discovery of 7-(4-(3-ethynylphenylamino)-7- methoxyquinazolin-6-yloxy)-n-hydroxyheptanamide...

Discovery of 7-(4-(3-Ethynylphenylamino)-7-methoxyquinazolin-6-yloxy)-N-hydroxyhep-tanamide(CUDC-101) as a Potent Multi-Acting HDAC, EGFR, and HER2 Inhibitor for the Treatment of Cancer

2015.03.06

Kiseon Baek

Contents Vorinostat, Erlotinib, Lapatinib

Introduction

Compound Design

Chemistry (Synthesis)

Result&Discussion

Non-hydroxamate type HDAC Inhibitor Enzyme assay

Hydroxamate type HDAC Inhibitor

SAHA(Vorinostat)

O

HN

O

NH

OH

화학명 N-hydroxy-N'-phenyl-octanediamide

분류 항악성종양제

적응증두 가지의 전신요법을 사용중이거나 사용한 후 , 진행성이거나 지속성 또는 재발성인 피부 T 세포 림프종

부작용 설사 , 구역 , 식욕부진 , 폐색전증 , 빈혈 등

상품명 Zolinza

개발회사 Merck

Erlotinib

화학명 N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine


적응증 비소세포폐암 , 췌장암

부작용 폐독성 , 심근경색 , 빈혈 , 설사 , 간염 , 안구 천공 등

상품명 Tarceva

개발회사 Roche

N

N

NH

OO

OO

Lapatinib

화학명N-[3-chloro-4-[(3-fluorophenyl)methoxy]phenyl]-6-[5-[(2-methylsulfonylethylamino)methyl]-2-furyl]quinazolin-4-amine


적응증 유방암

부작용 심장독성 , 간독성 , 설사 등

상품명 Tykerb

개발회사 GSK

N

N

HN

O

HN

SO

O

O

FCl

Introduction

HDACs comprise a family of 18 genes in humans and are

divided into four classes.

Among them are the Class I (HDAC1-3, 8) and II (HDAC4-

6, 7, 9-10) zinc-containing hydrolases.

HDAC inhibitors can impact a variety of cell functions by

blocking the deacetylation of histone or nonhistone pro-

teins, such as HSP90 and tubulin, causing cell cycle arrest,

differentiation, and/or apoptosis.

Introduction

The HDAC inhibitor vorinostat (SAHA) is an FDA-approved drug for the

treatment of cutaneous T-cell lymphoma (CTCL).

In our own study, vorinostat and erlotinib were used to achieve HDAC

inhibition. respectively, and a well-established mathematical model for

studying multidrug interactions was applied to assess whether there is a

synergistic effect between HDAC inhibition.

Here, we describe the design, synthesis, and structure-activity relation-

ship (SAR) of these novel compounds and the identification of 8 (CUDC-

101) as a clinical candidate currently in phase I clinical trials.

Compound Design

Chemistry

Result & Discussion

Conclusion

HDAC inhibitors can impact a variety of cell functions by blocking

the deacetylation of histone or non-histone proteins, such as HSP90

and tubulin, causing cell cycle arrest, differentiation, and/or apop-

tosis.

Compound 8 is a potent HDAC inhibitor with favorable drug-like

properties. Therefore, compound 8 has advanced to clinical develop-

ment as a novel anticancer agent.

Non-hydroxamate HDAC InhibitorEnzyme assay

Hydroxamate type HDAC InhibitorTotal Scheme

S N

O

O

OO

N

O O O O

NH2S(NH4)2S

MeOH, overnight

ethyl bromopyruvate

EtOH, reflux, 1h

Molecular Weight: 259.32Molecular Weight: 163.24Molecular Weight: 129.16

LiOH, H2OAcetone, reflux, 5h

NH

O

S

N O

F

NH

O

S

N O

F

S N

O

OH

OO

Molecular Weight: 231.27

O

NH

O

S

N O

F

HN OH

NHS, PhI(OAc)2, MeCN, 0°C, 1h

NH2OH, 12h


Molecular Weight: 278.30 Molecular Weight: 309.32

EDCI, HOBt hydrate4-fluorophenethylamine, TEA

ACN, DMF1M HCl

THF

S N

O

O

OO

N

O O O O

NH2S(NH4)2S

MeOH, overnight

ethyl bromopyruvate

EtOH, reflux, 1h

Molecular Weight: 259.32Molecular Weight: 163.24Molecular Weight: 129.16

LiOH, H2OAcetone, reflux, 5h

NH

O

S

N O

F

NH

O

S

N O

F

S N

O

OH

OO


O



EDCI, HOBt hydrate4-fluorophenethylamine, TEA

ACN, DMF1M HCl

THF

NH

O

S

N

Fethyl acrylateHoveyda 2nd Grubbs Cat.

Toluene, 2d

NH

O

S

NHN

O

OH

KOH, MeOH


NH

O

S

N


O

O

F F


NH2OH,HClNH2OH solution

CH3P(C6H5)3Br, LiHMDS, PhMe, THF, 0°C,1h

THF, -78°C, 18h

NH

N

HN

O

OOH

S

NH

N

HN

O

OOH

S

NH

N

O

S

NH

O OH

NH

N

O

S

NH

O OH

NH

N

O

S

NHOHO

F

F

F

F

F

NH O

O

N

SHN N

SO

O

F FNH OH NH OH

NH

N O

O

S

F

HN OH

Thank you

discovery of 7-(4-(3-ethynylphenylamino)-7- methoxyquinazolin-6-yloxy)-n-hydroxyheptanamide...

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