Synthesis and Biological Evaluation of N-Substituted Noscapine Analogues

Article abstract of DOI:10.1002/cmdc.201200365

Noscapine is a phthalideisoquinoline alkaloid isolated from the opium poppy Papaver somniferum. It has long been used as an antitussive agent, but has more recently been found to possess microtubule-modulating properties and anticancer activity. Herein we report the synthesis and pharmacological evaluation of a series of 6'-substituted noscapine derivatives. To underpin this structure-activity study, an efficient synthesis of N-nornoscapine and its subsequent reduction to the cyclic ether derivative of N-nornoscapine was developed. Reaction of the latter with a range of alkyl halides, acid chlorides, isocyanates, thioisocyanates, and chloroformate reagents resulted in the formation of the corresponding N-alkyl, N-acyl, N-carbamoyl, N-thiocarbamoyl, and N-carbamate derivatives, respectively. The ability of these compounds to inhibit cell proliferation was assessed in cell-cycle cytotoxicity assays using prostate cancer (PC3), breast cancer (MCF-7), and colon cancer (Caco-2) cell lines. Compounds that showed activity in the cell-cycle assay were further evaluated in cell viability assays using PC3 and MCF-7 cells.

Full text of DOI:10.1002/cmdc.201200365

MED
DOI: 10.1002/cmdc.201200365
Synthesis and Biological Evaluation of N-Substituted
Noscapine Analogues
Aaron J. DeBono,[a] Jin Han Xie,[b] Sabatino Ventura,[b] Colin W. Pouton,[b] Ben Capuano,[a] and
Peter J. Scammells*[a]
Noscapine is a phthalideisoquinoline alkaloid isolated from the
opium poppy Papaver somniferum. It has long been used as an
antitussive agent, but has more recently been found to pos-
sess microtubule-modulating properties and anticancer activity.
Herein we report the synthesis and pharmacological evaluation
of a series of 6’-substituted noscapine derivatives. To underpin
this structure–activity study, an efficient synthesis of N-norno-
scapine and its subsequent reduction to the cyclic ether deriv-
ative of N-nornoscapine was developed. Reaction of the latter
with a range of alkyl halides, acid chlorides, isocyanates, thio-
isocyanates, and chloroformate reagents resulted in the forma-
tion of the corresponding N-alkyl, N-acyl, N-carbamoyl, N-thio-
carbamoyl, and N-carbamate derivatives, respectively. The abili-
ty of these compounds to inhibit cell proliferation was as-
sessed in cell-cycle cytotoxicity assays using prostate cancer
(PC3), breast cancer (MCF-7), and colon cancer (Caco-2) cell
lines. Compounds that showed activity in the cell-cycle assay
were further evaluated in cell viability assays using PC3 and
MCF-7 cells.
Introduction
Microtubule-interfering agents for cancer therapy have been
validated through the use of taxanes and vinca alkaloids in the
treatment of various cancers.[1] There are a variety of antimitot-
ic agents that perturb microtubule dynamics: vinca alkaloids
(vinblastine, vincristine, vindesine and others) and taxanes (pa-
clitaxel and docetaxel). These antitumour agents are of signifi-
cant importance and are commonly used in current chemo-
therapy regimens. However, the emergence of multidrug-re-
sistance phenotypes and the inability of current antitumour
agents to selectively target malig-
microtubule (MT) depolymerising compounds.[4] Subsequent
biological testing of noscapine showed enhanced qualities
over current tubulin binding agents. Noscapine has the ability
to evade noncancerous cells and thus does not halt the segre-
gation of chromosomes in cells undergoing normal mitotic
separation. In comparison, currently available anticancer
agents either over-polymerise (taxanes) or depolymerise (vinca
alkaloids) MTs with no selectivity for malignant over normal
cells.[2] Noscapine does not appear to significantly change the
MT polymer mass even at higher concentrations.[5]
nant cells have led to a global
Noscapine does not alter the organisation of MT arrays at
the interphase stage of the cell cycle. Noscapine binds to tubu-
lin stoichiometrically during the pro-metaphase of mitosis and
induces subtle effects on the kinetic parameters of MTs result-
ing in the instability of MTs. These subtle effects in MT dynam-
ics increase the elapsed time the MTs spend in an attenuated
state, when neither microtubule shortening nor growth is de-
tected.[2,5] The subtle induced suppression of the MT dynamics
is sufficient to interfere with proper attachment of chromo-
somes to the kinetochore microtubules. This suppresses the
tension across the paired kinetochores, resulting in the spindle
checkpoints to block cells at a metaphase-like state. This is
similar to the actions of taxanes and vinca alkaloids at low con-
search for new anticancer drugs.
Noscapine (1) is a phthalideiso-
quinoline alkaloid used medicinally
as an antitussive drug in humans.
Its nontoxicity and oral availability
allow noscapine to bypass the
problems associated with the ad-
ministration methodologies of current cancer chemotherapy
agents such as parenteral injections and intravenous infusion.
These routes of administration generally result in such compli-
cations as anaphylactic reactions at the injection site causing
severe pain and thrombosis of blood vessels or embolisms.[2,3]
The discovery of noscapine originated from its isolation
from Papaver somniferum, more commonly known as the
opium poppy. Noscapine’s potential as an anticancer microtu-
bule binding agent was subsequently discovered by Ye et al. in
the 1990s.[2] The rational structure-based screening of naturally
derived compounds sharing structural similarities with toxic
microtubule-depolymerising agents such as colchicine and po-
dophyllotoxin demonstrated noscapine to possess both the
structural and binding similarities of these previously known
[a] A. J. DeBono, Dr. B. Capuano, Prof. P. J. Scammells
Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences
Monash University, 381 Royal Parade, Parkville VIC 3052 (Australia)
E-mail: peter.scammells@monash.edu
[b] J. H. Xie, Dr. S. Ventura, Prof. C. W. Pouton
Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences
Monash University, 381 Royal Parade, Parkville VIC 3052 (Australia)
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/cmdc.201200365.
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N-Substituted Noscapine Analogues
MED
centrations, at which the chromosomes do not complete con-
gression to the equatorial plane.[5] Noscapine then induces
apoptosis of malignant cells.
Binding studies are yet to ascertain specifically where nosca-
pinoids bind tubulin. A recent binding study by Joshi and co-
workers used the known binding interaction of colchicine in
an attempt to identify the binding site of noscapine on tubu-
lin.[6] These authors suggested that noscapine binds at or near
the binding site of colchicine.[6] To understand the binding of
noscapinoids, a competitive binding study between colchicine
and noscapine was conducted. Colchicine is nonfluorescent,
but shows clear fluorescence properties when bound to tubu-
lin.[7] The binding of colchicine is a somewhat complex bipha-
sic reaction. The initial phase results in the binding of colchi-
cine to a low-affinity site in which binding depends directly on
the intracellular diffusion of drug into the cell. Colchicine then
inhabits a site where it binds practically irreversibly and cannot
be dislodged by competing ligands of the same site.[6] This ob-
servable fact allows determination of whether other drugs
compete for the same site. To test this hypothesis, tubulin was
pre-incubated with the test ligands noscapine (1) and 9-bro-
monoscapine (4). Three different concentrations were used for
the colchicine competition studies. The highest concentration
of noscapine used (100 mm) had little inhibitory effect (<5%)
on the binding of colchicine. However, at the same concentra-
tion, the 9-bromonoscapine analogue showed a significant
66Æ5% decrease in colchicine binding.[6,8] A competitive bind-
ing study was also carried out at concentrations of 25 and
50 mm, and the respective inhibition values for colchicine were
found to be 23Æ7 and 40Æ4%. Lower concentrations of the
9-bromonoscapine analogue were not tested owing to the in-
ability to statistically measure inhibition of <5%.[6] The precise
site where noscapinoid binding occurs is not known, and thus
the probable binding site can only be inferred. The evidence
suggests that the site of noscapinoid binding is at or near the
colchicine site.
The effects of reducing the lactone moiety of noscapine to
the corresponding cyclic ether was also investigated; the cyclic
ether noscapinoid was fluorinated at the C9 position (6,
CEFNA), and its anticancer activity was analysed.[10] The emer-
gence of multidrug resistance is a major limitation to current
chemotherapeutics. The anticancer activity of CEFNA was
monitored with the MCF-7/Adr cancer cell line. This cancerous
cell line exhibits the multidrug-resistance phenotype through
an overexpression of the drug efflux pump P-glycoprotein,
where substrates such as paclitaxel are actively transported
out of the cell.[11,12] To determine whether the cyclic fluorinated
analogue is also a substrate for cellular efflux, the IC50 values of
CEFNA in both normal and MDR phenotype breast cancer cell
lines (MCF-7 and MCF-7/Adr) were found to be 6.2 and 6.9 mm,
respectively, suggesting that CEFNA is a weak substrate for
drug efflux.[10] The inherent base sensitivity of the lactone func-
tionality makes it an undesirable moiety if the intended route
of drug administration is oral. The retention of activity by
cyclic ether noscapinoids invites further research.
Anderson et al. investigated the manipulation of the benzo-
furanone moiety through regioselective O-demethylation at
the 7-position. This yielded a battery of O-alkylated derivatives,
including the hydroxy analogue, which was shown to be
~100-fold more potent than the parent noscapine.[13] This sug-
gests that chemical manipulations of the benzofuranone ring
do impact the biological activity of noscapine. Anderson et al.
further explored the 7-position, as the respective hydroxy
moiety allowed functionalisation via conversion into its trifluor-
omethanesulfonate. The 7-amino analogue showed inhibition
of tubulin polymerisation in adenocarcinoma human alveolar
basal epithelial (A549) cells, with an EC50 value of 0.3 mm,
which is similar to those of the 7-hydroxy analogue and vin-
blastine: 0.7 and 0.2 mm, respectively.[14]
A series of second-generation 7-position analogues were
synthesised and showed diminished steric hindrance through
selective O-demethylation at the 7-position, resulting in the 7-
hydroxy analogue, with a 100-fold improvement in efficacy
over noscapine.[14,15] Mishra et al. explored the hypothesis of
whether introducing a large group at this position would have
the opposite effect and decrease activity.[15] Acylation of the
hydroxy group led to synthesis of the acetyl and benzoyl ana-
logues; the phenolic group was also treated with available iso-
cyanates to yield a small number of 7-carbamate compounds.
The two acyl analogues, 7-acetyl and 7-benzoyl, with the 7-
ethyl, phenyl, and benzyl carbamates, showed varying degrees
of in vitro cytotoxicity. The A549, CEM, MCF-7, PC3, and MIA
Derivatisation of noscapine by Aneja et al. resulted in the
synthesis of the 9-halogenated analogues: 9-fluoronoscapine
(2), 9-chloronoscapine (3), 9-bromonoscapine (4), and 9-iodo-
noscapine (5), which possess higher binding affinities for tubu-
lin than noscapine.[9] The 9-halogenated analogues showed
a pronounced increase in the inhibition of cancer cell prolifera-
tion over noscapine. The 9-iodo analogue showed varying abil-
ities to inhibit cancer cell proliferation in the cell lines chosen.
The activity of 9-iodonoscapine in MDA-MB-231 cells showed
higher activity than noscapine, but lower activity in other cell
lines.[9] Two breast cancer cell lines (MCF-7 and MDA-MB-231)
and a T-cell lymphoma line, CEM, showed the cancer-active
halogenated analogues to have markedly lower IC50 values
than noscapine. The inhibition of cell proliferation was ob-
served after 4,6-diamidino-2-phenylindole (DAPI) staining to
reveal the appearance of numerous fragmented nuclei after
drug exposure and pronounced multi-polar spindles, which are
characteristic of apoptotic cell death.[9] From these results it is
evident that tubulin is a potential target for these compounds;
however, each of these analogues are cell-type dependent in
their anticancer effect.
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PaCa-2 cell lines were used to analyse the cytotoxicity of these
scribed by Scammells and co-workers for the N-demethylation
of various opiate alkaloids using FeSO4·7H2O at low tempera-
tures[17] was shown to be the most efficient method for the
generation of 7 in good yield (78%). In this reaction, the fer-
rous ion coordinates to the protonated N-oxide species and
promotes a single electron transfer resulting in the formation
of an aminium radical cation. The species then loses an a-
proton, undergoing an electron reorganisation to form the
more stable carbon-centered radical, which undergoes another
single electron transfer to afford the iminium ion intermediate.
