Structure-activity studies on seco-pancratistatin analogs: Potent inhibitors of human cytochrome P450 3A4

Article abstract of DOI:10.1016/j.bmcl.2009.08.032

Two total syntheses of fully functionalized seco-analogs of the anticancer compound pancratistatin are reported. Structure-activity relationship (SAR) studies identified potent and selective inhibitors of human cytochrome P450 3A4 (CYP3A4) and revealed se

Full text of DOI:10.1016/j.bmcl.2009.08.032

Bioorganic & Medicinal Chemistry Letters 19 (2009) 5607–5612
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Structure–activity studies on seco-pancratistatin analogs: Potent inhibitors
of human cytochrome P450 3A4
a
a
b
b
James McNulty a, , Jerald J. Nair , Mohini Singh , Denis J. Crankshaw , Alison C. Holloway
*
a Department of Chemistry and Chemical Biology, McMaster University, 1280 Main Street West, Hamilton, Ont., Canada L8S 4M1
b Department of Obstetrics and Gynecology, McMaster University, 1200 Main Street West, Hamilton, Ont., Canada L8N 3Z5
a r t i c l e i n f o
a b s t r a c t
Article history:
Two total syntheses of fully functionalized seco-analogs of the anticancer compound pancratistatin are
reported. Structure–activity relationship (SAR) studies identified potent and selective inhibitors of
human cytochrome P450 3A4 (CYP3A4) and revealed several core pharmacophoric elements. These stud-
ies identify potential roadblocks and will guide the further development of a viable selective clinical
pancratistatin derivative.
Received 21 July 2009
Revised 6 August 2009
Accepted 7 August 2009
Available online 13 August 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Cytochrome P450 3A4
CYP3A4
Pancratistatin
Anticancer agent
Ketoconazole
Several groups have been interested in the isolation, synthesis,
semi-synthesis and biological evaluation of various amaryllidaceae
alkaloids (1–7, Scheme 1) over the last few years.1 The potent anti-
cancer activity displayed by amaryllidaceae constituents such as
pancratistatin 5 and narciclasine 6 has fuelled an immense amount
of synthetic work in many laboratories.2 The amaryllidaceae alka-
loids are all derived biosynthetically from norbelladine 1 (Scheme
1).3 Sub-classification is readily discernible within the family on
structural grounds forming the crinane, lycorane and galantha-
mine-type compounds (2–7), although at least six other minor
groups are known to occur.3b
man leukemia (Jurkat) cells, and explored some elements of this
remarkable pharmacophore.5k
Returning to the lycorane derivatives pancratistatin 5 and narci-
clasine 6, significant efforts have revealed crucial core elements of
the anticancer pharmacophore.1,2 In particular, the stereochemi-
cally defined 2,3,4-trihydroxy functionalized ring C is essential
for potent apoptosis-inducing activity.1 The apoptotic mode of
death initiated by pancratistatin is indicated by early activation
of caspase-3 followed by flipping of phosphatidyl serine to the out-
er leaflet of the plasma membrane.6 This was shown by us to occur
selectively in cancer cells but not in normal cells and that mito-
chondria were the site of action.6 In view of the potential clinical
development of an anticancer agent within the series,2a–c we re-
cently documented the human cytochrome (CYP3A4) inhibitory
activity of a compound library consisting of 26 amaryllidaceae
alkaloids and derivatives.7 From this analysis we determined that
pancratistatin 5 exhibited low interaction with CYP3A4 while
narciclasine 6 proved to be a potent inhibitor, raising issues with
regard to its ultimate clinical efficacy. In addition, we determined
that lipophilic substitution at positions 1 and 2 in the lycorine ser-
ies 4 resulted in the formation of potent CYP3A4 inhibitors one
magnitude less active than the clinically used antifungal P450
inhibitor ketoconazole.
Galanthamine 7 is the first of these alkaloids to receive FDA ap-
proval, in this case for the treatment of Alzheimer’s disease due to
its unique ability to reversibly inhibit acetylcholinesterase.3c Cri-
nane compounds are known for a host of biological properties,
including antimalarial and antiproliferative action as well as pro-
tein synthesis inhibition.4a–e We have recently shown that
a-
bridged crinanes (such as 3) are distinguishable from b-forms
(such as 2) at selectively initiating apoptosis in rat liver hepatoma
(5123tc), but not in normal HEK293t cells.4f,g Lycorine 4 is the most
abundant of the amaryllidaceae alkaloids and its broad spectrum of
biological activities is well documented.4d,e,5a–k As a potential che-
motherapeutic, it has shown most promise as an antiproliferative
agent in a number of cancer cell lines.4e Recent work in our labora-
tories uncovered the apoptosis-initiating ability of lycorine in hu-
Human cytochromes P450 (CYP450) constitute a diverse super-
family of hemoproteins which use a plethora of both exogenous
and endogenous compounds as substrates in enzymatic reactions,
usually forming part of multicomponent electron transfer chains.
Human CYP450s consist of four major families (CYP1 to CYP4) of
* Corresponding author. Tel.: +1 905 525 9140; fax: +1 905 522 2509.
E-mail address: jmcnult@mcmaster.ca (J. McNulty).
0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2009.08.032

