Novel Drug Design

Modified Megestrol

by

Group II

Introduction

Hepatocellular carcinoma

Occur almost in patients witn - Chronic hapatitis virus C and/or B infection - CirrhosisRepresent the final step of the natural course for virus induced liver disease

500000More than , people are diagnosed each year tttttttttt ttt t tttt and over a million death per yearMore common in developing country in Africa and East asia

More frequent in men than in womenNo specific drug for the treatmentRisk 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 assignaling molecule

Estrogen Receptor in Liver

ER has been well characterized in human liver

Normal Liver wild-type ERs

Hepatocellular carcinoma

wild-type ERsVariant 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 agentsPlant Alkaloids Antitumor AntibioticsAntimetabolitesTopoisomerase inhibitorsMiscellaneous Antineoplastics Hormonal therapy

Alkylating agents Add alkyl groups to many electronegative groups e.g Nitrogen mustard (cytotoxic chemotherapy)

Hormonal therapy

e.g. Tamoxifen Megestrol acetate

Competitive binding to the receptor and block the action of hormone and thereby interfere with, or even prevent, the proliferation of cancer cell

Megestrol acetate

A synthetic female hormone belonging to the progesterone group

Survival of HCC patients therapy with megestrol acetate is increase

Slowdown tumor growth

Drug able to block both wtER and vER

Anti estrogen action

Usually for women whose cancers do not respond to the other hormone treatments

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

Modified Megestrol

Presentation Outline

- Production Ms. Jittima Khorungkul

- Mechanism Testing of the Drug Mr. Pasavi Ratchapongsirikul

- Preclinical Study Ms. Sirikan Nawapan

- Clinical TrialMs . Carolina Rusdy Akib - Marketing

Mr. Mahinda Chandrasiri Edirisooriya

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