Hydrolysis then affords the desired secondary amine.
second-generation benzofuranone-substituted
analogues.
These compounds showed varying results, with some ana-
logues exhibiting better activity than noscapine in a particular
cell line, and weaker activity than noscapine in others.[15] It was
expected that bulkier substituents at the 7-position would lead
to lower activity; however, these analogues were shown to be
significantly better than the parent compound noscapine. The
cancer cell sensitivity to these analogues is, however, cell-type
dependent.[15]
Noscapine was recently demonstrated to inhibit tumour
growth in temozolomide (TMZ)-resistant gliomas.[16] In order to
target glioblastoma multiforme (GMB), the drug must pene-
trate the blood–brain barrier (BBB). Landen et al. demonstrated
the ability of noscapine to cross the BBB using an in vitro
model.[3] Noscapine was evaluated against TMZ-resistant glio-
mas and was found to inhibit the proliferation of TMZ-resistant
human glioma cells. The highly vascularised GBM is character-
ised by extensive endothelial cell proliferation which migrates
readily. Noscapine administration resulted in significantly de-
creased migration and invasion of these cells in vitro.[16] The
co-administration of noscapine and TMZ exhibited a significant
additive effect for TMZ-sensitive cells relative to each drug
alone.[16]
The novel N-substituted cyclic ether analogues were syn-
thesised by using noscapinoid 9 as the scaffold. Previous re-
search by Aneja et al. showed the 9-fluorinated cyclic ether no-
scapine analogue to exhibit greater potency against the MCF-7
cell line.[10] The benefits of a reduced lactone are twofold: the
cyclic ether noscapine analogue improves the in vivo potential
of novel analogues, and decreases the in vivo base sensitivity
of compounds that may result in ring opening in situ, thereby
decreasing alkaloid binding through loss of the active struc-
ture.
Scheme 1 shows that there are two pathways to access the
secondary amine 9, thereby allowing structural diversification
Herein we describe an improved synthesis of N-nornosca-
pine (7) and subsequent reduction to the cyclic ether N-norno-
scapine analogue 9 in good yield allowing synthesis of a small
series of N-substituted analogues. Polonovski-type reaction
conditions for N-demethylation of apomorphine using
FeSO4·7H2O at low temperature[17] was shown to be the most
efficient method for the preparation of 7. Several years ago,
Joshi and colleagues[18] described the N-demethylation of no-
scapine via the N-oxide hydrochloride, to afford 1,3-dihydro-
6,7-dimethoxy-3-[1,2,3,4-tetrahydro-8-methoxy-6,7-(methylene-
dioxy)isoquinolin-1-yl]isobenzofuran-1-one (7, N-nornoscapine),
using ferric citrate in a buffer solution of citric acid at pH 1–2.
The reported isolated yield was 35%. A modified procedure for
the reduction of 7 using BF3·Et2O and NaBH4 in THF[18] deliv-
ered the N-demethylated cyclic ether analogue in good yield
(78%).
The cell-cycle arrest and decrease in proliferation of rapidly
dividing cells by cyclic ether noscapine analogues was investi-
gated by flow cytometry (using a DNA binding dye) and use of
the CellTiter-Blueꢁ assay as a surrogate marker of cell growth.
We observed that some of the novel cyclic ether noscapine an-
alogues are able to cause G2/M arrest in prostate (PC3), breast
(MCF-7), and colon (Caco-2) cancer cell lines.
Scheme 1. Reagents and conditions: a) 1. m-CPBA, CHCl3, 08C, 2. HCl, 95%;
b) FeSO4·7H2O, MeOH, À58C, 78%; c) NaBH4/BF3·Et2O, THF, reflux, 95%;
d) NaBH4/BF3·Et2O, THF, RT, 78%; e) FeSO4·7H2O, MeOH, À58C, 29%.
of noscapine through N-derivatisation. One pathway begins
with the synthesis of noscapine-N-oxide isolated as the hydro-
chloride salt. Recent work in our lab has shown that the N-de-
methylation of opiate N-oxide hydrochlorides improves the
yield of the desired noropiates relative to other opiate N-oxide
salts. A number of different conditions were trialed, including
temperature and solvent effects with various iron catalysts. It
was discovered that the most suitable conditions for N-deme-
thylation of noscapine involve FeSO4·7H2O in methanol at
À58C. A respectable yield of 78% was attained for the desired
secondary amine N-nornoscapine scaffold, which was sequen-
Results and Discussion
Synthesis of N-substituted noscapine analogues was hampered
by the relatively low yields in the N-demethylation of 1 for the
synthesis of the secondary amine N-nornoscapine (7). This
compound is a key synthetic intermediate that provides the
scaffold for N-derivatisation and is not commercially available.
Our research group used a nonclassical Polonovski reaction for
the synthesis of 8. The Polonovski reaction conditions de-
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N-Substituted Noscapine Analogues
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tially reduced to the cyclic ether analogue by the procedure
described by Ye et al.[2] Accordingly, the resultant yield for the
reduction was a modest 50%. A slight modification to the re-
action procedure, allowing the reduction reaction to proceed
at room temperature overnight rather than at reflux for 2 h re-
sulted in a modest increase in the yield of the desired cyclic
ether N-nornoscapine to 78%. The pathway that involved first
the reduction of the lactone moiety (95% yield) followed by N-
demethylation of cyclic N-oxide, which previously proved un-
successful,[18] gave a low yield of 29% of 9 using the iron sul-
fate method described herein. Given the greater mass recovery
of the pathway that involves N-demethylation followed by lac-
tone reduction and ease of purification, this pathway was used
for the synthesis of the cyclic ether nornoscapine scaffold 9.
The synthesis of 9 allowed for derivatisation of the secondary
amine, to furnish a number of novel N-substituted cyclic ether
noscapine analogues. Compound 9 was subsequently treated
with a number of alkyl halides, acid chlorides, chloroformate
reagents, isocyanates, and isothiocyanates (Scheme 2), to yield
a focused library of novel cyclic ether N-substituted analogues.
iodide (e.g. ethyl iodide for the preparation of 10a); this was
held at reflux overnight. The presence of two products was ob-
served by TLC analysis following reaction completion after
18 h. Column purification of the crude material using petrole-
um ether (PE)/ethyl acetate could not separate the desired
compound from other impurities present in the reaction mix-
ture. The reaction was then attempted using Cs2CO3 in acetoni-
trile instead of acetone to decrease the likelihood of reagent–
solvent reaction. The reaction was held at reflux overnight, and
TLC analysis showed completion within 18 h. The reaction mix-
tures were subsequently quenched with water and extracted
with chloroform. The crude material was then purified by flash
chromatography using PE/EtOAc to give the desired N-alkyl
derivatives. The straight-chain alkyl analogues N-ethyl, N-
propyl, and N-hydroxyethyl appeared to be relatively unstable,
and once purified, were subsequently converted into their hy-
drochloride salts.
A small series of N-acyl analogues were synthesised, where-
by 9 was dissolved in dichloromethane in the presence of trie-
thylamine (2 equiv); the reaction mixture was then cooled to
08C followed by the addition of the appropriate acid chloride.
If the acid chloride was not available, it was synthesised in situ
using the corresponding acid with DMF and oxalyl chloride.
After the addition of reagents, the reaction was allowed to
warm to ambient temperature until completion (2 h). The reac-
tion was quenched with water and extracted with dichlorome-
thane. The solvent was removed in vacuo, and flash chroma-
tography with PE/EtOAc gave moderate yields of the desired
amide analogues. NMR analysis of the N-amides showed the
presence of two rotameric forms of each of the N-acyl ana-
logues. The corresponding urea and thiourea analogues were
prepared by a procedure similar to that described by Aggarwal
et al.[18] This involved cooling of 9 in acetonitrile to 08C in the
presence of Cs2CO3 (2 equiv). The isocyanate/isothiocyanate re-
agent was added to the solution, and the mixture was allowed
to warm to ambient temperature. Reactions were generally
complete within 2 h of isocyanate addition. Reactions were
quenched with cold H2O and extracted in CHCl3. Purification of
crude reaction products was carried out by means of flash
chromatography using PE/EtOAc. Generally the compounds
were quite nonpolar and as a result elution could be facilitated
using 15% EtOAc in PE. The synthesis of the urea/thiourea ana-
logues proved efficient, with yields ranging from 59 to 98%,
with most analogues being prepared in yields of >85%.
The final class of N-substituted analogues is the carbamate
derivatives, which were prepared as follows: compound 9 was
cooled in dry dichloromethane in the presence of triethyla-
mine. The solution was cooled to À58C to which the chlorofor-
mate reagent was added, and the reaction was allowed to pro-
ceed at ambient temperature for 2 h. After this time, the reac-
tion mixture was quenched with water and extracted into an
organic solvent. The resulting crude material was purified by
flash chromatography using PE/EtOAc to give the desired car-
bamates in good yield. NMR analysis of the N-carbamates
showed the presence of two rotameric forms of each of these
analogues.
Scheme 2. Reagents and conditions: a) RX, Cs2CO3, MeCN, reflux, 18 h, 56–
81%; b) RCOCl, Et3N, CH2Cl2, RT, 3 h, 53–68%; c) ROCOCl, Et3N, CH2Cl2, RT,
24 h, 83–85%; d) RNCO/RNCS, MeCN, RT, 3 h, 59–98%.
Given the activity of noscapine was shown to inhibit the
progression of a number of tumour cell lines, investigation
into the tumour cell anti-proliferation effect of the presence of
larger alkyl chains was investigated. The synthesis of the N-
methyl, ethyl, propyl, hydroxyethyl, benzyl, and phenethyl ana-
logues followed. The initial reaction procedure involved disso-
lution of 9 in acetone in the presence of triethylamine
(2 equiv), followed by the addition of the appropriate alkyl
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Biological data
Table 1. Changes in the percentage of cells arrested at the G2/M phase following treatment with noscapine
analogues versus vehicle control, along with EC50 values for active compounds.
We investigated the possibility
that the novel N-nornoscapine
derivatives (Table 1) cause G2/M-
phase arrest through a disruption
of microtubule structures. Our
results suggest that specific N-
nornoscapine analogues show
anticancer activity by arresting
cells in mitosis in all three of the
cell lines tested, whereas at simi-
lar concentrations, noscapine (1)
is ineffective. The commercially
available microtubule inhibitor
vincristine, which has been in
common use for decades as an
anticancer drug, was used as
a positive control.
Compd
Y
Change in cell population at G2/M [%][a]
EC50 [mm][b]
PC3
MCF-7
Caco-2
PC3
MCF-7
1
Me
Et
Pr
2
1
1
À2
2
2
À2
3
2
2
3
2
À2
2
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
10a
10b
10c
10d
10e
11 a
11 b
11 c
11 d
12a
12b
13a
13b
13c
13d
13e
13 f
13g
13h
13i
Bn
(CH2)2Ph
(CH2)2OH
Me
2
96
2
3
86
À2
3
58
168
105
170
172
156
2
43
2
6.70
NA
NA
ꢀ10
NA
Et
Ph
Bn
OPh
OBn
NHEt
NHnPr
NHnBu
À2
47
48
28
27
60
47
À4
3
NA
To understand the cytotoxic
activity of these compounds,
86
81
67
79
133
123
À2
3
ꢀ10
ꢀ10
ꢀ10
5.27
3.91
ꢀ10
4.18
3.58
12.1
NA
a
cell-cycle cytotoxicity assay
7.70
was performed by treating pros-
tate cancer (PC3), breast cancer
(MCF-7), and colon cancer (Caco-
2) cell lines with compounds at
10 mm, as listed in Table 1. Cells
were then stained with Cell
Cycle Blue (a cell-cycle distribu-
tion dye) and cell-cycle phase
distribution was analysed by
flow cytometry (Figure 1). Com-
pounds that were able to cause
ꢀ50% change in the number of
cells in G2/M arrest were consid-
ered to be highly active; com-
pounds effecting changes be-
tween 10 and 50% were consid-
ered to be active.
