Synthesis And Aromatase Inhibitory Activity
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09/09/2004
Discovery Research
Synthesis and Aromatase Inhibitory Activity of Novel Pyridine-Containing Isoflavones Young –Woo Kim, John C Hackett and Robertt W. Brueggemeier College of Pharmacy, The Ohio State University J. Med. Chem. 2004, 47, 4032 - 4040
Dr. Venugopal Rao Veeramaneni 1
Highlights of the presentation Introduction of Cancer. Details of Breast Cancer. Aromatase enzyme and Steroid biosynthesis. Aromatase Inhibitors. Design and Synthesis of Isoflavones. Results and Discussions. Conclusions. 2
Cancers are a group of diseases that cause cells in the body to change and grow out of control. control 3
Cell Structure & Cell Division
4
5
Cancers (Tumors)
6
Estimated Cancer Deaths in 2004
7
Breast Cancer Normal Breast Structure Lobules ⇒ Produce Milk Ducts ⇒ Connect Lobules to Nipple Fatty Tissue Ligaments Blood Vessels Lymphatic Vessels 8
Normal Breast A = Ducts B = Lobules C = Dilated Section of duct to hold milk D = Nipple E = Fat F = Pectorails major muscle G = Chest wall A = Normal Duct cell B = Basement membrane C = Lumen (center of duct)
9
Cancer in the Breast
10
=< 2cm 98 %
11
> 2 cm to < 5cm 88 – 76 %
< 5cm, spread to
Advanced Cancer
Lymph node 49 – 46 %
16 %
Risk Factors Family History Genetic Risks Personal History Certain types of breast cancer Menstrual History
12
Reproductive History Oral Contraceptives Hormone Replacement Alcohol Weight
Early Detection Methods Breast Self Examination. Clinical Breast Examination. Screening Mammography.
13
Mammography
14
Aromatase Cytochrome P450 enzyme complex. First reported in human placental tissues by K J Rayan in 1959. Main expression sites: ovarian granulosa cells, placental syncytiotrophoblast, adipose tissue, skin fibroblasts and the brain. . Role in estrogen biosynthesis. 15
Hormone Dependent Breast Cancer
16
Biosynthesis of Steroid Hormones O OH
O
HO
O
Progesterone
17 α-hydroxylase
4,5-Isomerase
O
O
HO
O
17 hydroxyprogesterone
17 hydroxypregnenlone
17, 20 - Lyase
Side Chain Cleavage
17 α-hydroxylase O OH
HO
Cholestrol
HO
dehydroepiandrosterone
Pregnenolone
dehydrogenase
17, 20 - Lyase
OH
O
O
HO androstenedione
17
androstenediol
Biosynthesis of Steroid HormonesContd… Androstenedione
Androstenediol
Aromatase
4,5-Isomerase
OH
OH
O
Aromatase
dehydrogenase HO
HO
O
estradiol
estrone
testosterone
O
O
O
HO
O2
HO
O2
O
O
19,19I - dihydroxyandrostenedione
N
N
N
N
O O
Fe
Fe
O
OH
O HO
HO O H
O
H
O
18
HCO2H
N
N
19-oxoandrostenedione
O
N
N
O2
- H2O
O
19-hydroxy androstenedione
androstenedione
OH
O
O OH
HO
estrone
Classes of Drugs Used Treat Breast Cancer Class
Action
Examples
SERMs (Selective Estrogen Receptor Modulators)
