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Innovative Synthesis of Modified Megestrol for Liver Cancer Treatment

This project aims to synthesize a bifunctional molecule, Modified Megestrol, for liver cancer treatment. Modified Megestrol is designed to produce DNA adducts and bind to the estrogen receptor with high affinity. The structure consists of a Ligand Domain, Linker, and War Head. The molecule works by shielding adducts from repair enzymes in cancer cells, allowing it to "hijack" transcription factors. The synthesis process involves specific chemical reactions to create the final product. Modified Megestrol's chemical properties include a molecular weight of 746.89 and elemental analysis. This innovative molecule shows promising potential for targeted cancer therapy.

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Innovative Synthesis of Modified Megestrol for Liver Cancer Treatment

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  1. Production of Modified Megestrol by Jittima Khorungkul

  2. 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

  3. Bifunctional molecule structure Estrogen receptor Megestrol  Ligand Domain  Linker Binding to vER  War Head DNA adduct

  4. Undamaged cell How modified megestrol work….. Estrogen and ER complex Nuclear protein (e.g.ER) promoter Expression of essential gene

  5. Adduct shielded from Repair DNA repair enzyme Adduct persists

  6. In non-cancer cell (less express of vER) Adduct shielded from Repair DNA repair enzyme adduct

  7. Adduct shielded from Repair Cancer cell (over express of vER)

  8. Adduct “Hijacks”Transcription Factor Cancer cell (over express of vER) X

  9. 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

  10. 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

  11. Modified megestrol N,N -bis-chloroethylaniline (War Head) - Ability to alkylate DNA - From covalent DNA adduct at the N7 position of guanines

  12. Modified megestrol Alkyl-amino-carbamate (Linker) Consist of - amino - carbarmate group  provide a relatively rigid connection  resistant to hydrolytic enzyme

  13. Synthesis Procedure (3) (2) (1) (4) (5)

  14. Synthesis Procedure

  15. Synthesis Procedure Final Product: Modified megestrol

  16. 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

  17. 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

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