6.7
14.40
NA
NHnPent
NHPh
À2
155
3
NA
8.40
NA
NA
7.53
NA
134
3
61
2
NHBn
NH(2-ClPh)
NH(3-ClPh)
NH(4-ClPh)
NH(3,5-(CF3)2Ph)
NHEt
68
78
102
À2
147
3
14
99
117
3
153
À2
3
49
42
33
1
20
3
ꢀ10
ꢀ10
ꢀ10
11.1
NA
ꢀ10
ꢀ10
NA
13j
14a
14b
14c
14d
14e
14 f
14g
14h
ꢀ10
NA
4.87
NA
NA
NA
NA
NA
NA
NA
NHnPr
NHPh
NHBn
1
3
NA
À1
3
2
1
1
2
NA
NH(2-ClPh)
NH(3-ClPh)
NH(4-ClPh)
NH(3,5-(CF3)2Ph)
NA
NA
3
1
2
À1
1
2
2
2
1
NA
NA
[a] The percentage arrested was determined by reference to the number of cells in G2/M phase in vehicle con-
trol samples through the following formula: [(CellscompdÀCellsvc)/Cellsvc]ꢂ100%, in which Cellscompd is the
number of compound-treated cells arrested in G2/M phase, and Cellsvc is the number of vehicle control cells ar-
rested in G2/M phase. [b] Values estimated using the CellTiter-Blueꢁ assay; NA: not assayed.
Only
compounds
which
showed activity in the cell-cycle
assay were tested for potency.
This was determined by determi-
nation of an EC50 within PC3 and MCF-7 cells. Caco-2 cells were
not used to calculate potency because active compounds dis-
played consistently lower cell-cycle assay activity in this cell
line. PC3 and MCF-7 cell lines were treated with a range of
concentrations that were able to cause G2/M arrest. Cell viabili-
ty was measured by CellTiter-Blueꢁ assay (Table 1). Most of the
analogues showed low potency, with an EC50 value ꢀ10 mm,
whereas 10e, 12b, 13a, and 13e had EC50 values of ~7 mm in
PC3 and similar potency in MCF-7 cells. However, 11 c, 11 d,
and 14a had much lower EC50 values in MCF-7 cells, indicating
that the efficacy of N-nornoscapine derivatives may be cell-line
dependent.
prominent activity (95% more cells were arrested in G2/M rela-
tive to control in PC3 cells), with an EC50 value of 6.7 mm. Activ-
ity was also maintained for two of the amide analogues,
namely, the N-benzoyl and N-phenacyl cyclic ether noscapine
analogues (11 c and 11 d, respectively). The N-carbamate ana-
logues 12a,b showed moderate activity with 67 and 79% of
PC3 cells trapped in G2/M relative to the vehicle control. For
the structurally related amide analogues 11 c and 11 d, it is
clear that the activities are quite similar for both PC3 and MCF-
7 cell lines; however, the activities of carbamates 12a and 12b
in the Caco-2 cell line are half those of their respective amides.
This illustrates the cell-dependent nature of such compounds
in various cancer cell lines. Examination of N-urea and N-thio-
urea analogues shows similar trends, whereby the ureas and
Of the N-alkyl analogues synthesised (compounds 10a–e),
only the hydroxyethyl analogue 10e was found to exhibit
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ChemMedChem 2012, 7, 2122 – 2133

N-Substituted Noscapine Analogues
MED
Figure 1. FACS analysis of PC3 cells treated for 16 h with a) vehicle control, b) noscapine (10 mm), c) vincristine (5.36 nm [EC80]), and d) N-ethylurea cyclic ether
noscapine 13a (10 mm). Cells were stained with Cell Cycle 405-blue (Invitrogen) after treatment. The cell population in G2/M, having replicated its DNA, was
considered to be in G2 or mitosis. The percentage of cells arrested in G2/M (Table 1) revealed that the cyclic ether noscapine analogues have promising activi-
ty, given noscapine itself is inactive at 10 mm. Most of the active compounds show selectivity for prostate and breast cancer cells over colon cancer cells.
thioureas with short alkyl chains (13a/13b, 14a) show promis-
ing activity in PC3 and MCF-7 cells. On average, 140% of cells
were trapped in G2/M relative to vehicle control in both the
PC3 and MCF-7 cell lines. The alkyl ureas exhibited threefold
better activity than their respective thiourea counterparts in
the Caco-2 cell line, with the propyl thiourea analogue 14b
having very little activity in either of the cell lines used. The
phenyl urea 13e and chloro-substituted phenyl ureas 13g–
i showed moderate results in terms of percentage of cells
trapped; however, this was not reciprocated for their thiourea
complements with little to no activity observed. The noscapine
analogue with an ethyl urea (compound 13a) was shown to
be the most potent compound tested, having activity equal to
that of vincristine with 133, 171, and 60% increases in cells
trapped in the G2/M phase of PC3, MCF-7, and Caco-2 cells, re-
spectively.
G2/M phase for both N-acyl and N-carbamate analogues. The
N-urea and N-thiourea class produced the most potent ana-
logues within the series. The N-urea compounds showed more
activity than their N-thiourea counterparts, with 13a exhibiting
the most promising activity. Analogue 13e showed moderate
activity within the chosen cell lines; mono-chloro substitution
around the phenyl ring (compounds 13g–i) also showed activi-
ty but not as profound as the phenyl urea 13e.
Conclusions
An improved method for the N-demethylation of noscapine (1)
was developed which proceeded in 74% yield. The yield for
the reduction of the lactone moiety of N-nornoscapines was
also optimised (78%) to provide ready access to the cyclic
ether N-nornoscapine (9). A series of N-substituted noscapine
analogues were synthesised using 9 as the scaffold and were
evaluated for their ability to cause G2/M-phase arrest and cyto-
toxic activity. These compounds were initially tested in a cell
inhibition study using the PC3 cell line. Compounds that exhib-
ited notable anticancer activity were then tested against the
MCF-7 and Caco-2 cell lines, and the respective EC50 values
In summary, by studying the inhibition of cellular prolifera-
tion by cyclic ether N-substituted noscapine analogues, ana-
lysed with Cell Cycle 405-blue in PC3, MCF-7, and Caco-2 cell
lines, we identified that N-alkyl analogues did not improve in
activity relative to noscapine, with the exception of 10e. It was
observed that a phenyl group is essential to arrest cells in the
ChemMedChem 2012, 7, 2122 – 2133
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2127

P. J. Scammells et al.
MED
pound 3 (0.070 g, 0.130 mmol, 78%) as a yellow foam; Rf (EtOAc)
0.4; H NMR: d=6.93 (d, J=8.1 Hz,1H), 6.33 (s, 1H), 5.95 (m, 3H),
were calculated for these compounds using the PC3 cell line.
Some of these compounds exhibited a vast improvement in
anticancer activity relative to parent compound 1, with EC50
values ranging between 6.7 and 14.4 mm. Compound 13a, con-
taining the ethyl urea function, was found to be the most
active within the series and showed potent activity across all
three cancer cell lines used.
1
5.91 (d, J=3.3 Hz, 1H), 4.84 (d, J=3.3 Hz, 1H) 4.09 (s, 3H), 4.06 (s,
3H), 3.84 (s, 3H), 2.63 (m, 1H), 2.49 (m, 1H), 2.31 (m, 1H), 2.16 (m,
1H), 1.74 ppm (brs, 1H); 13C NMR: d=168.5, 152.2, 148.4, 147.9,
141.0, 140.4, 134.2, 131.9, 119.6, 118.5, 117.6, 116.9, 103.2, 100.8,
80.6, 62.3, 59.5, 56.7, 52.8, 39.5, 29.6 ppm; HRMS: m/z=400.1409,
calcd for [M+H]+ C21H21NO7: 400.1391.
Synthesis of (R)-5-((S)-4,5-dimethoxy-1,3-dihydroisobenzofuran-
1-yl)-4-methoxy-6-methyl-5,6,7,8-tetrahydro[1,3]dioxolo[4,5-
g]isoquinoline (8): To a solution of NaBH4 (0.20 g, 5.00 mmol) in
dry THF (20 mL) was added a solution of noscapine (1.00 g,
2.42 mmol) in BF3·Et2O (12 mL) dropwise at À58C. The mixture was
stirred at À58C for 1 h and then held at reflux for another 2 h. The
reaction was placed on ice and quenched with cold HCl (10%,
10 mL) and allowed to stir for a further 1 h. The reaction mixture
was then brought to pH 8 with 2.5m NaOH, extracted with CHCl3
(3ꢂ30 mL) and dried over anhydrous Na2SO4. Evaporation of sol-
vent afforded a crude product, which was purified by flash chro-
matography (EtOAc/hexane; 4:1) to afford the title compound as
white amorphous solid (0.91 g, 2.28 mmol, 94%); Rf (EtOAc) 0.26;
1H NMR: d=6.65 (d, J=8.1 Hz, 1H), 6.30 (s, 1H), 6.09 (d, J=8.1,
1H), 5.89 (s, 2H), 5.38 (d, J=2.7 Hz, 1H), 5.15 (dd, J=1.2 Hz, 2H),
4,22 (d, J=2.7 Hz, 1H), 3.90 (s, 3H), 3.83 (s, 3H), 3.82 (s, 3H), 2.82
(m, 1H), 2.56 (s, 3H), 2.43 (m, 2H), 2.16 ppm (m, 1H); 13C NMR: d=
150.9, 147.8, 142.6, 140.7, 134.3, 133.9, 133.1, 131.6, 118.4, 117.3,
111.6, 102.2, 100.5, 86.8, 71.5, 63.3, 59.9, 59.1, 56.2, 49.5, 45.7,
27.4 ppm; HRMS: m/z=400.1766, calcd for [M+H]+ C22H25NO6:
400.1755.
Experimental Section
General procedures: All solvents used were reagent grade. Dry
solvents were dispensed from the MBraun SPS-800 solvent purifica-
tion system under nitrogen. NMR spectra were obtained on
a Bruker 400 WB (400 MHz) spectrometer with Bruker Avance con-
sole. NMR spectra were run in CDCl3 unless otherwise stated; 1H
and 13C NMR spectra were obtained in CDCl3 at 400.13 and
100.62 MHz, respectively. Chemical shifts were measured relative to
the residual solvent peaks of the deuterated solvent: d=7.26 ppm
(1H NMR) and d=77.16 ppm (13C NMR). Signal multiplicities are re-
ported as: s=singlet; d=doublet; t=triplet; dd=doublet of dou-
blets; m=multiplet. Chemical shifts are reported as d values in
parts per million (ppm), and coupling constants (J) in Hertz (Hz).
Mass spectra were collected on a Waters Micromass LCT Premier
XE time-of-flight mass spectrometer fitted with an electrospray
(ESI) ion source and controlled with MassLynx software version 4.5.
Low-resolution mass spectrometry analysis was performed using
a
Micromass Platform II single-quadrupole mass spectrometer
equipped with an atmospheric pressure (ESI/APCI) ion source.
Chromatography was carried out on silica gel 60, particle size 40–
63 mm from Merck (Darmstadt, Germany) by gradient elution. Solu-
tion-phase reactions were monitored by thin-layer chromatography
(TLC). The samples were spotted on analytical aluminum plates
pre-coated with silica gel 60 F254 from Merck (Darmstadt). Nosca-
pine used in the project was supplied by GlaxoSmithKline Australia
(Port Fairy, Victoria, Australia).
