Targeted Radiotherapy of Estrogen Receptor Positive Tumors Page: 3 of 3
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Bischler-Napieralski and Pictet-Spengler cyclizations. Synthesis of ligand 4a-d and the
intermediates 4e-f and the active ester 15 longer time than anticipated due to various
technical difficulties. After considerable effort, ligands 4 a-b and
Scheme 2
1. CI(CH2)2000I NH2 . HCI
NH 2. Potassium N*.~
2 thalimide I N
MeO 3. POCl3 MeO 12
4. HCI
CO2Me CO2Su
C02H 1. MeOH, H+
2. AcSH, Et3N, 0 0C 1. NaOH
Br Br 3. MeOH, H2SO4 2. N-Hydroxysuccinimide,
13 4. Acetone, H+ X14 DCC 15
12 or 4e +15 CH3CN> 4c NaBH4 4b
Et3N
4 c-d were prepared in twelve steps as outlined in Scheme 2. The aminoimine 12 was
prepared from commercially available 3-methoxyphenylethylamine in four steps.
Preparation of the thioketal active ester 15 proved to be considerably more difficult than
had been anticipated. It was finally prepared in six steps from 2,3-dibromopropionic
acid. The alkylation of 2,3-dibromopropionate with thiolacetic acid must be carried out at
cold temperature, and the saponification of the corresponding bis(thioacetate) must be
carried out under acidic conditions over a period of 48 hours. The active ester 15 was
condensed with the aminoimine 12 to give the imino ligand 4c-d, which was then
reduced with sodium borohydride to give the desired amino ligand 4b as a roughly equal
mixture of two diastereomers.
The synthetic method developed for ligand 4b was further modified for the synthesis of
ligand 4a and it was completed. Ligand 4a was synthesized in a similar fashion starting
from 3-benzyloxy-phenylethylamine. The amine 4e was prepared in two steps from 3-
benzyloxybenzaldehyde by the published method. Reaction of 4f with chlorpropionyl
chloride, alkylation of the chloride with potassium phthalimide, and Bischler-Napieralski
cyclization of the phthalimide gave the desired imine 4d. The ligand 4a was obtained
roughly equal mixture of two diastereomers as 4b and Tc/Re metal complexation of
ligands 4b and 4a are in progress to evaluate their ER and SHBG binding
characteristics.
The synthesis of intermediates 9 and 10 are continuing to obtain ligands 5-6 for estrogen
mimics 2 and 3. The initial determination of ER and SHBG binding studies with the
diasteroemeric complexes of 4a will provide some insight into the usefulness of the
estrogen mimics 1 as well as the ongoing work on the preparation of estrogen mimics 2
and 3.
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Rajagopalan, Raghavan. Targeted Radiotherapy of Estrogen Receptor Positive Tumors, report, August 31, 2006; United States. (https://digital.library.unt.edu/ark:/67531/metadc877317/m1/3/: accessed March 28, 2024), University of North Texas Libraries, UNT Digital Library, https://digital.library.unt.edu; crediting UNT Libraries Government Documents Department.