Noscapine: Derivatization for

Optimization of Anticancer Activity

Ram C Mishra
Biology Department
Georgia State University
Noscapine & Colchicine
Isoquinoline MeO
O
1 9 8
O 7 MeO NHAc

2
N6
MeO

O 5
4 Me MeO
3
OMe 3
4 O
5 2
6 1 O
MeO 7
OMe
Benzo-furanone Podophyllotoxin
(Etoposide precursor)
Reaction sites:
O

H/R1 O N
CH3
H
O H3CO

O N
O
CH3
H3CO O
H3CO

O
H3CO/R2H/R1O N
H3CO
O O O CH3
O
H3CO NO
CH3
O HN3CH
CO 3
H3CO
H3CO

H/R1 H3CO O
H3CO O Y
O Y
H3CO
N
H3CO H/R1
H CO
O 3
O
O CH3
H3CO O N
CH3
H3CO H3CO O
H3CO O

H3CO/R2 H3CO O
O Y
H3CO/R2
Synthesis of 9-position derivatives
Br
O O

O N O N
CH3 I CH3
Br2 Water Cl
H3O
CO H3O
CO
O O
O N HBr, NH4OH N
O O O
NCH3 ICl NCH3
H3CO HO3CO CH3 H3CO HO3CO CH3
SO2Cl2
H3COH3CO O H
H3CO3 CO O
O CH3CN/Et3N O
H3CO O CH2Cl2/Et3N H3CO O
H3COH3CO O H3COH3CO O
H3CO O H3CO O
Synthesis of 9-amino derivatives
HN

Br O

O O N
Me
H
O N OMe
Me
Benzylamine, t-BuOK H
OMe H
H Palladacycle, Toluene, Reflux O OMe

OMe
O OMe O
9-benzylamino noscapine
OMe
O Ammonium formate,
Bromo noscapine
Pd/C 10 %, Methanol, Reflux

NH2 NH2 NH2

O O O
O N N
Me O Me O N
H + Prep HPLC Me
H H
MeO OMe OMe
Water/MeCN
H H H
O OMe O OMe O OMe
OMe OMe
O O OMe
O
9-Amino noscapine
Mechanism of epimerization
H B
O O + BH
MeO MeO
OMe O OMe O

H H
S R
O O
MeO MeO
OMe O OMe O
Cyclic Ether Analogs
R1
O O
O
O N N
N Me O Me
O Me Bromination
BF3.OEt2, NaBH4 0C OMe H
OMe H
OMe H H Chlorination or Iodination H
H THF, Reflux
OMe O OMe
O Y
O OMe
Y H OMe
H OMe
OMe Red Noscapine analogs
Red Noscapine, Y=CH2
Noscapine, Y = CO Y=CH2 R1 = Br or Cl or I
Synthesis of Reduced 9-amino derivatives

NH2
Br HN
O
O O
N O N
O BnNH2, t-BuOK N Me
Me O Me Ammonium formate/MeOH H
H MeO
MeO Pd Cat. Toluene, Reflux MeO H
Pd/C 10%, Reflux
H H
H
O OMe O OMe
O OMe
OMe OMe
Reduced Bromo-NOS OMe
Red Benzylamino NOS 9-Red-Amino NOS
Synthesis of 7-position analogs
O

O O N
CH3
H
N H3CO
O CH3 Ac2O/BzCl
H
H3CO H
O
NaN3, NaI H Base O OCH3
O N
CH3 OR2
H DMF, 140 C O OCH3 O
H3CO
H O OH R2 = Ac
R2 = Bz
O OCH3 EtNCO/
PhNCO/
O OCH3 BnNCO
Noscapine
O

O N
CH3
H
H3CO
H

O OCH3

O R2
R2 = OCONHEt
R2 = OCONHPh
R2 = OCONHBn,
Synthesis of 7-position analogs
O
O O
O N
N N Me
O Me O Me
NMP, BnNH2 OMe
HCOONH4, Pd/C
OMe OMe
140 C MeOH, Reflux
MeO O
MeO O MeO O
H2N
TfO BnHN O
O O
O

