl azide (27) on a large scale (62% overall from 1 without the need for chromatography). Treatment of 27 with differentially protected glutamates provides a convenient and high-yielding synthesis of differentially protected, optically pure folates.

Uptake and trafficking of fluorescent conjugates of folic acid in intact kidney determined using intravital two-photon microscopy

“…N 10 -trifluoroacetylpteroic acid was synthesized from folic acid (Sigma, St. Louis, MO) as described previously (31). Synthesis of ␥-COOH terminus-linked folate fluorescein was described in a previous report (28).…”

Tailored Albumin‐based Copolymers for Receptor‐Mediated Delivery of Perylenediimide Guest Molecules

“…[19] Noteworthy, FA offers two carboxylic acid groups that are in principle able to react with NHS yielding the a-or g-activated FA derivative ( Figure 1). [20] Since only the FA groups carrying the substituents at the g-position are pharmacologically active, i.e. are able to interact with their respective FA receptors, site directed activation and reaction is crucial.…”

“…[3] The procedure of the DPS test is based on a procedure that has been described previously. [23] Different standard solutions containing increasing cysteine concentrations (10,20,30,40, 80 mM) were prepared in 10 Â 10 À3 M phosphate buffer at pH 7.0. Each of these samples, the native protein HSA as well as (7) were incubated with a solution of constant amounts of DPS (360 Â 10 À6 M) in 10 Â 10 À3 M phosphate buffer at pH 7.0.…”

A Low Molecular Weight Folate Receptor Targeted Contrast Agent for Magnetic Resonance Tumor Imaging

“…The α-and β-isoforms belong to a family of membrane-anchored glycoproteins of which the α-isoform is overexpressed in many cancer types, particularly in epithelial ovarian and uterine carcinomas, with low expression in normal tissues [4][5][6]. The conjugation of imaging tracers or therapeutic moieties via the γ-carboxyl group of folic acid conserves molecular enantiomeric purity without apparent effects on ligand binding affinity to FR Kd ¼ 1 Â 1 À 10 M ð Þ [7]. Thus, folate is a valuable ligand for the development of FR-targeted imaging tracers, providing tumor-targeted imaging.…”