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Novel Drug Design

Novel Drug Design. Modified Megestrol. by. Group II. Introduction. Hepatocellular carcinoma. More than 500,000 people are diagnosed each year throughout the world and over a million death per year More common in developing country in Africa and East asia.

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Novel Drug Design

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  1. Novel Drug Design Modified Megestrol by Group II

  2. Introduction Hepatocellular carcinoma • More than 500,000 people are diagnosed each year throughout the world and over a million death per year • More common in developing country in Africa and East asia • Occur almost in patients witn - Chronic hapatitis virus C and/or B infection - Cirrhosis • Represent the final step of the natural course for virus induced liver disease

  3. More frequent in men than in women • No specific drug for the treatment • Risk factors: - HVB - HVC - aflatoxin - alcohol - sex hormones Geographic distribution of hepatocellular carcinoma.Incidence rates (%) in total population A, female; B, male.

  4. Estrogen Receptor (ER) • Receptor for estrogen located intracellular in many organs • Contain a specific site to which only estrogens (or closely related molecules) can bind • Act as a transcription factor, regulate the reading of DNAand production of protein  Two different ER are usually call  and  receptor

  5. Estrogen function as signaling molecule

  6. Estrogen Receptor in Liver • ER has been well characterized in human liver Normal Liver  wild-type ERs Hepatocellular carcinoma wild-type ERs Variant form of ER (vER) exon 5 deletion (ER5)

  7. Variant from of Estrogen Receptor and Hepatocellular carcinoma •  vER largely predominates in HCC • vER appears most frequent in patients infected with Hepatitis B virus • Growth rate of HCC in patient with vER higher than patient with wtER • vER  elevate proliferation rate  tumor aggressiveness  lack of hormonal control on tumor growth  (ER5) ---- > lack the hormone binding domain but being intact in the DNA-binding domain

  8. Chemotherapy “The use of chemical substances to treat the disease” Types Alkylating agentsPlant Alkaloids Antitumor AntibioticsAntimetabolitesTopoisomerase inhibitorsMiscellaneous Antineoplastics Hormonal therapy

  9. Alkylating agents Add alkyl groups to many electronegative groups e.g Nitrogen mustard(cytotoxic chemotherapy) Hormonal therapy Competitive binding to the receptor and block the action of hormone and thereby interfere with, or even prevent, the proliferation of cancer cell e.g.  Tamoxifen  Megestrol acetate

  10. Megestrol acetate A synthetic female hormone belonging to the progesterone group Anti estrogen action Drug able to block both wtER and vER Usually for women whose cancers do not respond to the other hormone treatments • Survival of HCC patients therapy with megestrol acetate is increase Slowdown tumor growth

  11. Modified Megestrol Bifunctional molecule  Produce DNA adducts  Specific bind the estrogen receptor - Inhibit DNA repair - Induction of growth inhibition, apoptosis and antitumor activity - Consist of => War head => Linker => ligand binding domain

  12. Presentation Outline • - Production • Ms. Jittima Khorungkul • Mechanism Testing of the Drug • Mr. Pasavi Ratchapongsirikul • Preclinical Study • Ms. Sirikan Nawapan • Clinical Trial • Ms. Carolina Rusdy Akib • - Marketing • Mr. Mahinda Chandrasiri Edirisooriya

  13. Production of Modified Megestrol by Jittima Khorungkul

  14. 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

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

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

  17. Adduct shielded from Repair DNA repair enzyme Adduct persists

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

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

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

  21. 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

  22. 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

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

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

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

  26. Synthesis Procedure

  27. Synthesis Procedure Final Product: Modified megestrol

  28. 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

  29. 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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