(R)-5-((S)-4,5-Dimethoxy-1,3-dihydroisobenzofuran-1-yl)-4-me-
thoxy-5,6,7,8-tetrahydro[1,3]dioxolo[4,5-g]isoquinoline (9): A so-
lution of NaBH4 (0.22 g, 5.8 mmol) in THF (18 mL) was stirred at
À58C. N-Nornoscapine (0.75 g, 1.88 mmol) dissolved in BF3·Et2O
(9 mL) was added dropwise at À58C. The reaction was allowed to
stir at À58C for 1 h, then allowed to warm to room temperature
and stirred overnight. The reaction was quenched with HCl (10%,
10 mL) and allowed to stir for 1 h before being extracted with
CHCl3 (3ꢂ30 mL). The organic layer was then washed with 2.2m
NaOH (20 mL) to yield the free-base form. The organic layer was
dried over Na2SO4 and the solvent was evaporated under reduced
pressure. The crude product was purified by flash chromatography
(CHCl3/MeOH/NH4OH; 85:14:1) as an eluent to afford the title com-
pound as a white foam (0.54 g, 1.39 mmol, 78%); Rf (CHCl3/MeOH/
N-Nornoscapine; (R)-5-((S)-4,5-dimethoxy-1,3-dihydroisobenzo-
furan-1-yl)-4-methoxy-5,6,7,8-tetrahydro[1,3]dioxolo[4,5-g]iso-
quinoline (7): To a cooled solution (À58C) of noscapine (2.00 g,
4.80 mmol, 97.4%) in CHCl3 (50 mL) was added m-CPBA (1.60 g,
9.70 mmol, 77%) portionwise. When the reaction was complete
(1 h), cold CHCl3 (100 mL) and iPrOH (15 mL) were added to the re-
action mixture. The resultant solution was washed with cold 10%
NaOH (3ꢂ10 mL), cold water (2ꢂ20 mL) and finally with 10% HCl
(2ꢂ15 mL). The organic layer was dried over anhydrous Na2SO4
and evaporated in vacuo to yield the N-oxide as a hydrochloride
salt in the form of a light-yellow foam (2.30 g, 4.90 mmol, 100%);
Rf (CHCl3/MeOH/NH3; 85:14:1) 0.56, 0.26; 1H NMR: d=8.01 (d, J=
8.1 Hz, 1H), 7.35 (d, J=8.7 Hz, 1H), 6.60 (s, 1H), 6.35 (s, 1H), 6.24
(s, 1H), 5.86 (m, 2H), 4.25 (m, 1H), 3.99 (s, 3H), 3.92 (s, 3H), 3.83
(m, 1H), 3.67 (s, 3H), 3.44 (m, 1H), 3.28 (s, 3H), 3.12 ppm (m, 1H);
HRMS: m/z=430.1490, calcd for [M+H]+ C22H23NO8: 430.1496. A
solution of noscapine-N-oxide·HCl (0.100 g, 0.220 mmol) in MeOH
(10 mL) was prepared and the mixture was stirred at À58C.
FeSO4·7H2O (0.120 g, 0.430 mmol) was added and stirring was con-
tinued until complete consumption of noscapine-N-oxide·HCl was
observed by TLC. The solvent was removed in vacuo to yield crude
product which was then taken up in CHCl3 (15 mL) and washed
with aqueous acidic 0.1m EDTA (3ꢂ5 mL). The organic layer was
subsequently washed with 1m NaOH (2ꢂ5 mL) to yield the N-nor-
noscapine in the free-base form. The organic layer was dried over
anhydrous Na2SO4 and the crude product was purified by flash
chromatography (EtOAc/PE; 2:1) and reduced to give title com-
1
NH4OH; 85:14:1) 0.25; H NMR: d=6.59 (d, J=8.2 Hz, 1H), 6.33 (s,
1H), 5.92 (q, J=1.5 Hz, 2H), 5.83 (dd, J=8.2, 0.9 Hz, 1H), 5.77 (td,
J=2.6, 1.3 Hz, 1H), 5.36 (dd, J=12.4, 2.8 Hz, 1H), 5.19–5.16 (m,
1H), 4.62 (d, J=4.0 Hz, 1H), 3.99 (s, 3H), 3.85 (s, 3H), 3.79 (s, 3H),
2.69–2.54 (m, 3H), 2.35–2.26 ppm (m, 2H); 13C NMR: d=151.3,
148.1, 143.0, 140.7, 134.4, 133.5, 132.7, 131.4, 118.7, 117.4, 112.2,
103.2, 100.7, 85.0, 71.8, 60.1, 59.5, 56.3, 55.3, 39.7, 29.9 ppm; HRMS:
m/z=386.1612, calcd for [M+H]+ C21H23NO6: 386.1598.
General procedure for tertiary amine synthesis: Compound 9
(0.100 g, 0.238 mmol) was dissolved in MeCN (10 mL) and Cs2CO3
(0.240 g, 0.737 mmol) was added. The alkyl halide (0.48 mmol) was
subsequently added and the reaction was heated at reflux over-
night. Reaction progress was monitored by TLC until complete
(18 h). The reaction volume was then decreased in vacuo and
taken up in CHCl3 (20 mL). The organic layer was washed with H2O
(5 mL) and then dried over anhydrous Na2SO4. After evaporation of
the solvent in vacuo, the crude product was purified by flash chro-
matography. The desired compound was then washed with 2m
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N-Substituted Noscapine Analogues
MED
HCl (5 mL) to give the N-alkylated derivative as the hydrochloride
salt.
d=151.9, 150.2, 143.0, 140.6, 133.8, 131.8, 131.0, 127.2, 118.0,
112.9, 109.5, 102.4, 101.2, 83.5, 72.2, 62.6, 60.2, 58.9, 56.68, 56.51,
44.7, 22.2 ppm; HRMS: m/z=430.1854, calcd for [M+H]+
C23H27NO7: 430.1860.
(R)-5-((S)-4,5-Dimethoxy-1,3-dihydroisobenzofuran-1-yl)-6-ethyl-
4-methoxy-5,6,7,8-tetrahydro[1,3]dioxolo[4,5-g]isoquinoline hy-
drochloride (10a): Yield: 75%; chromatography eluent: PE/EtOAc
General procedure for amide synthesis: Compound 9 (0.100 g,
0.238 mmol) was dissolved in dry CH2Cl2 (10 mL) and Et3N (0.050 g,
0.480 mmol) was added. The reaction was cooled to 08C. The acid
chloride (0.36 mmol) was added to the stirred solution, and the re-
action was then allowed to warm to room temperature. Reaction
progress was monitored by TLC until complete (2 h). The reaction
was quenched with H2O (5 mL) and extracted with CH2Cl2 (3ꢂ
10 mL). The organic layer was dried (anhydrous Na2SO4), reduced,
and then purified by flash chromatography (PE/EtOAc; 1:4) to give
the title compound as a colourless oil.
1
(1:1); Rf (PE/EtOAc; 2:1) 0.12; H NMR: d=7.00 (d, J=8.2 Hz, 1H),
6.89 (d, J=8.2 Hz, 1H), 6.39 (s, 1H), 6.27 (d, J=1.0 Hz, 1H), 5.87
(dd, J=12.3, 1.4 Hz, 2H), 4.94 (s, 1H), 4.91 (d, J=11.6 Hz, 1H), 4.59
(d, J=11.6 Hz, 1H), 4.00–3.96 (m, 1H), 3.87 (s, 3H), 3.79 (s, 3H),
3.37 (s, 4H), 3.08–3.00 (m, 3H), 2.94–2.87 (m, 1H), 1.52 ppm (t, J=
7.2 Hz, 3H); 13C NMR: d=151.8, 150.0, 143.0, 140.6, 133.8, 131.8,
131.5, 127.3, 118.0, 112.8, 109.7, 102.4, 101.2, 83.8, 72.2, 60.6, 60.2,
58.8, 56.5, 47.9, 42.9, 22.2, 10.2 ppm; HRMS: m/z=414.1927, calcd
for [M+H]+ C23H27NO6: 414.1911.
(R)-5-((S)-4,5-Dimethoxy-1,3-dihydroisobenzofuran-1-yl)-4-me-
thoxy-6-propyl-5,6,7,8-tetrahydro[1,3]dioxolo[4,5-g]isoquinoline
hydrochloride (10b): Yield: 81%; chromatography eluent: PE/
1-((R)-5-((S)-4,5-Dimethoxy-1,3-dihydroisobenzofuran-1-yl)-4-me-
thoxy-7,8-dihydro[1,3]dioxolo[4,5-g]isoquinolin-6(5H)-yl)etha-
none (11a): Yield: 68%; chromatography eluent: PE/EtOAc (1:4); Rf
(PE/EtOAc; 1:4) 0.32; 1H NMR: (rotamers: 5#:2*) d=6.89* (dd, J=
8.2, 0.8 Hz, 1H), 6.82* (d, J=8.2 Hz, 1H), 6.64# (d, J=8.2 Hz, 1H),
6.35# (s, 1H), 6.34* (s, 1H), 6.09* (d, J=2.8 Hz, 1H), 5.98* (d, J=
0.8 Hz, 1H), 5.95#* (dd, J=6.4, 1.4 Hz, 2H), 5.83* (dd, J=7.9, 1.5 Hz,
2H), 5.71–5.69# (m, 1H), 5.61–5.59* (m, 1H), 5.36# (d, J=5.1 Hz,
1H), 5.21–5.13 (m, 2H), 4.96* (d, J=12.2 Hz, 1H), 4.60* (dd, J=
12.3, 2.8 Hz, 1H), 4.31–4.25# (m, 1H), 4.09# (s, 3H), 3.85* (s, 3H),
3.83# (s, 3H), 3.81# (s, 3H), 3.76* (s, 3H), 3.56* (s, 3H), 3.52–3.48*
(m, 1H), 3.41–3.35* (m, 1H), 3.21–3.15* (m, 1H), 2.68–2.60#* (m,
2H), 2.43–2.37# (m, 1H), 2.23# (s, 3H), 2.16* (s, 3H), 2.15–2.09# ppm
(m, 1H); 13C NMR: d=171.1, 170.3, 151.7, 151.3, 148.8, 148.4, 143.5,
142.7, 140.6, 139.9, 134.3, 133.9, 133.7, 132.5, 132.2, 131.9, 131.2,
130.0, 118.2, 117.52, 117.36, 116.9, 112.31, 112.28, 102.9, 102.0,
101.0, 100.6, 87.4, 84.3, 71.9, 71.7, 60.2, 60.0, 59.6, 58.9, 56.5, 56.4,
56.3, 52.9, 43.1, 35.8, 29.3, 27.9, 22.6, 22.4 ppm; HRMS: m/z=
428.1703, calcd for [M+H]+ C23H25NO7: 428.1704.
1
EtOAc (1:1); Rf (PE/EtOAc; 1:1) 0.29; H NMR: d=6.92 (d, J=8.3 Hz,
1H), 6.81 (d, J=8.3 Hz, 1H), 6.31 (s, 1H), 6.21 (d, J=1.0 Hz, 1H),
5.79 (dd, J=13.9, 1.4 Hz, 2H), 4.86 (d, J=1.0 Hz, 1H), 4.83 (d, J=
12.1 Hz, 1H), 4.49 (d, J=12.1 Hz, 1H), 3.92–3.88 (m, 1H), 3.78 (s,
3H), 3.70 (s, 3H), 3.32–3.26 (m, 4H), 2.98–2.92 (m, 1H), 2.87–2.77
(m, 3H), 1.97–1.90 (m, 2H), 0.88 ppm (t, J=7.4 Hz, 3H); 13C NMR:
d=151.8, 150.0, 143.0, 140.6, 133.8, 131.8, 131.5, 127.3, 118.0,
112.8, 109.7, 102.4, 101.2, 83.8, 72.2, 61.2, 60.1, 58.8, 56.5, 54.4,
43.3, 22.2, 18.1, 11.3 ppm; HRMS: m/z=428.2081, calcd for [M+
H]+ C24H29NO6: 428.2068.
(R)-6-Benzyl-5-((S)-4,5-dimethoxy-1,3-dihydroisobenzofuran-1-
yl)-4-methoxy-5,6,7,8-tetrahydro[1,3]dioxolo[4,5-g]isoquinoline
(10c): Yield: 76%; chromatography eluent: PE/EtOAc (3:1); Rf (PE/
1
EtOAc; 1:1) 0.83; H NMR: d=7.28 (d, J=4.6 Hz, 4H), 7.24–7.22 (m,
1H), 6.70 (d, J=8.1 Hz, 1H), 6.35 (s, 1H), 6.21 (d, J=8.1 Hz, 1H),
5.91 (q, J=2.1 Hz, 2H), 5.48 (dd, J=2.6, 0.2 Hz, 1H), 5.23–5.19 (m,
1H), 5.09 (d, J=12.1 Hz, 1H), 4.43 (d, J=3.9 Hz, 1H), 4.18 (d, J=
13.9 Hz, 1H), 3.92 (s, 3H), 3.86 (s, 3H), 3.85 (s, 3H), 3.72 (d, J=
13.9 Hz, 1H), 2.84–2.78 (m, 1H), 2.55–2.48 (m, 1H), 2.40–2.34 (m,
1H), 2.30–2.23 ppm (m, 1H); 13C NMR: d=151.1, 148.0, 142.9,
141.1, 140.4, 134.8, 134.2, 132.9, 131.8, 128.40, 128.29, 126.8, 119.0,
117.5, 111.9, 102.5, 100.7, 87.2, 71.8, 62.2, 61.4, 60.0, 59.3, 56.4, 45.5,
27.1 ppm; HRMS: m/z=476.2067, calcd for [M+H]+ C28H29NO6:
476.2068.
