Division of Biofunctional Chemistry

The Chemical Society of Japan

Vol. 22, No.2 (2007. 8. 31)

- -

Bio-organic ”Biomimetic”

Breslow

CO

breakthrough

- -

Figure 1 :

1602

Phe

CH

CC trans gauche

- -

1600 1400 1200 1000 800 600 400

W a v e n u m b e r / c m - 1

0

9

1:13

2:19

5:54

100312501654 Time

(h:min)

1602

Figure 2 :

1800 1600 1400 1200 1000 800

W a v e n u m b e r / c m - 1

- 5min

3min

19min

36min

11min

1602

Time

Figure 3 : KCN

- -

Figure 4 : Figure 5 :

1602 1602

- -

Figure 6 :

-6-

kogure@mb.kyoto-phu.ac.jp

harasima@pharm.hokudai.ac.jp

(1)

PEG

pH

(2)

Tf PEG

-7-

Programmed Packaging

(3) Programmed Packaging Programming

Molecular

design Packaging 3

Programmed Packaging

PEG

Multifunctional

Envelope-type Nano Device (MEND)

(4)

DNA

CPP R8 R8

R8 DNA

(5) R8

R8

R8

R8 0.8

(6)

Programmed Packaging

R8 MEND R8-MEND(4)

DNA 100nm

-8-

MEND R8(STR-R8) R8

R8-MEND

R8-MEND

(3) in vivo

LacZ DNA R8-MEND 2

-gal R8-MEND

Lipofectamine LFN LFN

R8-MEND 25

Born morphogenetic protein

receptor type-1 a (BMPR1A)

R8-MEND

R8-MEND

R8-MEND

DNA ODN siRNA

DNA DNA

MEND 3

L PLL R8 STR-R8 ODN

3 100nm

ODN MEND 3 80%

R8-MEND(7)

siRNA 100nm 60nm STR-R8

PLL 200nm MEND

STR-R8/siRAN MEND(8)

STR-R8

DNA

RNA

siRNA

R8-MEND

ODN-R8-MEND PLL

STR-R8 R8-MEND

ODN R8-MEND

-9-

Lipofectamine2000 (LFN2000) LFN2000

ODN-R8-MEND( )

48(7)

siRNA-R8-MEND(STR-R8)

(8) LFN 2000

100 siRNA

R8-MEND LFN 2000 siRNA

GFPsiRNA LFN2000

5 LFN2000

GFPsiRNA

R8-MEND LFN2000

R8-MEND R8-MEND

R8-MEND

R8-MEND MEND

MEND

MEND

(1) Khalil I.A., Kogure K., Akita H., Harashima H. Pharmacol. Rev, 2006, 58, 32-45.

(2) Kamiya H., Akita H., Harashima H. Drug Discov. Today, 2003, 8, 990-996.

(3) Khalil I.A., Kogure K., Futaki K., Hama S., Akita H., Ueno M., Kishida H., Kudoh M., Mishina Y.,

Kataoka K., Yamada M., Harashima H. Gene Ther., 2007, 14, 682-689.

(4) Kogure K., Moriguchi R., Sasaki K., Ueno M., Futaki S., Harashima H. J. Control. Release, 2004, 98,

317-323.

(5) Khalil I.A., Futaki S., Niwa M., Baba Y., Kaji N., Kamiya H., Harashima H. Gene Ther., 2004, 11,

636-644.

(6) Khalil A.I., Kogure K., Futaki S., Harashima H. J. Biol. Chem., 2006, 281, 3544-3551.

(7) Nakamura Y., Kogure K.,Yamada Y., Futaki S., Harashima H. J. Pharm. Pharmacol., 2006, 58 ,

431-437.

(8) Nakamura Y., Kogure K., Futaki S., Harashima H. J. Control. Release, 2007, 119, 360–367.

-10-

9.0 8.0 7.0 5.0 4.0

O O

NN

XX

OOOO

OO

NN

NNN

N

R RR

X X XXXX

O OO OO

RRR

OOOO

O

O OO OOOOO

R R

OOO

O

R

R R

O

XXX X

O

1 2

O

N

R R

OOO OOO

N N NNNN N

R R RR

OO OOO O

N NNNN NNN

4: R=C11H23

4+

4 BF4-

Ag+ Ag+Ag+Ag+

R R

OO

O

AgBF4

OO OO O O

RR RR

OO

NN

NN

NN

NN

3: R=C11H23

-11-

OAcAcO

XY

XY

5

6: X=Y=OAc 7: X=Y=COOMe 8: X=OAc, Y=H

10: X=Y=OAc11: X=OAc, Y=H

9

AcO–(CH2)n–OAc

12: n=713: n=814: n=9

AcO

OAc

0 -1123 -2

free -COCH3

bound -COCH3

/ ppm5 6 4 1H NMR

170000 ± 20000

82000 ± 2000

410 ± 10

118 ± 5

80 ± 10

60 ± 8

113 ± 6

33 ± 1a

4900 ± 500a

73 ± 1a

7.13

6.70

3.56

2.82

2.59

2.42

2.80

2.07

5.03

2.54

Guest Ka (M-1) - G (kcal/mol)

4

a: -50°C

-12-

5

6

7

13

-7.8 ± 0.2

-5.61 ± 0.06

-2.4 ± 0.1

-1.55 ± 0.08

-2.4 ± 0.8

4.2 ± 0.2

5.9 ± 0.6

6.8 ± 0.5

Guest H (kcal/mol) S (cal/mol•K)

R1O OH

R2

OO

H

R1O O

H R2

OO

HR1

O OH

R1

OO

H

R1O OH

R2

OO

H

R2O OH

R2

OO

H

4 a) 5, b) 6, c) 7, d) 12, e) 13, f) 14

d) e) f)

a) b) c)

-13-

0.0 -2.02.0 / ppm

CH3COOH-OCOCH3

-OCOCH3 CH3CH2COOH

CH3CH2COOH

a)

b)

c)

MeO

O

H

O

O

HO

OMe

15

16 17 O

O

H

Me

a) b)

-14-

-15-

-16-

-17-

-18-

-19-

-20-

-21-

μ

-22-

-23-

-24-

-25-