老师糖药物进展

RNA作为遗传信息的携带传递者，执行重要的生物功能，但就其化学结构而言，由四个平面碱基组成，每个核苷带有负电荷，长期以来并不是

们看好的靶点。随着X射线单晶衍射及核磁技术的发展，发现RNA象蛋白一样，可以折叠成复杂的三维结构，从而为小分子特异的与RNA结合提供了可能。Chem.Biol.

1998,5:R277-R283以RNA为靶的药物研究X-ray

crystal

structure

of

A

site

bindingwith

paromomycinNATURE,VOL

407

,340Structure

of

A

site

binding

with

paromomycindeterminated

by

NMRSCIENCE,VOL

274

,1367RNA的结构siRNA是分子抗菌作用机理以16

S

rRNA

A-site为靶的2-DOS氨基糖苷干扰mRNA翻译:抑制翻译开始错误配对导致翻译出错使翻译提前终止OR2NH3HOR1OOH3R

HN+NH2R4OHOOHOO+NH3OHO+H3NOOHOHOHHOIII+OIIIIVVNeamineRibostamycinNeomycin

BParomomycin

ILividomycin

A+NH3

OHNH3

OHHHHH++HHNH3

OH

HOH

OH

HHHHOHR1R2

R3

R4氨基糖苷类抗生素的缺点:通常口服无效,只能局部给药或注射给药;剂量大时损害

和肾脏;耐药性问题日益严重。Ye,

X.-S.;

Zhang,

L.-H.

Curr.

Med.

Chem.

2002,

9,

929.氨基糖苷类抗生素与RNA的相互作用HOHONH2ONH2

OOHH2NNH2OOHOOHOR1:

R=

H2N3:

R

=2:

R

=

H2N4:

R

=OHNOHOHHOOHOOHOHH2NOH与核糖体RNA的作用1:

Kd

=

1.7

μM;2:

Kd

=

0.26

μMOH

OH

ON

H

2N

H

ONH:

v

a

r

i

a

b

l

eOH

2

NH

OH

ON

3OA

c

y

l

a

t

i

o

nR

e

d

u

c

t

i

v

eA

m

in

a

t

io

nR

1R

2组合化学途径HOHONH2OOHH2NNH2NH2

OORONHNHOHNHNHOMeNHH3CNHFNHMeONHNHCH3NH2223242526272829OH3031与信使RNA的作用有可能抑制癌RNA的转录OHOHONH

2NH

2

OOHH

2

NNH

2OOONH

2OHH

2

NHOOSNH

2

OOH2H

NNH

2OOONH

2OHHO2H

NHOOOSSHOO

HOSHONH

2ONe

o

-Ne

o与转移RNA的作用Interact

with

yeast

tRNApheR1563'' 2''

R3

OR1R2R3R4R538Kanamycin

BOHOHOHOHOH39TobramycinOHOHOHHOH404'-DeoxytobramycinOHOHOHHH416''-DeoxytobramycinHOHOHHOH424''-DeoxytobramycinOHHOHHOH432''-DeoxytobramycinOHOHHHOH44

6''-Amino-6''-deoxytobramycin

NH2OHOHHOH4''R2

OH2NHO2H

N21H2N46''

2'33'

R4

4'R5O5'

6'

NH2O

NH2作用于催化RNA抑制锤头型酶性核酸的催化能力HOHONH2OOH2H

NNH2NH2

OOONH2OHHOH2NO

HOOHOHOHONH2OOH2H

NNH2NH2

OOONH2OHH2NO

HOOHONNHSNeomycin

BNeo-acridine(45)OHO2H

NOHOHOH2NHONH2ONH2OH2H

NOOOHOHOHNHONOHNHNH

OOHH2NNHNH2HNNH2NHNHH2NHOHN2H

NNHBocHNNSO2CF3NHBoc465TFA作用于RNA抑制HIV的Rev蛋白-RNA复合物的形成OHNH2NH2OHOHONH2ONH2OORO

OHONH2OHOH26a:R=OHNeomycin

BOH

N2

HOHOO26c:

R=NH2OHOHOH2NO26d:

R=OHO2H

NHOOH2N26b:

R=OHNH226e:R=OOOH

OHHO26f:

R=OSOH

OHHO26g:

R=OOOH

OHH2NOHOHOHOO26h:

R=OHOH

N2

HOHOO26i:

R=OHOHOHO2H

NO26j:

R=NH2抑制Anthrax致死因子蛋白酶的活性HONH2OOHOH2NHONH2OOHONH2OHOHOOHNH2OHOH2NNH2OOHOHOHOOH

OOHNH2OH2NOOHOO

OH

HOHOO

OPO

OOHOOO

PH2OATPNH2APH(3')47Active

form48Hydrated

formNH2OHOH49Unstable

formNH2OHOH克服抗生素的耐药性Mobashery,

et

al.

J.

Am.

Chem.

Soc.

1999,

121,11922.策略一：ON3BnOBnON3OBnN3N3OROR

=

CH2CO2H:

neamineOON

NR'

R'linkerR'HHHlinker(CH2)3-10(CH2)12[(CH2)2O(CH2)3]2O(CH2)1260

PhCHCONHCH2CO2H50-575859NNOH

CH3CH3

OH**linkerlinker(CH2)2-4[(CH2)2]2O(CH2)2-4[(CH2)2]2O61-63

(S,S)64

(S,S)65-67

(R,R)68

(R,R)Wong,

et

al.

J.

Am.

Chem.

Soc.

2000,

122,

5230.J.

Am.

Chem.

Soc.

2004,

126,

4774.策略二：克服耐药性策略三：构象锁定的氨基糖苷类抗生素设计和

示例Conformationally

Locked

Aminoglycosides设计氨基糖苷药物的时候不应只考虑与16sRNA的A位点的结合力，还应该考虑药物对RNA的分子间和分子内动力学变化的影响。除结合力之外？J.

Am.

Chem.

Soc.

2006,

128,

1261-1271.16

S

rRNA-BA1493.....li,2A�941

—Drug16

S

rRNA／＼／＼＇tRNA

(codon(anticodon)三A』nmRNA(codonnoncognatetRNA(anticodon)NNHOCH3NCH3OHOHCH3OHHOH3CH3简单的氨基醇模拟氨基糖苷类化合物OOOHNHR2NHR2OHOHO2R

NHR1OO

OHR2HNOHR2HNOOHOHOONHR3NHR3OHOR2R1NHR3OOHHOR3HNOHHO4a5a4b5bParomomycinNeomycin

BGuanidino-paromomycinGuanidino-neomycin

BR1R2OHNH2OH(C=NH)NH2HH(C=NH)NH2(C=NH)NH21a

Kanamycin

A2a

Kanamyci