1-((R)-5-((S)-4,5-Dimethoxy-1,3-dihydroisobenzofuran-1-yl)-4-me-
thoxy-7,8-dihydro[1,3]dioxolo[4,5-g]isoquinolin-6(5H)-yl)propa-
none (11b): Yield: 53%; chromatography eluent: PE/EtOAc (1:1); Rf
(PE/EtOAc; 1:1) 0.33; 1H NMR: (rotamers; 1.8#:1*) d=6.96* (d, J=
8.2 Hz, 1H), 6.82* (d, J=8.2 Hz, 1H), 6.63# (d, J=8.2 Hz, 1H), 6.33#
(s, 1H), 6.33* (s, 1H), 6.07* (d, J=2.4 Hz, 1H), 5.98# (d, J=8.2 Hz,
1H), 5.93# (dd, J=6.0, 1.4 Hz, 2H), 5.80* (dd, J=9.6, 1.5 Hz, 2H),
5.66# (m, 1H), 5.58–5.57* (m, 1H), 5.40# (d, J=5.2 Hz, 1H), 5.17–
5.10# (m, 2H), 4.92* (d, J=12.2 Hz, 1H), 4.51* (dd, J=12.2, 2.8 Hz,
1H), 4.31–4.26# (m, 1H), 4.06# (s, 3H), 3.83* (s, 3H), 3.82# (s, 3H),
3.80# (s, 3H), 3.73* (s, 3H), 3.55* (m, 1H), 3.49* (s, 3H), 3.37–3.31*
(m, 1H), 3.25–3.18* (m, 1H), 2.65–2.58#* (m, 3H), 2.40#* (m, 4H),
2.18# (m, 1H), 1.18* (t, J=7.4 Hz, 3H), 1.10# ppm (t, J=7.4 Hz, 3H);
13C NMR: d=174.3, 173.5, 151.7, 151.2, 148.8, 148.3, 143.4, 142.7,
140.6, 139.9, 134.3, 133.79, 133.77, 132.6, 132.2, 131.8, 131.6, 130.1,
118.3, 117.49, 117.37, 117.1, 112.3, 103.0, 101.9, 101.0, 100.6, 87.8,
84.2, 71.86, 71.74, 60.17, 59.98, 59.6, 58.8, 56.46, 56.35, 55.2, 53.3,
42.2, 36.0, 29.4, 27.9, 27.4, 26.9, 9.7, 9.3 ppm; HRMS: m/z=
442.1861, calcd for [M+H]+ C24H27NO7: 442.1862.
(R)-5-((S)-4,5-Dimethoxy-1,3-dihydroisobenzofuran-1-yl)-4-me-
thoxy-6-phenethyl-5,6,7,8-tetrahydro[1,3]dioxolo[4,5-g]isoquino-
line (10d): Yield: 63%; chromatography eluent: PE/EtOAc (2:1); Rf
1
(PE/EtOAc; 2:1) 0.73; H NMR: d=7.28–7.24 (m, 2H), 7.20–7.16 (m,
3H), 6.68 (d, J=8.2 Hz, 1H), 6.32 (m, 2H), 5.88 (q, J=1.9 Hz, 2H),
5.37 (s, 1H), 5.10 (d, J=12.4 Hz, 1H), 5.04 (d, J=11.9 Hz, 1H), 4.34
(d, J=3.8 Hz, 1H), 3.87 (s, 3H), 3.84 (s, 3H), 3.83 (s, 3H), 2.96–2.80
(m, 5H), 2.64–2.57 (m, 2H), 2.27–2.22 ppm (m, 1H); 13C NMR: d=
151.2, 148.0, 142.9, 141.1, 140.8, 134.8, 134.1, 132.9, 131.4, 128.9,
128.4, 126.0, 119.1, 117.6, 111.9, 102.6, 100.6, 86.5, 71.7, 61.6, 60.1,
59.2, 58.6, 56.4, 45.6, 34.6, 26.3 ppm; HRMS: m/z=490.2203, calcd
for [M+H]+ C29H31NO6: 490.2224.
1-((R)-5-((S)-4,5-Dimethoxy-1,3-dihydroisobenzofuran-1-yl)-4-me-
thoxy-7,8-dihydro[1,3]dioxolo[4,5-g]isoquinolin-6(5H)-yl)-
(phenyl)methanone (11c): Yield: 54%; chromatography eluent:
2-((R)-5-((S)-4,5-Dimethoxy-1,3-dihydroisobenzofuran-1-yl)-4-me-
thoxy-7,8-dihydro[1,3]dioxolo[4,5-g]isoquinolin-6(5H)-yl)ethanol
(10e): Yield: 56%; chromatography eluent: PE/EtOAc (1:4); Rf (PE/
1
PE/EtOAc (1:4); Rf (PE/EtOAc; 1:1) 0.18; H NMR: (rotamers; 1.5#:1*)
d=7.39–7.33#* (m, 10H), 6.77* (d, J=8.2 Hz, 1H), 6.68# (d, J=
8.2 Hz, 1H), 6.60* (d, J=8.3 Hz, 1H), 6.42# (s, 1H), 6.35* (d, J=
3.3 Hz, 1H), 6.32* (s, 1H), 5.97# (d, J=8.3 Hz, 1H), 5.95# (s, 2H),
5.90* (s, 2H), 5.83–5.81# (m, 1H), 5.48–5.42* (m, 2H), 5.19–5.10# (m,
3H), 4.98–4.95* (m, 1H), 4.36–4.31# (m, 1H), 3.85* (s, 3H), 3.84# (s,
1
EtOAc; 1:4) 0.25; H NMR: d=6.87 (s, 2H), 6.39 (s, 1H), 6.20 (s, 1H),
5.88 (d, J=7.5 Hz, 2H), 5.23 (s, 1H), 5.06 (s, 1H), 4.93 (d, J=
12.2 Hz, 1H), 4.70 (d, J=13.0 Hz, 1H), 4.05 (s, 2H), 3.97–3.91 (m,
1H), 3.85 (s, 3H), 3.79 (s, 3H), 3.58–3.52 (m, 1H), 3.44 (s, 3H), 3.20–
3.16 (m, 2H), 3.01–2.97 (m, 2H), 2.11–1.94 ppm (m, 1H); 13C NMR:
ChemMedChem 2012, 7, 2122 – 2133
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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2129

P. J. Scammells et al.
MED
9H), 3.82 (s, 3H), 3.78* (m, 3H), 3.45–3.40* (m, 1H), 3.07–2.99* (m,
1H), 2.92–2.82* (m, 1H), 2.71–2.54#* ppm (m, 4H); 13C NMR: d=
172.3, 171.2, 151.7, 151.5, 148.9, 148.5, 143.5, 143.0, 140.6, 139.9,
137.04, 137.02, 134.6, 134.2, 133.8, 132.8, 132.1, 130.0, 129.8, 129.5,
129.4, 128.6, 128.3, 127.4, 126.7, 118.0, 117.4, 117.2, 112.4, 112.3,
103.2, 102.3, 101.1, 100.8, 86.4, 84.3, 72.1, 71.5, 60.2, 60.1, 59.5,
59.2, 57.0, 56.4, 56.4, 52.9, 43.1, 36.8, 29.3, 27.9 ppm; HRMS: m/z=
490.1877, calcd for [M+H]+ C28H27NO7: 490.1860.
J=4.5 Hz, 1H), 5.64–5.63 (m, 1H), 5.58–5.56 (m, 1H), 5.24–5.11 (m,
4H), 5.06–4.98 (m, 2H), 4.91 (dd, J=12.4, 2.4 Hz, 1H), 4.73 (dd, J=
12.4, 2.5 Hz, 1H), 3.83–3.81 (m, 9H), 3.78 (s, 3H), 3.76 (s, 3H), 3.70
(s, 4H), 3.58–3.52 (m, 1H), 3.24–3.17 (m, 1H), 2.92–2.84 (m, 2H),
2.71–2.68 (m, 2H), 2.65–2.57 ppm (m, 1H); 13C NMR: d=156.2,
156.1, 151.5, 151.3, 148.5, 148.4, 143.2, 142.9, 140.4, 140.2, 137.2,
134.3, 134.0, 133.5, 133.4, 132.2, 132.1, 130.9, 130.5, 128.6, 128.5,
128.0, 127.9, 117.9, 117.7, 117.4, 112.2, 112.2, 102.8, 102.3, 100.8,
100.7, 86.6, 85.6, 77.2, 71.8, 71.71, 67.3, 67.1, 60.1, 60.0, 59.3, 59.1,
56.4, 54.7, 54.2, 40.3, 39.6, 28.8, 28.3 ppm; HRMS: m/z=520.1979,
calcd for [M+H]+ C29H29NO8: 520.1966.
1-((R)-5-((S)-4,5-Dimethoxy-1,3-dihydroisobenzofuran-1-yl)-4-me-
thoxy-7,8-dihydro[1,3]dioxolo[4,5-g]isoquinolin-6(5H)-yl)-2-phe-
nylethanone (11d): Yield: 62%; chromatography eluent: PE/EtOAc
1
(1:4); Rf (PE/EtOAc;1:4) 0.42; H NMR: d (rotamers; 1.8#:1*) d=7.33–
General procedure for urea synthesis: Compound 9 (0.110 g,
0.261 mmol) was dissolved in MeCN (2.5 mL) and cooled to À58C.
The appropriate isocyanate (0.360 mmol) dissolved in MeCN
(2.5 mL) was then added dropwise. The reaction was then stirred
at room temperature until complete (2 h). The reaction was
quenched with cold water (1 mL) and extracted with CHCl3 (3ꢂ
10 mL). Organic layers were combined and dried with anhydrous
Na2SO4 and reduced in vacuo. The crude product was purified by
flash chromatography.
7.14#* (m, 10H), 6.78* (q, J=8.2 Hz, 2H), 6.63#(d, J=8.2 Hz, 1H),
6.32# (s, 1H), 6.29* (s, 1H), 6.13* (d, J=2.7 Hz, 1H), 5.95# (d, J=
8.2 Hz, 1H), 5.92# (dd, J=3.9, 1.4 Hz, 2H), 5.81* (dd, J=6.9, 1.4 Hz,
2H), 5.70–5.68# (m, 1H), 5.63–5.62* (m, 1H), 5.48# (d, J=5.1 Hz,
1H), 5.25–5.16# (m, 2H), 4.92* (d, J=12.3 Hz, 1H), 4.50* (dd, J=
12.3, 2.8 Hz, 1H), 4.33–4.27# (m, 1H), 3.99# (d, J=15.45 Hz, 1H),
3.91–3.86# (s, 4H), 3.84# (s, 3H), 3.82* (s, 3H), 3.81# (s, 3H), 3.79* (d,
J=4.1 Hz, 2H), 3.71* (s, 3H), 3.55* (s, 3H), 3.45–3.41* (m, 2H),
3.07–3.00* (m, 1H), 2.67–2.59# (m, 1H), 2.54–2.47* (m, 1H), 2.43–
2.37# (m, 1H), 2.24–2.16# ppm (m, 1H); 13C NMR: d=171.6, 170.7,
151.8, 151.2, 148.7, 148.4, 143.5, 142.7, 140.5, 139.9, 135.8, 135.1,
134.5, 133.85, 133.65, 132.4, 132.2, 131.7, 131.1, 129.8, 129.0, 128.8,
128.5, 126.8, 126.5, 118.1, 117.44, 117.27, 116.9, 112.32, 112.22,
103.0, 102.0, 101.0, 100.6, 87.2, 84.3, 71.9, 71.7, 60.2, 60.0, 59.6,
58.9, 56.4, 56.3, 55.6, 53.3, 42.5, 41.8, 41.1, 36.3, 29.2, 27.8 ppm;
HRMS: m/z=504.2041, calcd for [M+H]+ C29H29NO7: 504.2017.
