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Production. of. Modified Megestrol. by. Jittima Khorungkul. Modified Megestrol. Production. Goal : Synthesis bifunctional molecule that can use in Liver cancer treatment. Bifucntional molecule: Produce DNA adduct Specific binding the
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Production of Modified Megestrol by Jittima Khorungkul
Modified Megestrol Production Goal: Synthesis bifunctional molecule that can use in Liver cancer treatment Bifucntional molecule:Produce DNA adduct Specific binding the estrogen receptor with high affinity
Bifunctional molecule structure Estrogen receptor Megestrol Ligand Domain Linker Binding to vER War Head DNA adduct
Undamaged cell How modified megestrol work….. Estrogen and ER complex Nuclear protein (e.g.ER) promoter Expression of essential gene
Adduct shielded from Repair DNA repair enzyme Adduct persists
In non-cancer cell (less express of vER) Adduct shielded from Repair DNA repair enzyme adduct
Adduct shielded from Repair Cancer cell (over express of vER)
Adduct “Hijacks”Transcription Factor Cancer cell (over express of vER) X
Modified megestrol Consisted of : N,N -bis-chloroethylaniline (War Head) Alkyl-amino-carbamate (Linker) Megestrol acetate (Ligand Domain) War Head (CH2)2Cl H H O -N (CH2)6-N-(CH2)2-0 N-(CH2)3- (CH2)2Cl Ligand Domain Linker
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 7 alpha position Megestrol acetate
Modified megestrol N,N -bis-chloroethylaniline (War Head) - Ability to alkylate DNA - From covalent DNA adduct at the N7 position of guanines
Modified megestrol Alkyl-amino-carbamate (Linker) Consist of - amino - carbarmate group provide a relatively rigid connection resistant to hydrolytic enzyme
Synthesis Procedure (3) (2) (1) (4) (5)
Synthesis Procedure Final Product: Modified megestrol
Properties of Modified Megestrol Chemical Formula: C42H65Cl2N3O4 Exact Mass: 745.44 Molecular weight: 746.89 Element Analysis: C, 67.54; H, 8.77; Cl, 9.49; N, 5.63; O, 8.57
Summary • Modified Megestrol is the bifunctional molecule that • consist of ‘Warhead’, ‘Linker’ and ‘Ligand binding domain’ • It has the abilities to produce DNA adduct and capable of • binding the vER • - vER-DNA adduct complexes will shielded from DNA repair enzyme Megestrol acetate Linker War head Modified Megestrol