O N
Me
OMe

MeO O
AcHN
O
Bis-Substituted Analogs
R1
R1
R1 O
O
O Ac2O N
N /Tf2O O Me
O Me NaN3, NaI N /BzCl
O Me /BnCl OMe H
OMe H DMF, 140 C or H
H OMe H
MicroWave radiation /EtNCO
H
/PhNCO O OMe
O OMe /BnNCO
O OMe R2
O OMe R1 = Cl, Br, I O
O OH R2 = OAc, OTf OBz, OBn
R1 = Cl, Br, I OCONHEt/Ph/Bn

H Br
O O

N O N
O Me Br2 Water Me
OMe H HBr OMe H
H H H Br

O OMe O OMe

OH O OH
O
Reaction of Organo Lithium and Metal
hydrides
O
O
O N
CH3 N
O CH3
H3CO n-BuLi, CO2
H3CO
-78 C, 30 min.
H3CO O
H3CO O
H3CO O n-Bu
H3CO HO
Chemical Formula: C22H23NO7
Molecular Weight: 413.42 Chemical Formula: C26H33NO7
Molecular Weight: 471.54

O O

O N O N
Me Me
OMe DIBAL-H, THF OMe
-78 C
MeO O MeO O

MeO MeO OH
O
Proposed partial reduction
Structure Vs Activity
S/N R1 IC50 (mM)
R1 PC-3 MDA-MB-231 BxPC-3
O
1 H 251 74 158
S/N R1 R2 IC508.2
(mM)
2 F
N 3 Cl PC-3
22 MDA-MB-231
8 BxPC-3
25
O CH3 1 4 Cl Br OH 200 3 63 14 236
H3CO 2 Cl S/N OAcR2
5 I 100-nd- 1-nd-(mM)
<IC50 -nd-
22
R1 3 6 BrS/N R1
NHBn OH Y PC-3
200 5 20 1 IC50 (mM)
MDA-MB-231 40< 1BxPC-3
O 4 7 Br1(Br)
NH2 OHOH 71 6 25 PC-3 < 1 4 30MDA-MB-231 2225 178 BxPC-3
H3CO O
5 8 Br1 NHCONHBn-I
OAc
HOAc CH2 1 2563 10020 22 6325
28 25
N 2 9 6
H3CO
O O CH3 6 9 Br2 NHCONHBn-II
OBz
F CH2 79 63.1 245.47
1 -nd-
5.7
65
O H3CO 7 10 Br3 OBn
3 NHCSNHPh
Cl
OBz
CH2 79-nd-
16
1 -nd-
21 -nd- < 1
16
8 Br44 OCONHEtCH2
OCONHEt
Br 9 25 18 3 8 103 25 6
R1 N
O CH3 9 Br5 OCONHBn
I OCONHPhCH2 20 36 4 100 < 1 50
HH O O 10 Br6 OTf 95.520 1.6245.4725 -nd- 59 13
3CO
3CO NHBn
OCONHBnCH2 40
Y 11 Br7(Br) NHBn
NH2 CH2 20 1.6 25 2810 50 4
HO3CO N 7 OTf 251 74
CH3 12 I 8 OH
H -nd-
C(OH)-nBu -nd- -nd- -nd-
-nd- -nd-
H3CO H3CO O 13 I 89 OAcNHBn -nd-50
Br (Br) C(OH)-nBu -nd- -nd-
26 -nd- 25 -nd-
-nd-
9 NH2 <1 5 50
R2 O 10 OEtNH2 -nd- -nd- -nd-
H3CO O
11 NHAc -nd- -nd- -nd-
R2 O
Comments on SAR
7-Position Analogs are comparatively more potent
Larger groups at 9-position are accomodated
Lactone ring reduction has little or no effect with 9-
substitution
Disubstituted analogs are better than 9-substituted
only, analogs
Partial reduction of lactone ring (generating another
H-bondong site) could enhance activity
Cyclic ether analogs with 7-position derivatives should
also be evaluated
Future molecules
R1
OH/OCOCH3/CN/COOH/CONH2
O O
O
O N O N
CH3 N COCH3
O O CH3 H3CO
H3CO O
H3CO
O N N
CH3 O Me O
H3CO O H3CO O H3CO
Y H H
R2 H3CO H H3CO O
O H3CO O
R1 = Br, Y = CH2, RH
2 =CO
NH2
3
H O OMe
NH OH
O HO
O O O NH2
O N O N
CH3 O N CH3
CH3
H3CO H3CO
H3CO

O O
O
H3CO H3CO
H3CO
H3CO S HN O
O O
AminoAcids/Carbox Acids
Pentose/Hexose Sugar
Thank You All!