(R)-5-((S)-4,5-Dimethoxy-1,3-dihydroisobenzofuran-1-yl)-N-ethyl-
4-methoxy-7,8-dihydro[1,3]dioxolo[4,5-g]isoquinoline-6(5H)-car-
boxamide (13a): Yield: 84%; chromatography eluent: PE/EtOAc
(3:1); Rf (PE/EtOAc; 4:1) 0.1; 1H NMR: d=6.62 (d, J=8.2 Hz, 1H),
6.32 (s, 1H), 6.01 (d, J=8.2 Hz, 1H), 5.98 (bs, 1H), 5.93 (m, 2H),
5.80 (m, 1H), 5.32 (d, J=3.22 Hz, 1H), 5.12 (m, 2H), 4.04 (s, 3H),
3.82 (s, 3H), 3.81 (s, 4H), 3.33 (m, 1H), 3.21 (m, 1H), 2.57 (m, 1H),
2.21 (m, 2H), 1.19 ppm (t, J=7.19 Hz, 3H); 13C NMR: d=160.0,
151.7, 148.5, 143.3, 139.9, 134.3, 132.2, 131.9, 131.1, 117.7, 116.6,
112.2, 103.0, 100.9, 86.2, 71.9, 60.3, 59.6, 56.6, 56.4, 38.1, 35.8, 28.3,
15.9 ppm; HRMS: m/z=457.1991, calcd for [M+H]+ C24H28N2O7:
457.2029.
General procedure for carbamate synthesis: Compound
9
(0.143 g, 0.340 mmol) was dissolved in dry CH2Cl2 (10 mL) and Et3N
(0.075 g, 0.74 mmol) was added. The reaction was cooled to À58C
and the appropriate chloroformate was added (0.55 mmol). The re-
action was then allowed to warm to room temperature and stir
overnight. The reaction was quenched with H2O (5 mL) and ex-
tracted with CH2Cl2 (3ꢂ10 mL). The organic layer was dried (anhy-
drous Na2SO4) and evaporated under reduced pressure. The crude
product was purified by flash chromatography.
(R)-5-((S)-4,5-Dimethoxy-1,3-dihydroisobenzofuran-1-yl)-4-me-
thoxy-N-propyl-7,8-dihydro[1,3]dioxolo[4,5-g]isoquinoline-6(5H)-
carboxamide (13b): Yield: 91%; chromatography eluent: PE/EtOAc
(2:1); Rf (PE/EtOAc; 5:1) 0.1.1H NMR: d=6.62 (d, J=8.2 Hz, 1H),
6.33 (s, 1H), 6.06 (bs, 1H), 6.02 (d, J=8.2 Hz, 1H), 5.94 (dd, J=6.0,
1.4 Hz, 2H), 5.82–5.80 (m, 1H), 5.32 (d, J=3.6 Hz, 1H), 5.15 (d, J=
2.4 Hz, 1H), 5.12 (d, J=12.0 Hz, 1H), 4.04 (s, 3H), 3.83 (s, 4H), 3.81
(s, 3H), 3.29–3.25 (m, 1H), 3.18–3.11 (m, 1H), 2.56 (m, 1H), 2.21 (s,
2H), 1.60–1.56 (m, 2H), 0.98 ppm (t, J=7.4 Hz, 3H); 13C NMR: d=
160.1, 151.7, 148.5, 143.3, 139.8, 134.3, 132.2, 131.9, 131.1, 117.7,
116.6, 112.2, 102.9, 100.9, 86.1, 71.9, 60.2, 59.5, 56.6, 56.3, 42.8, 38.1,
28.3, 23.6, 11.7 ppm; HRMS: m/z=471.2140, calcd for [M+H]+
C25H30N2O7: 471.2175.
(R)-Phenyl 5-((S)-4,5-dimethoxy-1,3-dihydroisobenzofuran-1-yl)-
4-methoxy-7,8-dihydro[1,3]dioxolo[4,5-g]isoquinoline-6(5H)-car-
boxylate (12a): Yield: 83%; chromatography eluent: PE/EtOAc
1
(2:1); Rf (PE/EtOAc; 2:1) 0.40; H NMR: d (rotamers; 1.6:1) d=7.38–
7.33 (m, 5H), 7.21–7.08 (m, 5H), 6.79 (s, 2H), 6.70 (d, J=8.2 Hz,
1H), 6.39 (s, 1H), 6.38 (s, 1H), 6.24 (d, J=8.2 Hz, 1H), 5.93 (q, J=
1.3 Hz, 2H), 5.87 (d, J=4.9 Hz, 1H), 5.85 (dd, J=9.0, 1.3 Hz, 2H),
5.76 (d, J=2.9 Hz, 1H), 5.70–5.69 (m, 2H), 5.21–5.13 (m, 2H), 5.02
(d, J=12.2 Hz, 1H), 4.70 (dd, J=12.2, 2.9 Hz, 1H), 3.94 (s, 3H), 3.84
(s, 3H), 3.83 (s, 7H), 3.78 (s, 3H), 3.65–3.60 (m, 4H), 3.17–3.09 (m,
1H), 2.83–2.63 ppm (m, 5H); 13C NMR: d=154.86, 154.76, 151.76,
151.67, 151.4, 148.72, 148.55, 143.4, 142.9, 140.5, 140.2, 134.4,
133.9, 133.4, 133.2, 132.3, 132.0, 131.4, 130.1, 129.36, 129.30, 125.3,
122.1, 122.0, 118.1, 117.5, 117.4, 117.3, 112.4, 112.3, 102.8, 102.3,
101.0, 100.7, 87.2, 85.2, 71.9, 71.8, 60.2, 60.1, 59.4, 59.0, 56.5, 55.3,
54.6, 41.4, 39.4, 29.0, 28.2 ppm; HRMS: m/z=506.1827, calcd for
[M+H]+ C28H27NO8: 506.1809.
(R)-N-Butyl-5-((S)-4,5-dimethoxy-1,3-dihydroisobenzofuran-1-yl)-
4-methoxy-7,8-dihydro[1,3]dioxolo[4,5-g]isoquinoline-6(5H)-car-
boxamide (13c): Yield: 76%; chromatography eluent: CH2Cl2/
EtOAc (4:1), Rf (CH2Cl2/EtOAc; 4:1) 0.27; 1H NMR: d=6.62 (d, J=
8.1 Hz, 1H), 6.32 (s, 1H), 6.01 (d, J=8.1 Hz, 2H), 5.93 (dd, J=6.0,
1.4 Hz, 2H), 5.81–5.80 (m, 1H), 5.31 (d, J=3.6 Hz, 1H), 5.17–5.09
(m, 2H), 4.04 (s, 3H), 3.83 (s, 4H), 3.81 (s, 3H), 3.35–3.28 (m, 1H),
3.22–3.15 (m, 1H), 2.64–2.56 (m, 1H), 2.27–2.21 (m, 2H), 1.60–1.52
(m, 2H), 1.45–1.36 (m, 2H), 0.96 ppm (t, J=7.3 Hz, 3H); 13C NMR:
d=160.2, 151.8, 148.6, 143.3, 139.8, 134.3, 132.2, 131.7, 131.0,
117.7, 116.5, 112.3, 103.0, 101.0, 86.2, 71.9, 60.3, 59.6, 56.7, 56.4,
41.0, 38.4, 32.6, 28.3, 20.4, 14.0 ppm; HRMS: m/z=485.2274, calcd
for [M+H]+ C26H32N2O7: 485.2282.
(R)-Benzyl 5-((S)-4,5-dimethoxy-1,3-dihydroisobenzofuran-1-yl)-
4-methoxy-7,8-dihydro[1,3]dioxolo[4,5-g]isoquinoline-6(5H)-car-
boxylate (12b): Yield: 85%; chromatography eluent: PE/EtOAc
1
(2:1); Rf (PE/EtOAc; 2:1) 0.35; H NMR: d (rotamers; 1:1) d=7.39–
7.27 (m, 10H), 6.72 (d, J=8.1 Hz, 1H), 6.65 (d, J=8.2 Hz, 1H), 6.59
(d, J=8.1 Hz, 1H), 6.35 (s, 1H), 6.32 (s, 1H), 6.23 (d, J=8.2 Hz, 1H),
5.89 (s, 2H), 5.85 (d, J=4.2 Hz, 2H), 5.76 (d, J=3.5 Hz, 1H), 5.69 (d,
(R)-5-((S)-4,5-Dimethoxy-1,3-dihydroisobenzofuran-1-yl)-4-me-
thoxy-N-pentyl-7,8-dihydro[1,3]dioxolo[4,5-g]isoquinoline-6(5H)-
carboxamide (13d): Yield: 78%; chromatography eluent: CH2Cl2/
2130
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ChemMedChem 2012, 7, 2122 – 2133

N-Substituted Noscapine Analogues
MED
EtOAc (4:1); Rf (CH2Cl2/EtOAc; 4:1) 0.13; 1H NMR: d=6.62 (d, J=
8.1 Hz, 1H), 6.32 (s, 1H), 6.02 (d, J=8.1 Hz, 2H), 5.93 (dd, J=6.0,
1.4 Hz, 2H), 5.81–5.79 (m, 1H), 5.31 (d, J=3.6 Hz, 1H), 5.17–5.09
(m, 2H), 4.04 (s, 3H), 3.82 (s, 4H), 3.81 (s, 3H), 3.33–3.25 (m, 1H),
3.20–3.14 (m, 1H), 2.61–2.53 (m, 1H), 2.27–2.17 (m, 2H), 1.59–1.53
(m, 2H), 1.38–1.34 (m, 4H), 0.92 ppm (t, J=7.0 Hz, 3H); 13C NMR:
d=160.1, 151.7, 148.5, 143.3, 139.9, 134.3, 132.2, 131.9, 131.1,
117.7, 116.7, 112.2, 103.0, 100.9, 86.2, 71.9, 60.3, 59.6, 56.6, 56.4,
41.1, 38.2, 30.2, 29.5, 28.3, 22.6, 14.3 ppm; HRMS: m/z=499.2463,
calcd for [M+H]+ C27H34N2O7: 499.2439.
132.0, 131.5, 130.5, 129.2, 127.3, 123.2, 122.9, 122.1, 117.6, 116.1,
112.2, 103.0, 101.0, 85.5, 72.2, 60.2, 59.7, 57.1, 56.3, 38.1, 28.1 ppm;
HRMS: m/z=539.1601, calcd for [M+H]+ C28H27ClN2O7: 539.1580.
(R)-N-(4-Chlorophenyl)-5-((S)-4,5-dimethoxy-1,3-dihydroisoben-
zofuran-1-yl)-4-methoxy-7,8-dihydro[1,3]dioxolo[4,5-g]isoquino-
line-6(5H)-carboxamide (13i): Yield: 59%; chromatography eluent:
PE/EtOAc (5:1); Rf (PE/EtOAc; 4:1) 0.12; 1H NMR: d=8.71 (s, 1H),
7.33 (d, J=8.9 Hz, 2H), 7.24 (d, J=8.9 Hz, 2H), 6.63 (d, J=8.2 Hz,
1H), 6.35 (s, 1H), 5.99–5.93 (m, 4H), 5.46 (d, J=3.2 Hz, 1H), 5.30
(dd, J=12.2, 2.4 Hz, 1H), 5.21 (d, J=12.2 Hz, 1H), 4.10 (s, 3H),
3.92–3.87 (m, 1H), 3.83 (s, 3H), 3.18 (s, 3H) 2.68–2.59 (m, 1H),
2.26–2.18 ppm (m, 2H); 13C NMR: d=157.2, 151.9, 148.8, 143.4,
139.8, 138.8, 134.4, 131.9, 131.0, 130.7, 128.9, 127.2, 120.61, 120.52,
117.7, 115.8, 112.3, 103.0, 101.0, 86.2, 72.1, 60.3, 59.7, 56.9, 56.4,
38.2, 28.1 ppm; HRMS: m/z=539.1595, calcd for [M+H]+
C28H27ClN2O7: 539.1580.
