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

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Title: Part 1. Synthesis of n-15 labled (R)-deuterioglycine Part 2. Synthesis of carbon-linked analogs of retinoid glycoside conjugates
Author: Walker, Joel R
Description: (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.
Permanent Link: http://rave.ohiolink.edu/etdc/view?acc_num=osu1060698580
http://hdl.handle.net/2374.OX/7449
Date: 2003

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