synthesis and aromatase inhibitory activity

8/14/2019 Synthesis and Aromatase Inhibitory Activity

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Discovery Research

Synthesis andSynthesis and AromataseAromatase Inhibitory Activity ofInhibitory Activity ofNovelNovel PyridinePyridine--ContainingContaining IsoflavonesIsoflavones

09/09/2004

Young Woo Kim, John C Hackett and Robertt W. BrueggemeierCollege of Pharmacy, The Ohio State University

J. Med. Chem. 2004, 47, 4032 - 4040

Dr. Venugopal Rao VeeramaneniDr. Venugopal Rao Veeramaneni


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Highlights of the presentationHighlights of the presentation

Introduction of Cancer.Introduction of Cancer.

Details of Breast Cancer.Details of Breast Cancer.

Aromatase enzyme and Steroid biosynthesis.Aromatase enzyme and Steroid biosynthesis.

Aromatase Inhibitors.Aromatase Inhibitors.

Design and Synthesis ofDesign and Synthesis ofIsoflavonesIsoflavones..

Results and Discussions.Results and Discussions.Conclusions.Conclusions.


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Cancers are a group of diseases that cause cells inCancers are a group of diseases that cause cells in

the body to change and grow out of controlthe body to change and grow out of control.


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Cell Structure &Cell Structure & Cell DivisionCell Division


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Cancers (Cancers (TumorsTumors))


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Estimated Cancer Deaths in 2004Estimated Cancer Deaths in 2004


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Breast CancerBreast Cancer

Lobules Produce MilkDucts Connect Lobules to NippleFatty Tissue

Ligaments

Blood Vessels

Lymphatic Vessels

NormalNormal Breast StructureBreast Structure


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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)

Normal BreastNormal Breast


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Cancer in the BreastCancer in the Breast


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=< 2cm > 2 cm to < 5cm< 5cm, spread to

Lymph nodeAdvanced Cancer

98 % 88 76 %49 46 %

16 %


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Family History

Genetic Risks

Personal History

Certain types ofbreast cancer

Menstrual History

Reproductive HistoryOral Contraceptives

Hormone Replacement

AlcoholWeight

Risk FactorsRisk Factors


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Early Detection MethodsEarly Detection Methods

Breast Self Examination.

Clinical Breast Examination.

Screening Mammography.


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Mammography


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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.

Aromatase


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Hormone Dependent Breast Cancer


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Biosynthesis of Steroid HormonesBiosynthesis of Steroid Hormones

HO Cholestrol

O

HOPregnenolone

O

OProgesterone

Side Chain Cleavage

O

HO 17 hydroxypregnenlone

OH

O

O17 hydroxyprogesterone

OH

HOandrostenediol

OH

Oandrostenedione

O

HOdehydroepiandrosterone

O4,5-Isomerase 17 -hydroxylase17 -hydroxylase

17, 20 - Lyase

17, 20 - Lyasedehydrogenase


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Biosynthesis of Steroid HormonesBiosynthesis of Steroid HormonesContd

AndrostenedioneAndrostenedione AndrostenediolAndrostenediol

HOestrone

O

O

OH

testosteroneHO

estradiol

OHAromataseAromatase

AromataseAromatasedehydrogenase

4,5-Isomerase

Oandrostenedione

O

O

O

HO

19-hydroxy androstenedione O

O

HOOH

19,19I - dihydroxyandrostenedione

O2 O2

O

O

19-oxoandrostenedione

O

- H2O

N

N

N

N

Fe

O

O

O

OHHO

N

N

N

N

Fe

OH

O

O

H

HO OH

HOestrone

O

O2

HCO2H


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Classes of Drugs Used Treat Breast CancerClasses of Drugs Used Treat Breast Cancer

Herceptine (Trastuzumab)Bind with certain proteinson breast cancer cells,

preventing their growth

Biologic Responsemodulators

Aromasin (Exemestane)

Femara (Letrozole)

Arimdex (anastrozole)