(R)-5-((S)-4,5-Dimethoxy-1,3-dihydroisobenzofuran-1-yl)-4-me-
thoxy-N-phenyl-7,8-dihydro[1,3]dioxolo[4,5-g]isoquinoline-6(5H)-
carboxamide (13e): Yield: 98%; chromatography eluent: PE/EtOAc
1
(4:1) Rf (PE/EtOAc; 4:1) 0.05; H NMR: d=8.66 (bs, 1H), 7.39 (d, J=
7.6 Hz, 2H), 7.29 (t, J=7.0 Hz, 2H), 6.99 (t, J=7.6 Hz, 1H), 6.63 (d,
J=8.2 Hz, 1H), 6.35 (s, 1H), 5.99 (d, J=8.2 Hz, 1H), 5.97–5.93 (m,
3H), 5.50 (d, J=3.6 Hz, 1H), 5.33 (dd, J=12.2, 2.7 Hz, 1H), 5.22 (d,
J=12.2 Hz, 1H), 4.09 (s, 3H), 3.96–3.89 (m, 1H), 3.83 (s, 3H), 3.81 (s,
3H), 2.69–2.60 (m, 1H), 2.28–2.15 ppm (m, 2H); 13C NMR: d=157.4,
151.9, 148.8, 143.4, 140.2, 139.9, 134.4, 132.0, 131.3, 130.8, 129.0,
122.4, 119.4, 117.7, 116.1, 112.3, 103.0, 101.0, 86.2, 72.1, 60.3, 59.7,
57.0, 56.4, 38.2, 28.2 ppm; HRMS: m/z=505.1993, calcd for [M+
H]+ C28H28N2O7: 505.1969.
(R)-N-(3,5-Bis(trifluoromethyl)phenyl)-5-((S)-4,5-dimethoxy-1,3-di-
hydroisobenzofuran-1-yl)-4-methoxy-7,8-dihydro[1,3]dioxolo-
[4,5-g]isoquinoline-6(5H)-carboxamide (13j): Yield: 85%; chroma-
1
tography eluent: PE/EtOAc (8:1); Rf (PE/EtOAc; 8:1) 0.05; H NMR:
d=9.17 (s, 1H), 7.89 (s, 2H), 7.49 (s, 1H), 6.66 (d, J=8.3 Hz, 1H),
6.38 (s, 1H), 6.00–5.97 (m, 4H), 5.49 (d, J=3.6 Hz, 1H), 5.32–5.25
(m, 2H), 4.13 (s, 3H), 3.95–3.90 (m, 1H), 3.85 (s, 3H), 3.83 (s, 3H),
2.67 (m, 1H), 2.30–2.21 ppm (m, 2H); 13C NMR: d=156.8, 152.1,
149.0, 143.4, 141.8, 139.8, 134.4, 132.2 (q, J=32.9), 131.8, 130.60,
130.51, 123.5 (q, J=271), 118.9 (q, J=3), 117.7, 115.4 (m), 115.3,
112.5, 103.0, 101.1, 86.2, 72.2, 60.3, 59.7, 56.9, 56.3, 38.5, 28.0 ppm;
HRMS: m/z=641.1729, calcd for [M+H]+ C30H26F6N2O7: 641.1717.
(R)-N-Benzyl-5-((S)-4,5-dimethoxy-1,3-dihydroisobenzofuran-1-
yl)-4-methoxy-7,8-dihydro[1,3]dioxolo[4,5-g]isoquinoline-6(5H)-
carboxamide (13 f): Yield: 91%; chromatography eluent: PE/EtOAc
1
(7:1); Rf (PE/EtOAc; 4:1) 0.08; H NMR: d=7.40–7.33 (m, 4H), 7.29–
7.27 (m, 1H), 6.61 (d, J=8.1 Hz, 1H), 6.40–6.36 (bs, 1H), 6.33 (d, J=
3.3 Hz, 1H), 6.01 (d, J=8.1 Hz, 1H), 5.93 (dd, J=5.3, 1.4 Hz, 2H),
5.79 (td, J=3.0, 1.1 Hz, 1H), 5.38 (d, J=3.0 Hz, 1H), 5.07–4.99 (m,
2H), 4.51 (dd, J=14.6, 6.1 Hz, 1H), 4.38 (td, J=8.0, 4.3 Hz, 1H), 4.01
(s, 3H), 3.90–3.83 (m, 1H), 3.81 (s, 3H), 3.80 (s, 3H), 2.59 (m, 1H),
2.29–2.22 ppm (m, 2H); 13C NMR: d=159.9, 151.7, 148.6, 143.3,
140.3, 139.9, 134.3, 132.1, 131.8, 131.0, 128.6, 128.0, 127.2, 117.7,
116.5, 112.2, 102.9, 100.9, 86.0, 71.8, 60.2, 59.6, 56.50, 56.37, 45.2,
38.3, 28.3 ppm; HRMS: m/z=519.2109, calcd for [M+H]+
C29H30N2O7: 519.2126.
General procedure for thiourea synthesis: Compound 9 as the
free-base form (0.088 g, 0.228 mmol) was dissolved in MeCN
(3.0 mL) and cooled to 58C. The appropriate isothiocyanate
(0.270 mmol) in MeCN (3.0 mL) was then added dropwise and the
reaction was then stirred at room temperature for 2 h. The reaction
was quenched with cold water (1 mL) and extracted with CHCl3
(3ꢂ10 mL). The combined organic layer was dried (anhydrous
Na2SO4) and reduced to give crude product. The product was puri-
fied by column chromatography.
(R)-N-(2-Chlorophenyl)-5-((S)-4,5-dimethoxy-1,3-dihydroisoben-
zofuran-1-yl)-4-methoxy-7,8-dihydro[1,3]dioxolo[4,5-g]isoquino-
line-6(5H)-carboxamide (13g): Yield: 80%; chromatography
eluent: PE/EtOAc (5:1); Rf (PE/EtOAc; 5:1) 0.03; 1H NMR: d=8.85
(bs, 1H), 7.86 (dd, J=8.3, 1.3 Hz, 1H), 7.36 (dd, J=8.0, 1.4 Hz, 1H),
7.20 (ddd, J=8.4, 7.3, 1.3 Hz, 1H), 6.93 (ddd, J=8.4, 7.3, 1.3 Hz,
1H), 6.64 (d, J=8.2 Hz, 1H), 6.36 (s, 1H), 6.03 (d, J=8.2 Hz, 1H),
5.97–5.94 (m, 3H), 5.55 (d„ J=3.5 Hz, 1H), 5.38 (d, J=11.9 Hz, 1H),
5.22 (d, J=11.9 Hz, 1H), 4.07 (s, 3H), 3.98 (s, 1H), 3.83 (s, 3H), 3.82
(s, 3H), 2.69 (m, 1H), 2.34–2.29 (m, 1H), 2.15 ppm (m, 1H);
13C NMR: d=157.1, 151.8, 148.7, 143.4, 139.9, 137.1, 134.4, 132.0,
131.5, 130.5, 129.2, 127.3, 123.2, 122.9, 122.1, 117.6, 116.1, 112.2,
103.0, 101.0, 85.5, 72.2, 60.2, 59.7, 57.1, 56.3, 38.1, 28.1 ppm; HRMS:
m/z=539.1606, calcd for [M+H]+ C28H27ClN2O7: 539.1580.
(R)-5-((S)-4,5-Dimethoxy-1,3-dihydroisobenzofuran-1-yl)-N-ethyl-
4-methoxy-7,8-dihydro[1,3]dioxolo[4,5-g]isoquinoline-6(5H)-car-
bothioamide (14a): Yield: 93%; chromatography eluent: toluene/
EtOAc (10:1); Rf (toluene/EtOAc; 10:1) 0.10; 1H NMR: d=7.48 (bs,
1H), 6.64 (d, J=8.2 Hz, 1H), 6.33 (s, 1H), 6.11 (bs, 1H), 5.95 (m, 1H),
5.93 (dd, J=5.8, 1.4 Hz, 2H), 5.57 (bs, 1H), 5.08 (m, 2H), 4.62 (s,
1H), 4.02 (s, 3H), 3.82 (s, 3H), 3.81 (s, 4H), 3.63–3.56 (m, 1H), 2.77
(m, 1H), 2.37 (s, 2H), 1.29 ppm (t, J=7.2 Hz, 3H); 13C NMR: d=
185.6, 151.8, 148.8, 143.4, 139.6, 134.3, 131.8, 131.4, 131.0, 117.6,
115.8, 112.4, 103.0, 101.0, 85.9, 71.7, 60.3, 59.70, 59.58, 56.4, 44.0,
40.8, 27.8, 14.8 ppm; HRMS: m/z=473.1743, calcd for [M+H]+
C24H28N2O6S: 473.1741.
(R)-5-((S)-4,5-Dimethoxy-1,3-dihydroisobenzofuran-1-yl)-4-me-
thoxy-N-propyl-7,8-dihydro[1,3]dioxolo[4,5-g]isoquinoline-6(5H)-
carbothioamide (14b): Yield: 91%; chromatography eluent: tolu-
(R)-N-(3-Chlorophenyl)-5-((S)-4,5-dimethoxy-1,3-dihydroisoben-
zofuran-1-yl)-4-methoxy-7,8-dihydro[1,3]dioxolo[4,5-g]isoquino-
line-6(5H)-carboxamide (13h): Yield: 85%; chromatography
eluent: PE/EtOAc (5:1); Rf (PE/EtOAc; 4:1) 0.14; 1H NMR: d=8.78
(bs, 1H), 7.47 (t, J=2.0 Hz, 1H), 7.29–7.26 (m, 1H), 7.20 (t, J=
8.0 Hz, 1H), 6.98–6.95 (m, 1H), 6.64 (d, J=8.2 Hz, 1H), 6.36 (s, 1H),
5.99–5.95 (m, 3H), 5.93 (t, J=3.6 Hz, 1H), 5.46 (d, J=3.2 Hz, 1H),
5.32 (dd, J=12.2, 2.6 Hz, 1H), 5.23 (d, J=12.2 Hz, 1H), 4.10 (s, 3H),
3.93–3.88 (m, 1H), 3.83 (s, 3H), 3.82 (s, 3H), 2.65 (s, 1H), 2.22 ppm
(m, 2H); 13C NMR: d=157.1, 151.8, 148.7, 143.4, 139.9, 137.1, 134.4,
1
ene/EtOAc (8:1); Rf (toluene/EtOAc; 7:1) 0.38; H NMR: d=7.59 (s,
1H), 6.65 (d, J=8.2 Hz, 1H), 6.34 (s, 1H), 6.09 (bs, 1H), 5.96 (m,
1H), 5.94 (dd, J=6.1, 1.4 Hz, 2H), 5.56 (bs, 1H), 5.10 (s, 2H), 4.64
(bs, 1H), 4.03 (s, 3H), 3.83 (s, 3H), 3.81 (s, 3H), 3.76–3.71 (m, 1H),
3.53 (m, 1H), 2.83–2.75 (m, 1H), 2.35 (bs, 2H), 1.75–1.69 (m, 2H),
1.02 ppm (t, J=7.4 Hz, 3H); 13C NMR: d=185.7, 151.8, 148.8, 143.4,
139.6, 134.3, 131.7, 131.3, 130.9, 117.6, 115.8, 112.4, 103.0, 101.0,
85.8, 71.7, 60.3, 59.8, 59.6, 56.3, 47.9, 44.0, 27.8, 22.6, 11.7 ppm;
HRMS: m/z=487.1917, calcd for [M+H]+ C25H30N2O6S: 487.1897.
