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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 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 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. 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 DNA and production of protein Two different ER are usually call and receptor Estrogen function as signaling molecule 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 (ER5) 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 (ER5) ---- > lack the hormone binding domain but being intact in the DNA-binding domain Chemotherapy “The use of chemical substances to treat the disease” Types Alkylating agents Plant Alkaloids Antitumor Antibiotics Antimetabolites Topoisomerase inhibitors Miscellaneous Antineoplastics Hormonal therapy 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 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 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 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 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 Megestrol Ligand Domain Linker Binding to vER War Head DNA adduct How modified megestrol work….. Undamaged cell Estrogen and ER complex Nuclear protein (e.g.ER) promoter Expression of essential gene Adduct shielded from Repair DNA repair enzyme Adduct persists Adduct shielded from Repair In non-cancer cell (less express of vER) adduct DNA repair enzyme 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 H O H (CH2)6-N-(CH2)2-0 N-(CH2)3- (CH2)2Cl -N (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 Cl N 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 H 3C O H 3C OH H H 3C H H 3C HO OH, H O O CH3 (1) H 3C t- B D M S C l im id a z o le , T H F H O O t- B D M S H CH3 H 3C H H O O H 3C H H 3C OH (5) O t- B D M S H 3C ( b u ty l) 4 N F H 3C O CH3 H (3) O t- B D M S H O O H H 3C CH3 (2) C u B rM e 2 S , T H F OH H 3C O o x o n e , p H 1 0 .5 H 2O , C H 3C N t- B D M S O ( C H 2 ) 6 M g B r O (4) H 3C CH3 O O H 3C H O H 3C H H 3C O C H 3S O 2C l H O H H H 3C + OH CH3 O H H ( C H 2 ) 6 O t- B D M S O t- B D M S imidazole, THF O CuBrMe2 S, THF O CH 3 Synthesis Procedure (4) H3 C H3 C CH3 SO2 Cl NaBH4 H 3C H 3C (butyl) 4NF H O H (7) (6) H 3C DEAD PPh 3, Br2 H 3C H H O H Ot -BDMS O Ph P NH(CH2 )2 Ot-BDMS Ph O CH 3 H3 C H3 C (8) H H3 C (butyl)4 NF H O O Ot-BDMS CH 3 (10) O H P Ph (CH 2) 6N Ph O O2 N (CH 2) 2OH Cl O P Ph (CH 2) 6N Ph (CH 2) 2O-tBDMS H 3C O H3C H H O O Ot-BDMS H CH 3 (9) CH 3 H3 C H H O (CH 2) 6Br O H (CH 2) 6OH O CH 3 Ot -BDMS H H O (CH 2) 6Ot -BDMS O OH (5) Ot-BDMS H (CH 2) 6Ot-BDMS O H C 3 CH3 (11) Ot-BDMS O P Ph (CH2 )6 N Ph (CH2 )2 O O O H NO2 Synthesis Procedure H3 C H 3C i) DIPEA, THF H H O NH 2 BOC CH 3 (CH 2) 3 OH O H P Ph O Ph (CH 2) 6N (CH2 )2 O N H Cl N (12) N Cl ii) Cl Cl H 3C HCl, THF H H 3C LiOH OH H O CH3 H O (CH 2 )6 NH (CH2 )2 O N H (13) Cl N Cl 2-(6-((7R,8R,9S,10R,13S,14S,17S)-17-hydroxy-6,10,13-trimethyl-3-oxo-2,3,6,7,8,9,10,11,12,13,14,15,1 tetradecahydro-1H-cyclopenta[a]phenanthren-7-yl)hexylamino)ethyl 3-(4-(bis(2chloroethyl)amino)phenyl)propylcarbamate 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 H3 C Megestrol acetate H3 C OH Linker H H H O CH 3 War head O (CH 2) 6NH (CH 2) 2O N H Cl N Modified Megestrol Cl