Bind estrogen receptors in breast cancer cells
Tamoxifen (Nolvadex) Evista (Raloxifene) Fareston (Toremifen)
Aromatase Inhibitors
Prevent Production of estrogen in adrenal glands
Aromasin (Exemestane) Femara (Letrozole) Arimdex (anastrozole) Megace (Megestrol)
Biologic Response modulators
Bind with certain proteins on breast cancer cells, preventing their growth
Herceptine (Trastuzumab)
19
Classification of aromatase Inhibitors
20
Generation
Type 1 (Steroidal)
Type 2 (Nonsteroidal)
First
None
Aminoglutethimide
Second
Formestane
Fadrozole Rogletimide
Third
Exmestane
Anastrozole Letrozole Vorozole
Irreversibly inactivates the enzyme
reversibly bind the enzyme
Aromatase Inhibitors O
OH
OH
Ph
OH
N
O H O
O
O OH
Ph
O
Tamoxifen
Megestrol
O
OH
O
O
CH3
O
Ellence
1973, Astrazeneca
1963, BMS
OH
N
Formestane
OH
1984, Pfizer
1992, Novartis
NH2
O
OH
O OH
N N
OH N
N
N
H
H
O
N
N
N N
Fadrozole
O
Anastrozole
Letrozole
1995, Astrazeneca 1995, Novartis
O
OH
O
O
Adriamycin
N
1996, Novartis
OH
1996, BMS
NH2
O
H3C O
O HO N
N
O
H
HO
Xeloda
N H F
1998, Roche 21
O
N
H
4
O
O P
N O
1999, Pfizer
N
OH
N
OH
H
Aromasin
N
OH
Zometa
P
N
OH OH
2000, Novartis
N Cl
CH3
N
Vorozole
Pre-Registered, Janssen
Designing of Novel Inhibitor OH
O OH
OH
O
HO HO
OH
O
O
O
HO
Chrysin
Biochanin A
Biological Testing, Lion
Phase II, Yamanouchi O
R3 O
S
R1 = H, Me, OMe, OH R2 = OH, OMe, OBn R3 = Allyl, Benzyl, Pyridylmethyl
2,4,7-tri substituted isoflavone
22
O
Genistein
R1
R2
O
Phase II, Nihon University
Synthesis of Isoflavones R1
R1 O
O
R2OH
HO
Ph3P, DIAD R2 THF, O °C, 0.5 h
OH
(1) R1 = H, Me, OMe
O
OH
(2) R1 = H, Me, OMe R2 = Me, Bn
R1
R1
O
O
n-BuN.HSO4, aq. NaOH CS2, R3X, THF, r.t overnight
BBr3, CHCl3, r.t or
R2
R3 O
O
S
(3) R1 = H, Me, OMe, OH R2 = OH, OMe, OBn R3 = Allyl, Benzyl, Pyridylmethyl
23
BF3.OEt2, Me2S, CH2Cl2 r.t, overnight
R3 HO
O
S
(4) R2 = OH, OMe, OBn R3 = Allyl, Benzyl, Pyridylmethyl
Results and Discussion O
O
O
Bn O
O
IC 50
Bn
S
Bn
Bn O
100
O
IC 50
O
O
O
O
O
S
O
IC 50
100
S
O
IC 50 = 1.6
N
O
O
S
O
IC 50
IC 50 = 9.2 N O
O
100
O
O
O
S
S
100
N
O
O
Bn O
O
O
S
O
IC 50 = 3.0
O
S
IC 50 = 3.1
N
HO
O
IC 50 = 0.61
24
HO N
O
IC 50 = 0.28
N
O O
O
S
S
N
OH O
O
IC 50 = 0.21
HO
S
O
IC 50 = 0.22 N
S N
Results and Discussion O OH
HO
O
O
O
O
O
O
Biochanin A IC 50 = 34 µM
O
O
O
S
O
S N
N
IC 50 = 3.1 µM
IC 50 = 0.53 µM
NH2
O
O
O
N H
O
HO
O
O
S
25
O
S
N
Aminoglutithimide IC 50 = 2.8 µM
O
IC 50 = 0.21 µM
N
IC 50 = 0.22 µM
Conclusions Aromatase inhibitory activity can be achieved with Isoflavone Scaffold. The SAR studies indicates binding modes of 7prortected analogues might be different from 7hydroxy analogues. Based on kinetic studies these compounds compete at active site of aromatase with the natural substrate, androstenedione.