ChemMedChem 2012, 7, 2122 – 2133
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemmedchem.org
2131

P. J. Scammells et al.
MED
(R)-5-((S)-4,5-Dimethoxy-1,3-dihydroisobenzofuran-1-yl)-4-me-
thoxy-N-phenyl-7,8-dihydro[1,3]dioxolo[4,5-g]isoquinoline-6(5H)-
carbothioamide (14c): Yield: 89%; chromatography eluent: tolu-
11.5 Hz, 1H), 5.20 (d, J=12.1 Hz, 1H), 4.81 (d, J=6.8 Hz, 1H), 4.04
(s, 3H), 3.82 (s, 3H), 3.78 (s, 3H), 2.80 (ddd, J=16.7, 11.4, 5.6 Hz,
1H), 2.33–2.27 ppm (m, 2H); 13C NMR: d=185.2, 152.0, 149.1,
143.5, 139.6, 139.2, 134.3, 131.5, 130.76, 130.6, 129.8, 128.7, 125.3,
117.6, 115.2, 112.7, 103.0, 101.1, 85.9, 72.0, 60.4, 59.9, 59.7, 56.4,
44.0, 27.7 ppm; HRMS: m/z=555.1341, calcd for [M+H]+
C28H27ClN2O6S: 555.1351.
1
ene/EtOAc (8:1); Rf (toluene/EtOAc; 8:1) 0.15; H NMR: d=9.64 (bs,
1H), 7.45 (dd, 2H, J=8.4, 1.2 Hz), 7.36 (dd, 2H, J=8.4, 7.6 Hz), 7.26
(t, 1H, J=7.3 Hz), 6.67 (d, 1H, J=8.2 Hz), 6.38 (s, 1H), 6.09–6.07 (m,
1H), 6.05 (bs, 1H), 5.96 (dd, 2H, J=9.7, 1.4 Hz), 5.84 (bs, 1H), 5.35
(dd, 1H, J=11.9, 0.2 Hz), 5.25 (d, 1H, J=11.9 Hz), 4.87 (bs, 1H),
4.08 (s, 3H), 3.87 (s, 3H), 3.83 (s, 3H), 2.91–2.83 (m, 1H), 2.36 ppm
(m, 2H); 13C NMR: d=185.3, 152.0, 149.0, 143.6, 140.6, 139.6, 134.3,
131.6, 131.0, 130.7, 128.7, 124.7, 124.1, 117.6, 115.4, 112.6, 103.0,
101.1, 85.9, 71.9, 60.4, 59.9, 59.7, 56.4, 43.9, 27.7 ppm; HRMS: m/
z=521.1766, calcd for [M+H]+ C28H28N2O6S: 521.1741.
(R)-N-(3,5-bis(trifluoromethyl)phenyl)-5-((S)-4,5-dimethoxy-1,3-di-
hydroisobenzofuran-1-yl)-4-methoxy-7,8-dihydro[1,3]dioxolo-
[4,5-g]isoquinoline-6(5H)-carbothioamide (14h): Yield: 62%; chro-
matography eluent: toluene/EtOAc (20:1); Rf (toluene/EtOAc; 20:1)
1
0.50; H NMR: d=9.94 (s, 1H), 7.92 (s, 2H), 7.58 (s, 1H), 6.68 (d, J=
8.0 Hz 1H), 6.39 (s, 1H), 6.12–6.11 (m, 1H), 6.01 (d, J=8.0 Hz, 1H),
5.97 (dd, J=10.8, 1.4 Hz, 2H), 5.83–5.83 (m, 1H), 5.36–5.28 (m, 2H),
4.89–4.82 (m, 1H), 4.11 (s, 3H), 3.87 (s, 3H), 3.83 (s, 3H), 2.88–2.81
(m, 1H), 2.39–2.37 ppm (m, 2H); 13C NMR: d=184.8, 152.2, 149.2,
143.6, 142.2, 139.6, 134.4, 131.6 (q, J=33.3), 131.4, 130.4, 130.4,
123.4 (q, J=271), 123.2 (q, J=1.4), 117.6, 117.3 (m), 114.8, 112.8,
103.0, 101.2, 85.8, 72.1, 60.4, 60.0, 59.7, 56.4, 44.2, 27.6 ppm; HRMS:
m/z=657.1481, calcd for [M+H]+ C30H26F6N2O6S: 657.1489.
(R)-N-benzyl-5-((S)-4,5-dimethoxy-1,3-dihydroisobenzofuran-1-
yl)-4-methoxy-7,8-dihydro[1,3]dioxolo[4,5-g]isoquinoline-6(5H)-
carbothioamide (14d): Yield: 65%; chromatography eluent:
CH2Cl2/EtOAc; (8:1); Rf (CH2Cl2/EtOAc; 8:1) 0.25; 1H NMR: d=7.78
(s, 1H), 7.42–7.35 (m, 4H), 7.33–7.28 (m, 1H), 6.65 (d, J=8.2 Hz,
1H), 6.34 (s, 1H), 6.14 (bs, 1H), 5.94–5.92 (m, 3H), 5.66 (bs, 1H),
5.06 (dd, J=14.7, 5.3 Hz, 1H), 5.01–4.98 (m, 2H), 4.78 (dd, J=14.7,
4.9 Hz, 1H), 4.64 (s, 1H), 3.99 (s, 3H), 3.81 (s, 3H), 3.80 (s, 3H),
2.84–2.76 ppm (m, 1H), 2.57–2.47 (m, 2H); 13C NMR: d=185.9,
151.8, 148.8, 143.4, 139.7, 138.7, 134.3, 131.7, 131.4, 130.9, 128.7,
128.0, 127.5, 117.7, 115.8, 112.5, 102.9, 101.0, 85.8, 71.7, 60.2, 59.7,
59.5, 56.4, 50.2, 44.4, 27.8 ppm; HRMS: m/z=535.1916, calcd for
[M+H]+ C29H30N2O6S: 535.1897.
Pharmacology
Cell culture and reagents: Three human cancer cell lines (PC3, MCF-
7, and Caco-2) were purchased from ATCC and cultured in 5% CO2
at 378C in F-12K, a-MEM and DMEM (Invitrogen) supplemented
with 10% fetal bovine serum (FBS; Invitrogen) and penicillin–strep-
tomycin solution (100 U; Invitrogen). Cells were seeded at 104 cells
per well in 24-well plates for 48 h. Cells were then treated with an-
alogues, vincristine, or vehicle control at 10 mm for 16 h. Culture
medium with 0.1% DMSO was used as a vehicle control.
(R)-N-(2-Chlorophenyl)-5-((S)-4,5-dimethoxy-1,3-dihydroisoben-
zofuran-1-yl)-4-methoxy-7,8-dihydro[1,3]dioxolo[4,5-g]isoquino-
line-6(5H)-carbothioamide (14e): Yield: 88%; chromatography
eluent: PE/EtOAc (6:1); Rf (PE/EtOAc; 6:1) 0.13; 1H NMR: d=9.63
(bs, 1H), 7.78 (dd, J=8.0, 0.9 Hz, 1H), 7.42 (dd, J=8.0, 1.3 Hz, 1H),
7.23 (td, J=7.8, 1.5 Hz, 1H), 7.09 (ddd, J=8.0, 7.4, 1.5 Hz, 1H), 6.66
(d, J=8.2 Hz, 1H), 6.38 (s, 1H), 6.09–6.07 (m, 1H), 6.01 (bs, 1H),
5.96 (dd, J=9.7, 1.3 Hz, 2H), 5.89 (bs, 1H), 5.43 (d, J=11.8 Hz, 1H),
5.24 (d, J=11.8 Hz, 1H), 4.88 (bs, 1H), 4.08 (s, 3H), 3.86 (s, 3H),
3.82 (s, 3H), 2.93–2.85 (m, 1H), 2.36–2.32 ppm (m, 2H); 13C NMR:
d=185.9, 151.9, 149.0, 143.5, 139.6, 137.9, 134.3, 131.7, 131.1,
130.5, 129.5, 127.8, 127.3, 126.6, 125.7, 117.5, 115.4, 112.6, 103.0,
101.1, 85.0, 72.3, 60.3, 60.3, 59.7, 56.3, 44.1, 27.6 ppm; HRMS: m/
z=555.1375, calcd for [M+H]+ C28H27ClN2O6S: 555.1351.
Cell-cycle assay: After the incubation, cells were detached using
0.05% trypsin (Invitrogen) for 5 min and fixed with 4% paraformal-
dehyde (PFA) for 15 min. Cells were then washed with phosphate-
buffered saline (PBS) and permeablised with 0.5% Triton X-100 for
30 min. Cells were stained with Cell Cycle 405-blue (Invitrogen) for
30 min and analysed by flow cytometry (FACSCanto II analyser, BD
Biosciences, Australia) using the pacific blue channel (l 450 nm) to
detect the various stages of the cell proliferation cycle.
(R)-N-(3-Chlorophenyl)-5-((S)-4,5-dimethoxy-1,3-dihydroisoben-
zofuran-1-yl)-4-methoxy-7,8-dihydro[1,3]dioxolo[4,5-g]isoquino-
line-6(5H)-carbothioamide (14 f): Yield: 93%; chromatography
EC50 determination: EC50 values were determined for all compounds
that were observed to cause arrest of cells in G2/mitosis. PC3 and
MCF-7 cells were seeded at 2000 cells per well in 96-well plates,
48 h before treatment. After five days treatment, the CellTiter-
Blueꢁ assay (Promega G8080) was performed according to the
manufacturer’s protocol. Briefly, a fluorescent product was pro-
duced by viable cells and detected using an Envision Microplate
reader (PerkinElmer) at l 560 nm excitation. Higher fluorescence in-
dicated the presence of greater numbers of viable cells. Fluores-
cence values were plotted against log[inhibitor], and EC50 values
were calculated using GraphPad Prism 5 statistical software.
1
eluent: PE/EtOAc (6:1); Rf (PE/EtOAc; 6:1) 0.08; H NMR: d=9.66 (s,
1H), 7.46 (t, J=2.0 Hz, 1H), 7.37 (ddd, J=8.1, 2.0, 1.0 Hz, 1H), 7.27
(s, 1H), 7.09 (ddd, J=8.0, 2.0, 1.0 Hz, 1H), 6.66 (d, J=8.2 Hz, 1H),
6.37 (s, 1H), 6.07 (dd, J=3.8, 2.9 Hz, 1H), 6.01 (d, J=6.9 Hz, 1H),
5.96 (dd, J=9.8, 1.4 Hz, 2H), 5.79 (bs, 1H), 5.32 (d, J=12.0 Hz, 1H),
5.25 (d, J=12.1 Hz, 1H), 4.86–4.83 (m, 1H), 4.08 (s, 3H), 3.86 (s,
3H), 3.82 (s, 3H), 2.89–2.80 (m, 1H), 2.35 ppm (m, 2H); 13C NMR:
d=184.9, 152.0, 149.0, 143.5, 141.8, 139.6, 134.3, 134.1, 131.4,
130.69, 130.53, 129.5, 124.4, 123.7, 122.0, 117.6, 115.1, 112.6, 102.9,
101.1, 85.8, 71.9, 60.3, 59.9, 59.7, 56.3, 43.9, 27.6 ppm; HRMS: m/
z=555.1375, calcd for [M+H]+ C28H27ClN2O6S: 555.1351.
(R)-N-(4-Chlorophenyl)-5-((S)-4,5-dimethoxy-1,3-dihydroisoben-
zofuran-1-yl)-4-methoxy-7,8-dihydro[1,3]dioxolo[4,5-g]isoquino-
line-6(5H)-carbothioamide (14g): Yield: 76%; chromatography
eluent: toluene/EtOAc (8:1); Rf (toluene/EtOAc; 6:1) 0.27. Yield:
Acknowledgements
1
81%; H NMR: d=9.60 (s, 1H), 7.34 (d, J=8.9 Hz, 2H), 7.25 (d, J=
The authors thank GSK Australia for financial support. We also
thank Dr. Jason Dang (Monash University) for the acquisition of
MS data.
8.9 Hz, 2H), 6.63 (d, J=8.2 Hz, 1H), 6.33 (s, 1H), 6.05–6.04 (m, 1H),
5.99 (s, 1H), 5.91 (dd, J=8.9, 1.4 Hz, 2H), 5.77 (s, 1H), 5.28 (d, J=
2132
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ChemMedChem 2012, 7, 2122 – 2133

N-Substituted Noscapine Analogues
MED
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·
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structure–activity
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Revised: September 12, 2012
Published online on October 10, 2012
ChemMedChem 2012, 7, 2122 – 2133
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemmedchem.org
2133