Transcript ภาพนิ่ง 1

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 (ER5)
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
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
H3C
O
H3C
OH
H3C
H
H3C
H
HO
OH, H
O
O
CH3
H3C
imidazole, THF
H3C
H
CH3
O
H
O
O
CH3
(4)
H3C
H3C
H
H
H
O
O
Ot-BDMS
t-BDMSO(CH2)6MgBr
CuBrMe2S, THF
H3C
O H C
3
OH
(5)
H3C
(butyl)4NF
H3C
H
O
CH3
H
(3)
Ot-BDMS
H
H
O
Ot-BDMS
H
H3C
CH3
oxone, pH 10.5
H2O, CH3CN
OH
H3C
O
H3C
H
H3C
O
CH3SO2Cl
O
O
(2)
(1)
t-BDMSCl
H
O
H
H
H3C
+
OH
CH3
O
H
(CH2)6Ot-BDMS
Ot-BDMS
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