Synthesis and evaluation of (17.alpha.,20E)-21-[125I]iodo-19-norpregna-1,3,5(10),20-tetraene-3,17-diol and (17.alpha.,20E)-21-[125I]iodo-11.beta.-methoxy-19-norpregna-1,3,5(10),20-tetraene-3,17-diol [17.alpha.-iodovinyl)estradiol derivatives] as high specific activity potential radiopharmaceuticals
Abstract:Two 17 alpha-[125I]iodovinyl estradiol derivatives 4b,d possessing high specific activity have been prepared and tested as potential radiopharmaceuticals. The use of the 3-acetyl derivatives 2c,e and the replacement of iodine monochloride with sodium iodide and Chloramine-T in THF/phosphate buffer (pH 7.0) permitted us to synthesize no-carrier-added (17 alpha,20E)-21-[125I]iodo-19-norpregna-1,3,5(10),20-tetraene-3,17-d iol (4b) and (17 alpha,20E)-21-[125I]iodo-11 beta-methoxy-19-norpregna-1,3,5(10),20-tetraene… Show more
“…Encouraged by these results, especially by the excellent reactivity of the vinylboronic acid 3e 9 (entry 5, Table ), we decided to try this reaction on compound 5 (Scheme ), an estradiol derivative containing a vinylboronic acid group in the 17α position.…”
“…Encouraged by these results, especially by the excellent reactivity of the vinylboronic acid 3e 9 (entry 5, Table ), we decided to try this reaction on compound 5 (Scheme ), an estradiol derivative containing a vinylboronic acid group in the 17α position.…”
“…A more detailed discussion of this substituent effect is given later. Vinylic boronic acids ( 7e , Table , and 9 , Scheme ) also afforded good yields of the product complexes. 3 Nucleophile structural features affecting reaction yield (where relevant, nucleophilic sites have been circled). 2 One-Step Synthesis of Estradiol Derivative 10 from Boronic Acid 9…”
We have investigated the scope and mechanism of the “three-component” synthesis of
substituted CpRe(CO)3 complexes which involves the reaction of nucleophiles with diazocyclopentadiene (C5H4N2) and a fac-Re(CO)3
+ species. We found that only moderately strong
nucleophiles (halogen, carboxylates, boronic acids) are suitable for this transformation and
that it shows a great sensitivity to the steric and electronic features of the nucleophile. A
Hammett-type ρσ analysis of the effect of para-substituents on the relative rate of this
reaction with several benzoates showed that the reaction is accelerated by electron-donating
substituents. A mechanistic analysis, based on structure/reactivity relationships and NMR
experiments, indicated that the nucleophile initially reacts with the rhenium precursor. Then,
in the rate-determining step, the resulting preassociated rhenium−nucleophile intermediate
reacts with C5H4N2 via a concerted SN2-like transition state. The same general mechanistic
pathway seems to be followed by two very different classes of nucleophiles, carboxylates
and boronic acids, in the synthesis of acyloxy- and carbon-substituted CpRe(CO)3 complexes,
respectively. In particular, the lack of reactivity of boronic esters can be explained by the
necessary preassociation step between the rhenium and a deprotonated hydroxy group of
the nucleophile, which is possible only with free boronic acids.
“…Replacing PPh 3 with the bulky phosphine ligand ( o -tolyl) 3 P resulted in a modest improvement in the yield of 9a to 45%. These relatively low yields with the Heck reaction prompted us to investigate the Suzuki/Miyaura coupling procedure. , The vinyl boronic acid derivative 8b was prepared according to the literature procedure from ethynylestradiol and catechol borane, followed by hydrolysis . The Suzuki coupling of 8b with 2-chloro-5-iodo pyridine 6 was accomplished with Pd(PPh 3 ) 4 /CsF .…”
The development of (99m)Tc-estradiol radiopharmaceuticals would be advantageous for the detection of estrogen receptor-positive breast tumors. Estradiol derivatives conjugated to organometallic tricarbonyl-Tc(I) and related Re(I) complexes are capable of achieving high receptor binding affinity, but effective methods for synthesizing radiolabeled complexes in water are not available. Our interest in the synthesis of 2-hydrazinopyridines as ligands for Tc and Re led us to investigate Pd-catalyzed amination reactions of halo-pyridine substrates with di-tert-butyl hydrazodiformate. Both 2- and 4-substituted halo-pyridine substrates undergo C-N coupling with di-tert-butyl hydrazodiformate to produce Boc-protected pyridine hydrazine derivatives. Only highly electrophilic 3-pyridine halides were converted to the hydrazine. The Boc-protected 5-bromopyridin-2-yl hydrazine substrate 3 was prepared by regioselective substitution at the 2-position of 2,5-dibromopyridine. This bifunctional chelate was attached to ethynyl or vinyl groups at the 17alpha position of estradiol, using Sonogashira and Suzuki/Miyaura coupling reactions to synthesize 1 and 2 in high yields, respectively. Deprotection of 1 under acidic conditions provided the hydrazine hydrochloride salt 25. The 17alpha-estradiol-tricarbonylrhenium(I) complex 4 was synthesized by labeling 25 with fac-[Re(OH(2))(3)(CO)(3)](+) in aqueous ethanol. This complex exhibited excellent stability and high receptor binding affinity for the estrogen receptor, and it is a promising model for evaluation of the analogous Tc-99m complexes as diagnostic imaging agents for breast tumors.
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