Part 1. Synthesis of n-15 labled (R)-deuterioglycine Part 2. Synthesis of carbon-linked analogs of retinoid glycoside conjugates

Part 1. Synthesis of n-15 labled (R)-deuterioglycine Part 2. Synthesis of carbon-linked analogs of retinoid glycoside conjugates

Bibliographic Details
Main Author: Walker, Joel R.
Language:English
Published: The Ohio State University / OhioLINK 2003
Subjects:
labeled amino acids
ruthenium tetraoxide oxidation
carbon-linked glycosides
retinoid anticancer agents
Online Access:http://rave.ohiolink.edu/etdc/view?acc_num=osu1060698580
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spelling ndltd-OhioLink-oai-etd.ohiolink.edu-osu10606985802021-08-03T05:48:09Z Part 1. Synthesis of n-15 labled (R)-deuterioglycine Part 2. Synthesis of carbon-linked analogs of retinoid glycoside conjugates Walker, Joel R. labeled amino acids ruthenium tetraoxide oxidation carbon-linked glycosides retinoid anticancer agents (R)-Glycine-d-15N has been used to permit assignments of the prochiral a-protons of glycine residues in the FK-506 binding protein. A key and low yielding step in the synthetic route to (R)-glycine-d-15N occurred in the ruthenium tetraoxide-mediated degradation of N-t-BOC-p-methoxybenzyl amine to the N-t-BOC-glycine after both 2H and 15N are incorporated. In order to improve this step, investigation of the oxidation reaction conditions along with various aromatic ring carboxylate precursors were undertaken. It was found that using ruthenium chloride, periodic acid as the stoichiometric re-oxidant, and N-(p-methoxyphenylmethylamine)-2,2,2-trichloroethyl carbamate were the optimal conditions and substrate. This improvement was paramount for the applicability of this route for large scale production of labeled glycine that could be used in other biological applications. The retinoic acid analog N-(4-hydroxyphenyl)retinamide (4-HPR) is an effective chemopreventative and chemotherapeutic for numerous types of cancer. In vivo, 4-HPR is metabolized to 4-HPR-O-glucuronide (4-HPROG) which has been shown to be more effective than the parent molecule in rat mammary tumor models. To investigate whether 4-HPROG was an active agent, the carbon linked analog (4-HPRCG) was synthesized and subsequently found to be a more effective chemopreventative than 4-HPROG or 4-HPR. In the original synthesis of 4-HPRCG, the route to a key C-glycoside was lengthy and inefficient. In order to investigate 4-HPRCG as a chemotherapeutic, the synthesis was redesigned and significantly improved by access to a key C-benzyl-glucuronide intermediate through employment of a Suzuki coupling reaction between an exoanomeric methylene sugar and an aryl bromide. Subsequently, 4-HPRCG was tested in an animal model and shown to possess effective chemotherapeutic actions. In vivo, potential cleavage of the amide bond of 4-HPR would liberate retinoic acid, which may explain some of its side effects. This same cleavage may occur with 4-HPRCG, thus the fully carbon linked analog of 4-HPROG (4-HBRCG) was proposed and synthesized. The synthetic route for 4-HBRCG focused on the production of a key C-benzylbromide-glucuronide obtained through the employment of Suzuki coupling chemistry. Once the benzylbromide was obtained, a key alkylation of a retinal Umpolung derivative yielded the carbon skeleton for 4-HBRCG. Subsequent biological testing will reveal the actions and potency of 4-HBRCG. 2003-10-16 English text The Ohio State University / OhioLINK http://rave.ohiolink.edu/etdc/view?acc_num=osu1060698580 http://rave.ohiolink.edu/etdc/view?acc_num=osu1060698580 unrestricted This thesis or dissertation is protected by copyright: all rights reserved. It may not be copied or redistributed beyond the terms of applicable copyright laws.
collection NDLTD
language English
sources NDLTD
topic labeled amino acids
ruthenium tetraoxide oxidation
carbon-linked glycosides
retinoid anticancer agents
spellingShingle labeled amino acids
ruthenium tetraoxide oxidation
carbon-linked glycosides
retinoid anticancer agents
Walker, Joel R.
Part 1. Synthesis of n-15 labled (R)-deuterioglycine Part 2. Synthesis of carbon-linked analogs of retinoid glycoside conjugates
author Walker, Joel R.
author_facet Walker, Joel R.
author_sort Walker, Joel R.
title Part 1. Synthesis of n-15 labled (R)-deuterioglycine Part 2. Synthesis of carbon-linked analogs of retinoid glycoside conjugates
title_short Part 1. Synthesis of n-15 labled (R)-deuterioglycine Part 2. Synthesis of carbon-linked analogs of retinoid glycoside conjugates
title_full Part 1. Synthesis of n-15 labled (R)-deuterioglycine Part 2. Synthesis of carbon-linked analogs of retinoid glycoside conjugates
title_fullStr Part 1. Synthesis of n-15 labled (R)-deuterioglycine Part 2. Synthesis of carbon-linked analogs of retinoid glycoside conjugates
title_full_unstemmed Part 1. Synthesis of n-15 labled (R)-deuterioglycine Part 2. Synthesis of carbon-linked analogs of retinoid glycoside conjugates
title_sort part 1. synthesis of n-15 labled (r)-deuterioglycine part 2. synthesis of carbon-linked analogs of retinoid glycoside conjugates
publisher The Ohio State University / OhioLINK
publishDate 2003
url http://rave.ohiolink.edu/etdc/view?acc_num=osu1060698580
work_keys_str_mv AT walkerjoelr part1synthesisofn15labledrdeuterioglycinepart2synthesisofcarbonlinkedanalogsofretinoidglycosideconjugates
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