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天然物化学とは? PowerPoint PPT Presentation


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天然物化学とは?. 生薬学. 生化学. 有機化学. 分析化学. 学問は全て繋がっている。. 天然物から創薬へ・・. Key word :. lead 化合物、コンビナトリアルケミストリー、ハイスループットスクリーニング( HTS). ターゲット(標的)の探索. 疾患、生体内における標的部位の決定 天然物からの探索. in vitro (試験管内)、 in vivo (生体内)における薬物評価系を決める. スクリーニングの構築. Lead 化合物の探索. 抽出・分離・構造決定. 生理活性を有する天然由来抽出物から目的化合物を単離精製.

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天然物化学とは?

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Key word :

leadHTS)

in vitroin vivo

Lead

-


morphine

(Serturner)

1803morphine

1818quinine

1819caffeine

1831atropine

1855cocaine

1885ephedrine

1895tubocrarine

1929peniciline

1952reserpine

1953kainic acid

1958vinbrastine

1971paclitaxel

quinine

caffeine

atropine

cocaine

ephedrine

tubocurarine

oeniciline

(Fleming)

kainic acid

reserpine

paclitaxel

vinblastine


A. Fleming

E. Jenner

G. Domagk

B.N. Ames

P. Ehrlich

S.A. Waksman

R. Koch

J. Pasturner

F. Serturner

H.A. Krebs

Mutation test

TCA

B1


a) B. N. Amesmutation test

b) P. Ehrlichsalvarsan

c) G. Domagkpenicillin

d) S. A. Waksmanstreptomycin

e) A. Flemingsulfa drug

82


Taxusbaccata

Taxaceae

paclitaxel (taxol)


paclitaxel(taxol)

retrosynthesis)

E. J. Corey1991


paclitaxel(taxol)


Podophyllumpeltatum

Berberidaceae

Natural products

drug

Podophyllotoxin

PodophyllotoxinGlucoside

Etoposide



-

C2CoA

C6-C2

C5

C5


1


2

Ex)

Krebs/ TCA


3

Ex)


1

Krebs

CoA-

-

1- 5-

1- 5-


2

1) CoA

CoA

(PG)

*

*2

2)

+

4-


3

3)

CoA x 3

4)

+

3-

5)

Krebs

Krebs


81

1) C1 : ONCL-S-

2) C2 : CoA

3) C5 : isoprene unit)


82

4) C6C3

5) C6C2N

6) - C2N


83

7) C4N

8) C5N


84

podophylotoxin

papaverine

2 x C6C3 + 4 x C1

C6C2N + C6C2 + 4 x C1

C6C3


CoA


1

L-C1

SAM S

O - , N


2

L-C1

C


3

DMAPP = C5

O

SN1


1


2

A)

B)

C)

D) SAM


3

A)

SP2

B) /

1

C)


Wanger - Meerwein

C5

A) 1, 2

D) 1, 3

B) 1, 2

E) 1, 2

C) 1, 2


AldolClaisen

-


AldolClaisen

A)

B)

A + B


Acetyl CoAMalonylCoA


MalonylCoAAcetoacetylCoA

Claisen


Claisen

Aldol


C N1)

Mannich

Schiff

A) 1

B) 2

Schiff


C N2)

Mannich

(tautomerism)

2


C N3)

Mannich

.hemibrevetoxin B)


(transamination) 1

1)


(transamination) 2

2)


(decarboxylation) 1

1

1) aldolclaisen

2)

Ex)


(decarboxylation) 2

A)

PLP


(decarboxylation) 3

B) b

6


(decarboxylation) 4-1

C) a


(decarboxylation) 4-2

C) a


(decarboxylation) 4-3

C) a


1

1) NADH NAD+, NADPH NADP+, FAD FADH, FMN FMNH2)

2) peroxidase etc)

3) mono oxygenase, dioxygenase etc)

4) monoamine oxidase, diamineoxidase)

5) Bayer Villiger

6)


2

1) NADH NAD+, NADPH NADP+)2


3

1) FAD FADH, FMN FMNH2


4

2) oxidase


5

3) oxygenase

(mono oxygenase)

(dioxygenase)

P450hydroxylase)

450nm


6

3) oxygenase

(mono oxygenase)

(dioxygenase)

P450


7

3) oxygenase

(mono oxygenase)

(dioxygenase)

P450


8

3) oxygenase2

(mono oxygenase)

(dioxygenase)


9

3) oxygenase

(mono oxygenase)

(dioxygenase)


10

4) amineoxidase

(monoamine oxidase)

FAD

(diamineoxidase)


11

5) Baeyer Villiger

NADPHP450FAD


12

6)

P450


b

X

X = O, N, S, C

()

A) O

B) C


O

b-

b-

b-

b-


1

(PG)

(


MalonylCoAAcetoacetylCoA

2

1) NADH NAD+, NADPH NADP+)2


2

(PG)

(

16

18

18

18

18

20

0

0

1

2

3

4


3

(PG)

(

(PG)C20


4

(PG)

(

(PG)3


5

(PG)

(


6

(PG)

(


7

(PG)

(


(decarboxylation) 3

B) b

6


8

(PG)

(


1

L-L-L-

Styrylpyrone


Illiciumverum


2


3

C6 C3 L Phe, L Tyr, L Trp


4

C6 C3


Cinnamomi Cortex

Cinnamomum cassia

Moutan Cortex

Paeoniasuffruticosa


CaryophylliFlos

Syzygiumaromaticum

(Clove )

(4)

()...600g

()...1

...3

...1

[A]

...10cm

...1/3

...1/2

[]

...1

...1/2

...

...

...2

...

...

...

1.

2.(A)

3.(2)(1)2003040

4.(3)

5.5mm

6.(5)(4)


5

C6 C3


hemiterpenes

C10

monoterpenes (C10), iridoids

IPP

C15

sesquiterpenes (C15)

X 2

IPP

C20

diterpenes (C20)

X 2

IPP

C25

sesterterpenes (C25)

C30

triterpenoids (C30)

steroids (C18 C30)

tetraterpenoids (C40), carotenoids

C40


l menthol cholesterol


1

-1


2

-2


3

-1


(decarboxylation) 4-2

C) a


4

-2


5

(C10) - 1


6

(C10) - 2


7

(C10) 1

Ex)

Nepetacatania

- 1


8

(C10) 2

- 2


9

(C15) 1


10

(C15) 2


11

(C20) 1


12

(C20) 3


Taxusbaccata

Taxaceae

paclitaxel (taxol)


13

(C20) 2 (paclitaxel)


14

(C25)

Helminthosporiummaydisophioboleneophiobolin A


15

(C30) 1

Squalene - 1


16

(C30) 2

Squalene - 2


17

(C30) 3


18

(C30) 4


19

(C40) 1

carotenoid1


20

(C40) 2


1

L-PheL-TyrL-Trp

L-OrnL-Lys


2

1)

2)


3

1)

2)

(-)-hyoscyamine


4

1)

2)

cocaine


5

1)

2)


6

- 1


7

- 2


8


9

- 4


10

colchicine

noscapin

tubocrarine

Colchicum autumnale

Papaversomniferum

Chondodendrontomentosum

Strychnostoxifera

palmatine

Coptis japonica

Phellodendronamurense


11

-1


12

-2

reserpine

ergometrine

ergotamine

vincristine

vinbrastine

physostigmine


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