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Synthesis and Biological Investigation into the Metabolism of Retinoids

MACKAY, LAURA (2010) Synthesis and Biological Investigation into the Metabolism of Retinoids. Masters thesis, Durham University.



Retinoids have a wide variety of applications. They can act as potent inducers of stem cell differentiation, as chemopreventative and chemotherapeutic agents, and have been utilised for the treatment of dermatological conditions. However, natural retinoids readily undergo photo-isomerisation in the presence of natural light and / or in physiological conditions. This propensity for isomerisation is believed to be the cause of many unwanted problems / side effects. Synthetic retinoids have been made by replacing key functional groups with more robust pharmacophores which retain the key functionalities of natural retinoids but are resistant to isomerisation. Previous studies have shown that synthetic retinoids, such as EC23 and EC19 have very high stability and are more potent than their natural analogues ATRA and 13cisRA.
The high potency of synthetic retinoids such as EC23 implies that they do not undergo metabolism. An in vivo investigation into the metabolism of retinoids was initiated. AG1 X2 polymer beads were used to deliver various concentrations of AT retinol solutions in DMSO to the anterior margin of a stage 20 chick limb bud which was then observed at stage 36 for signs of abnormal development such as digit duplication. Occurrence of digit duplication would suggest that AT retinol had been metabolised to ATRA, a known inducer of teratogenic effects, within the limb bud; however, only normal development was observed. This suggests that an alternative route for delivering uncharged molecules to limb buds is required.
Sonogashira cross coupling reactions were employed to synthesise ether acetate analogues of EC23 and EC19, (EC23 OAc and EC19 OAc) from TMNA with acetic acid 4-bromo-benzyl ester and acetic acid 3-iodo-benzyl ester respectively, with the intention of hydrolysing them into EC23 OH and EC19 OH, i.e. synthetic analogues of AT retinol, to be investigated for teratogenic effects in the chick limb bud as above. If successful delivery of AT retinol produced limb defects, while EC23-OH did not, this would be consistent with the idea that EC23 and its analogues are refractory to normal retinoid metabolism.
A variety of useful retinoid precursors were also synthesised from cross coupling reactions and borylation techniques. Synthetic retinoids methyl 5',6',7',8'-tetrahydro-2,2'-binaphthyl-6-carboxylate and (E)-methyl-3-(4-(5,6,7,8-tetrahydronaphthalen-2-yl)phenyl)acrylate were made by Suzuki Miyaura Cross coupling reactions, also to be tested in vivo.

Item Type:Thesis (Masters)
Award:Master of Science
Keywords:Synthetic Retinoids; Vitamin A; ATRA; EC23; EC19; AT-retinol; Chick limb bud; Teratogen; Cross-Coupling; Sonogashira; Suzuki Miyaura; Borylation;
Faculty and Department:Faculty of Science > Chemistry, Department of
Thesis Date:2010
Copyright:Copyright of this thesis is held by the author
Deposited On:19 Oct 2010 10:27

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