26
Thanks To All
Arise awake, and stop not Till the goal is reached 27
Discovery Research
Synthesis and Aromatase Inhibitory Activity of Novel Pyridine-Containing Isoflavones Young –Woo Kim, John C Hackett and Robertt W. Brueggemeier College of Pharmacy, The Ohio State University J. Med. Chem. 2004, 47, 4032 - 4040
Dr. Venugopal Rao Veeramaneni 1
Highlights of the presentation Introduction of Cancer. Details of Breast Cancer. Aromatase enzyme and Steroid biosynthesis. Aromatase Inhibitors. Design and Synthesis of Isoflavones. Results and Discussions. Conclusions. 2
Cancers are a group of diseases that cause cells in the body to change and grow out of control. control 3
Cell Structure & Cell Division
4
5
Cancers (Tumors)
6
Estimated Cancer Deaths in 2004
7
Breast Cancer Normal Breast Structure Lobules ⇒ Produce Milk Ducts ⇒ Connect Lobules to Nipple Fatty Tissue Ligaments Blood Vessels Lymphatic Vessels 8
Normal Breast A = Ducts B = Lobules C = Dilated Section of duct to hold milk D = Nipple E = Fat F = Pectorails major muscle G = Chest wall A = Normal Duct cell B = Basement membrane C = Lumen (center of duct)
9
Cancer in the Breast
10
=< 2cm 98 %
11
> 2 cm to < 5cm 88 – 76 %
< 5cm, spread to
Advanced Cancer
Lymph node 49 – 46 %
16 %
Risk Factors Family History Genetic Risks Personal History Certain types of breast cancer Menstrual History
12
Reproductive History Oral Contraceptives Hormone Replacement Alcohol Weight
Early Detection Methods Breast Self Examination. Clinical Breast Examination. Screening Mammography.
13
Mammography
14
Aromatase Cytochrome P450 enzyme complex. First reported in human placental tissues by K J Rayan in 1959. Main expression sites: ovarian granulosa cells, placental syncytiotrophoblast, adipose tissue, skin fibroblasts and the brain. . Role in estrogen biosynthesis. 15
Hormone Dependent Breast Cancer
16
Biosynthesis of Steroid Hormones O OH
O
HO
O
Progesterone
17 α-hydroxylase
4,5-Isomerase
O
O
HO
O
17 hydroxyprogesterone
17 hydroxypregnenlone
17, 20 - Lyase
Side Chain Cleavage
17 α-hydroxylase O OH
HO
Cholestrol
HO
dehydroepiandrosterone
Pregnenolone
dehydrogenase
17, 20 - Lyase
OH
O
O
HO androstenedione
17
androstenediol
Biosynthesis of Steroid HormonesContd… Androstenedione
Androstenediol
Aromatase
4,5-Isomerase
OH
OH
O
Aromatase
dehydrogenase HO
HO
O
estradiol
estrone
testosterone
O
O
O
HO
O2
HO
O2
O
O
19,19I - dihydroxyandrostenedione
N
N
N
N
O O
Fe
Fe
O
OH
O HO
HO O H
O
H
O
18
HCO2H
N
N
19-oxoandrostenedione
O
N
N
O2
- H2O
O
19-hydroxy androstenedione
androstenedione
OH
O
O OH
HO
estrone
Classes of Drugs Used Treat Breast Cancer Class
Action
Examples
SERMs (Selective Estrogen Receptor Modulators)
Bind estrogen receptors in breast cancer cells
Tamoxifen (Nolvadex) Evista (Raloxifene) Fareston (Toremifen)