Megace (Megestrol)

Prevent Production of

estrogen in adrenal glands

Aromatase Inhibitors

Tamoxifen (Nolvadex)

Evista (Raloxifene)

Fareston (Toremifen)

Bind estrogen receptors inbreast cancer cells

SERMs (SelectiveEstrogen Receptor

Modulators)

ExamplesActionClass


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Classification of aromatase Inhibitors

reversibly bind the enzymeIrreversibly inactivates the

enzyme

Anastrozole

Letrozole

Vorozole

ExmestaneThirdThird

Fadrozole

Rogletimide

FormestaneSecondSecond

AminoglutethimideNoneFirstFirst

Type 2Type 2

((NonsteroidalNonsteroidal))

Type 1Type 1

(Steroidal)(Steroidal)

GenerationGeneration


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Ph

Ph

O

N

TamoxifenO O

O

OH

OH O

OHOH

O O CH3

NH2

OH

Ellence

O

OH

H

Megestrol

O

HH

OH

O

O

Formestane

N

N

N

N

N

Anastrozole

1963, BMS1973, Astrazeneca

1984, Pfizer1992, Novartis

NN

Fadrozole

NN

N

NLetrozole

O O

O

OH

OH O

OHOH

O O CH3

NH2

OHAdriamycin

1996, BMS1995, Astrazeneca

1996, Novartis1995, Novartis

O

N N

O

F

NH

O

OHO

HO

H3C

4

Xeloda

1998, Roche

N

N

P

OH

P OH

O OH

O

OH

OH

Zometa

2000, Novartis

HH

OAromasin

H

O

1999, Pfizer

N N

N

VorozoleN

N

N

Cl

Pre-Registered, Janssen

Aromatase Inhibitors


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O

OH

HO

OO

Biochanin A

O

OH

HO

OOH

Genistein

O

OH

HO

O

Chrysin

O

O

SR2

R3

R1

R1 = H, Me, OMe, OHR2 = OH, OMe, OBn

R3 = Allyl, Benzyl, Pyridylmethyl

2,4,7-tri substituted isoflavone

Designing of Novel Inhibitor

Biological Testing, Lion Phase II, Yamanouchi Phase II, Nihon University


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Synthesis of Isoflavones

n-BuN.HSO4, aq. NaOH

CS2, R3X, THF, r.t

overnight O

O

SO

R3

R1

R1 = H, Me, OMe, OH

R2 = OH, OMe, OBn


R2

(3)

Ph3P, DIAD

THF, O C, 0.5 h

O

OHO

R1

R2

R2OH

R2 = Me, Bn

R1 = H, Me, OMe

(2)

O

OHHO

R1

R1 = H, Me, OMe

(1)

O

O

S

R3

R1

BBr3, CHCl3, r.t or

BF3.OEt2, Me2S, CH2Cl2

r.t, overnightHO

R2 = OH, OMe, OBn


(4)


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Results and Discussion

O

O

SHO

N

O

O

O

SO

N

IC 50 = 0.22 MIC 50 = 0.21 M

IC 50 = 34 M

IC 50 = 2.8 M

O

O

SO

N

O

O

O

SO

N

O

NH

O O

Aminoglutithimide

NH2

O

OH

HO

O

O

Biochanin A

IC 50 = 3.1 M IC 50 = 0.53 M


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Aromatase inhibitory activity can be achieved withIsoflavone Scaffold.

TheThe SARSAR studies indicates binding modes of 7studies indicates binding modes of 7--prortected analogues might be different from 7prortected analogues might be different from 7--

hydroxy analogueshydroxy analogues..

Based on kinetic studies these compounds compete atBased on kinetic studies these compounds compete atactive site of aromatase with the natural substrate,active site of aromatase with the natural substrate,

androstenedioneandrostenedione..

Conclusions


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Arise awake, and stop notArise awake, and stop notTill the goal is reachedTill the goal is reached

Thanks To AllThanks To All

synthesis and aromatase inhibitory activity

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