Please use this identifier to cite or link to this item: https://hdl.handle.net/11147/11077
Title: Studies toward the asymmetric synthesis of novel chiral 1,4-oxazepan-5-one derivatives
Other Titles: Yeni kiral 1,4-okzazepan-5-on türevlerinin asimetrik sentezine yönelik çalışmalar
Authors: Çağır, Ali
Vural, Ezgi
01. Izmir Institute of Technology
Keywords: Asymmetric synthesis
Pharmacophore
p53-MDM2 interaction
Cancer drugs
Drug discovery
Issue Date: Dec-2020
Publisher: 01. Izmir Institute of Technology
Source: Vural, E. (2020). Studies toward the asymmetric synthesis of novel chiral 1,4-oxazepan-5-one derivatives. Unpublished master's thesis, İzmir Institute of Technology, İzmir, Turkey
Abstract: Pharmacophore design to inhibit the interaction between p53 and MDM2 became a novel approach for cancer therapy. p53, known as the guardian of genome, controls the cell cycle arrest, apoptosis and DNA repair under stress. Nonetheless, when over-expressed, MDM2 causes proliferation in the cell and eventually tumorgenesis. The feedback mechanism between p53 and MDM2 arises from the interaction of p53 through the hydrophobic cleft which consists of Phe19, Trp23 and Leu26 aminoacids in the N-terminal of MDM2. In this study, it was aimed to synthesize a new, chiral 1,4-oxazepan-5-one derivatives by asymmetric synthesis. (R)-2-amino-2-(4-chlorophenyl)acetic acid was used as starting material. Amino group was protected by trityl group then the carboxylic acid part was reduced by LiAlH4 to produce N-trityl-protected amino alcohol. Dess Martin periodinane was used for the oxidation of the alcohol to the aldehyde, then 3-chlorophenylmagnesium bromide was added to the aldehyde by Grignard reaction. Deprotection of N-trityl was performed with TFA then, coupling reactions of produced aminoalcohol with different α,β-unsaturated carboxylic acids were performed by HATU and DIPEA. Despite all of the attempts, cyclization to seven membered 1,4-oxazepan-5-one ring was never achieved.
p53 ve MDM2 arasındaki etkileşimi engellemek için farmakofor tasarımı kanser terapisinde yeni bir yaklaşım olmaktadır. Genomum koruyucusu olarak bilinen p53 stres altında hücre siklusunda aresti, apaptozu ve DNA tamirini kontrol eder. Bununla birlikte, MDM2 fazla eksprese edildiğinde hücrenin çabuk çoğalmasına ve neticede tümör oluşumuna neden olur. p53 ve MDM2 arasındaki geribesleme mekanizması p53'ün, MDM2'nin N-ucundaki Phe19, Trp23 ve Leu26 aminoasitlerinden oluşan hidrofobik boşluktan etkileşir. Bu çalışmada asimetrik sentez ile yeni kiral 1,4-oksazepan-5-on türevlerinin sentezlenmesi amaçlanmıştır. (R)-2-amino-2-(4-chlorophenyl)acetik asit başlangıç maddesi olarak kullanıldı. Amino grubu tritil grubu ile korundu ve daha sonra maddenin karboksilik asit kısmı LiAlH4 ile N-korunmalı amino alkol elde edmek üzere indirgendi. Dess Martin periodinane alkolün aldehite oksidasyon için kullanıldı, daha sonra 3-klorofenilmagnezyum bromür Grignard reaksiyonu ile aldehite eklendi. Koruyucu tritil grubu TFA ile uzaklaştırıldı ve oluşan aminoalkolün farklı α,β-doymamış karboksilik asit ile bağlanma reaksiyonları HATU ve DIPEA kullanılarak gerçekleştirildi. Tüm denemelere rağmen yedi üyeli 1,4-oksazepan-5-on halkalaşması hiç bir zaman gerçekleştirilemedi.
Description: Thesis (Master)--Izmir Institute of Technology, Chemistry, Izmir, 2020
Includes bibliographical references (leaves. 52-56)
Text in English; Abstract: Turkish and English
URI: https://hdl.handle.net/11147/11077
Appears in Collections:Master Degree / Yüksek Lisans Tezleri

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