Aromatase Inhibitors
Prevent Production of estrogen in adrenal glands
Aromasin (Exemestane) Femara (Letrozole) Arimdex (anastrozole) Megace (Megestrol)
Biologic Response modulators
Bind with certain proteins on breast cancer cells, preventing their growth
Herceptine (Trastuzumab)
19
Classification of aromatase Inhibitors
20
Generation
Type 1 (Steroidal)
Type 2 (Nonsteroidal)
First
None
Aminoglutethimide
Second
Formestane
Fadrozole Rogletimide
Third
Exmestane
Anastrozole Letrozole Vorozole
Irreversibly inactivates the enzyme
reversibly bind the enzyme
Aromatase Inhibitors O
OH
OH
Ph
OH
N
O H O
O
O OH
Ph
O
Tamoxifen
Megestrol
O
OH
O
O
CH3
O
Ellence
1973, Astrazeneca
1963, BMS
OH
N
Formestane
OH
1984, Pfizer
1992, Novartis
NH2
O
OH
O OH
N N
OH N
N
N
H
H
O
N
N
N N
Fadrozole
O
Anastrozole
Letrozole
1995, Astrazeneca 1995, Novartis
O
OH
O
O
Adriamycin
N
1996, Novartis
OH
1996, BMS
NH2
O
H3C O
O HO N
N
O
H
HO
Xeloda
N H F
1998, Roche 21
O
N
H
4
O
O P
N O
1999, Pfizer
N
OH
N
OH
H
Aromasin
N
OH
Zometa
P
N
OH OH
2000, Novartis
N Cl
CH3
N
Vorozole
Pre-Registered, Janssen
Designing of Novel Inhibitor OH
O OH
OH
O
HO HO
OH
O
O
O
HO
Chrysin
Biochanin A
Biological Testing, Lion
Phase II, Yamanouchi O
R3 O
S
R1 = H, Me, OMe, OH R2 = OH, OMe, OBn R3 = Allyl, Benzyl, Pyridylmethyl
2,4,7-tri substituted isoflavone
22
O
Genistein
R1
R2
O
Phase II, Nihon University
Synthesis of Isoflavones R1
R1 O
O
R2OH
HO
Ph3P, DIAD R2 THF, O °C, 0.5 h
OH
(1) R1 = H, Me, OMe
O
OH
(2) R1 = H, Me, OMe R2 = Me, Bn
R1
R1
O
O
n-BuN.HSO4, aq. NaOH CS2, R3X, THF, r.t overnight
BBr3, CHCl3, r.t or
R2
R3 O
O
S
(3) R1 = H, Me, OMe, OH R2 = OH, OMe, OBn R3 = Allyl, Benzyl, Pyridylmethyl
23
BF3.OEt2, Me2S, CH2Cl2 r.t, overnight
R3 HO
O
S
(4) R2 = OH, OMe, OBn R3 = Allyl, Benzyl, Pyridylmethyl
Results and Discussion O
O
O
Bn O
O
IC 50
Bn
S
Bn
Bn O
100
O
IC 50
O
O
O
O
O
S
O
IC 50
100
S
O
IC 50 = 1.6
N
O
O
S
O
IC 50
IC 50 = 9.2 N O
O
100
O
O
O
S
S
100
N
O
O
Bn O
O
O
S
O
IC 50 = 3.0
O
S
IC 50 = 3.1
N
HO
O
IC 50 = 0.61
24
HO N
O
IC 50 = 0.28
N
O O
O
S
S
N
OH O
O
IC 50 = 0.21
HO
S
O
IC 50 = 0.22 N
S N
Results and Discussion O OH
HO
O
O
O
O
O
O
Biochanin A IC 50 = 34 µM
O
O
O
S
O
S N
N
IC 50 = 3.1 µM
IC 50 = 0.53 µM
NH2
O
O
O
N H
O
HO
O
O
S
25
O
S
N
Aminoglutithimide IC 50 = 2.8 µM
O
IC 50 = 0.21 µM
N
IC 50 = 0.22 µM
Conclusions Aromatase inhibitory activity can be achieved with Isoflavone Scaffold. The SAR studies indicates binding modes of 7prortected analogues might be different from 7hydroxy analogues. Based on kinetic studies these compounds compete at active site of aromatase with the natural substrate, androstenedione.
26
Thanks To All
Arise awake, and stop not Till the goal is reached 27
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