Folate-conjugated metal chelates have been proposed as potential imaging agents for cancers that overexpress folate receptors. In a previous study, folic acid was linked through its gamma-carboxyl group to deferoxamine (DF), and the 67Ga-labeled complex ([67Ga]DF-folate) was examined for in vivo tumor targeting efficiency in athymic mice with a human tumor cell implant. Although superb tumor-to-background contrast was obtained, slow hepatobiliary clearance would compromise imaging of abdominal tumors such as ovarian cancer. In the present study, folic acid was conjugated to an alternative chelator, diethylenetriaminepentaacetic acid (DTPA), via an ethylenediamine spacer. The desired DTPA-folate (gamma) regioisomer was synthesized by two different approaches, purified by reversed phase column chromatography, and characterized mainly by analytical HPLC, mass spectroscopy, and NMR. In cultured tumor cells, uptake of [111In]DTPA-folate (gamma) was found to be specific for folate receptor-bearing cells, and the kinetics of uptake were similar to those of free folate and other folate-conjugated molecules. In the normal rat, intravenously administered [111In]DTPA-folate (gamma) was found to be rapidly excreted into the urine, giving intestinal levels of radiotracer 10-fold lower than those observed with [67Ga]DF-folate (gamma) at 4 h. In a preliminary mouse imaging study, a folate receptor-positive KB cell tumor was readily visualized by gamma scintigraphy 1 h following intravenous administration of [111In]DTPA-folate (gamma).
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.
Enantiopure epoxy cycloheptenyl sulfones syn-7b and anti-7b are prepared in five high-yielding and stereospecific operations from 1, 3-cycloheptadiene. These substrates serve as effective precursors for cis- and trans-substituted tetrahydrofurans (12, 10) which are segments of the antineoplastic agent IKD-8344.
The structure of the North spiroketal moiety of ritterazine M has been corrected from 1a to 1b. This was accomplished by comparison of published spectra of the natural product with five synthetic spiroketal-alcohols. Synthesis of these models was efficiently accomplished by reductive cleavage of the spiroketal and Sharpless asymmetric dihydroxylation of an isopentyl, methyl 1,1-disubstituted olefin, followed by Suarez iodine[III] oxidative spirocyclization of monoprotected 1 degree,3 degree 1,2 diols.
A three-operation conjunctive strategy is available for the synthesis of EE, EZ, and ET dienes. This protocol employs a sequential Wadsworth−Emmons reaction using a GAPPS reagent followed by alkylation of an allylic sulfone anion, and finally ligand-mediated, palladium-catalyzed desulfonylation.
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