Production

of

Modified Megestrol

by

Jittima Khorungkul

Modified MegestrolProduction

Goal: Synthesis bifunctional molecule that can use in Liver cancer treatment

Bifucntional molecule: Produce DNA adduct Specific binding the estrogen receptor with high affinity

Megestrol Estrog

en rec

eptor

DNA adduct

Binding to vER

Bifunctional molecule structure

Ligand Domain

Linker

War Head

Expression of essential

gene

Undamaged cellUndamaged cell

Nuclear protein (e.g.ER)

promoter

How modified megestrol work…..

Estrogen and ER complex

Adduct shielded from Adduct shielded from RepairRepair

DNA repair enzyme

Adduct persists

Adduct shielded from RepairAdduct shielded from Repair

In non-cancer cell

(less express of vER)

DNA repair enzyme

adduct

Adduct shielded from Adduct shielded from RepairRepair

Cancer cell(over express of vER)

Adduct “Hijacks”Adduct “Hijacks”Transcription FactorTranscription Factor

X

Cancer cell(over express of vER)

Modified megestrol

N,N -bis-chloroethylaniline (War Head)

Alkyl-amino-carbamate (Linker)

Megestrol acetate (Ligand Domain)

Consisted of :

(CH2)6-N-(CH2)2-0 N-(CH2)3- -N

H O H (CH2)2

Cl

(CH2)2

ClLigand Domain Linker

War Head

Modified megestrol

Megestrol acetate (Ligand Domain)

-Binding to the linker at 7 alpha position Large alkyl groups can be attached with retention of high affinity for ER

Megestrol acetate

7 alpha position

Modified megestrol

N,N -bis-chloroethylaniline (War Head)

- Ability to alkylate DNA- From covalent DNA adduct at the N7 position of guanines

N

Cl

Cl

N,N -bis-chloroethylaniline

Modified megestrol

Alkyl-amino-carbamate (Linker)

Consist of - amino - carbarmate group provide a relatively rigid connection resistant to hydrolytic enzyme

Synthesis Procedure

(1) (2) (3)

(4) (5)

Synthesis Procedure

Synthesis Procedure

Final Product: Modified megestrol

Properties of Modified Megestrol

Chemical Formula: C42H65Cl2N3O4

Exact Mass: 745.44Molecular weight: 746.89Element Analysis: C, 67.54; H, 8.77; Cl, 9.49; N, 5.63; O, 8.57

Summary

H

CH3

H3C

H

H

H3C OH

(CH2)6NH(CH2)2O

O

NH

NCl

Cl

O

Modified Megestrol

-Modified Megestrol is the bifunctional molecule thatconsist of ‘Warhead’, ‘Linker’ and ‘Ligand binding domain’ -It has the abilities to produce DNA adduct and capable ofbinding the vER - vER-DNA adduct complexes will shielded from DNA repair enzyme

War head

LinkerMegestrolacetate