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J. McNulty et al. / Bioorg. Med. Chem. Lett. 19 (2009) 5607–5612
OH
N
OH
OCH3
OH
HO
HO
11
O
O
O
O
O
O
HO
HO
11
H
H
12
N
N
N
H
12
1. Norbelladine
2. Crinine
3. Crinamine
4. Lycorine
OH
OH
C
OH
1
3
HO
10
OH
OH
2
10b
4OH
OH
O
9
8
O
O
O
O
4a
10a
A
B
N CH3
NH
NH
6a
6
7
OH
O
OH
O
H3CO
6. Narciclasine
5. Pancratistatin
7. Galanthamine
Scheme 1. Structurally-diverse alkaloid representatives of the plant family amaryllidaceae.
O
H
O
N
O
OH
N
O
10
O
O
O
O
O
O
O
a
O
11
O
O
O
b
9
8
O
O
O
O
12
OTBS
TMSO
TMSO
O
O
OTBS
OTBS
O
O
O
O
O
d
O
13
O
+
O
c
N
N
O
O
O
95 : 5
13
14
O
O
O
O
O
O
O
HO
O
O
OTBS
OTBS
TBSO
O
H
O
O
O
O
O
g
e
f
OH
Br
O
15
16
17
O
O
O
O
O
O
O
HO
O
HO
OTBS
OTBS
h
OH
O
O
i
O
O
j
HN
N3
HN
O
O
19
O
18
21
O
K
OH
4
3
HO
2'
OH
5
2
O
O
6OH
O
3'
4'
O
O
1
1'
MOMO
OTBS
HN
6'
5'
O
O
1"
2"
6"
5"
HN
3"
4"
20
27
O
Scheme 2. Synthesis of seco-pancratistatin analogs via Evans’ catalytic anti-aldol reaction and radical-mediated benzylidene fragmentation as key steps. Reagents and
conditions: (a) PivCl, TEA, DEE, À78 °C to rt, 2 h; (b) LiHMDS, THF, À78 °C to rt, 6 h, 84%; (c) MgCl2, TEA, TMSCl, EtOAc, rt, 12 h, 95%; (d) LiBH4, THF/MeOH (1:1), 0 °C to rt, 3 h,
88%; (e) BDMA, TsOH (cat), DCM, rt, 1 h, 91%; (f) NBS, AIBN, Ph, 60 °C, 1 h, 70%; (g) NaN3, DMF, rt, 5 h, 85%; (h) 5% Pd/C, H2, THF, rt, 2 h, 94%; (i) 2 M HCl, THF, rt, 2 h, 87%; (j)
TBAF, THF, rt, 1 h, 96%; (k) DIPEA, MOMCl, DCM, 0 °C to rt, 10 h, 95%.

J. McNulty et al. / Bioorg. Med. Chem. Lett. 19 (2009) 5607–5612
5609
mono-oxygenase enzymes which are expressed primarily on
smooth ER membranes of hepatocytes and by cells along the intes-
tinal tract mucosal surface.8a They are involved in the detoxifica-
tion of a wide variety of xenobiotics such as drugs, biogenic
amines from food sources, environmental toxins, and chemical car-
cinogens, and in the oxidation of steroids, fatty acids, prostaglan-
dins, leukotrienes, and fat-soluble vitamins.8b The CYP3A
subfamily comprises about 30% of the total liver cytochrome
P450 enzyme pool in humans, and the isoenzyme CYP3A4 accounts
for approximately 60% of drugs metabolized.8b In addition, an esti-
mated 70% of CYP protein in the small intestinal epithelium is
formed by this isoenzyme.8c Furthermore, it is widely known that
co-administration of multiple CYP3A4 substrates, inducers or
inhibitors, including compounds from food sources, may alter
pharmacokinetic and pharmacodynamic parameters of many pre-
scribed drugs. Thus, evaluation of CYP3A4-drug interactions is crit-
ical to the furthering of a clinical candidate. In view of the selective
lycorane-CYP interactions identified7 and the potential of pancrat-
istatin in the anticancer field, we now report the extension of this
CYP3A4 assay to a wide array of conformationally flexible semi-
synthetic derivatives uncovering valuable structural information
concerning CYP3A4 inhibitory activity.
Figure 1. X-ray structure of 1,3-benzylidene 16.
We recently reported the total synthesis of ring-B, C seco-panc-
ratistatin analogs such as 20 (Scheme 2).1g While these derivatives
possess all of the essential elements of the known anticancer phar-
macophore, including the stereochemically defined 1,2,3,4-tetra-
hydroxy motif and the amide function, they were shown to be
devoid of anticancer activity.1g Key steps towards the synthesis
of 20 include: (i) A highly efficient and diastereoselective catalytic
Evans’ aldol leading to 13 (Scheme 2, step c); (ii) an oxidative reg-
iospecific radical-mediated fragmentation of a 1,3-benzylidene
(Scheme 2, step f); and (iii) an intramolecular O- to N-acyl migra-
tion (Scheme 2, step h). The stereochemical outcome of the aldol
was confirmed by single-crystal X-ray structural determination
of benzylidene 16 (Fig. 1),1f indicating that the desired non-Evans
anti-adduct was highly favoured in this process. The above data
confirm the stringent configurational requirements that are neces-
sary for anticancer activity. The differences between the anticancer
pharmacophore and CYP3A4 inhibitory pharmacophore are exem-
plified by the data reported for narciclasine (potent anticancer, po-
tent CYP3A4 inhibitory) and pancratistatin (potent anticancer,
CYP3A4 inactive) leading us to hypothesize that conformationally
flexible seco-derivatives might unravel further attributes of the
CYP3A4 interaction. In order to gain further insights into this cyto-
chrome inhibitory pharmacophore, the seco-analogs 18 to 20 de-
picted in Scheme 2 were screened for CYP3A4 activity, see Table
1. This analysis revealed the hydroxybenzamide 19 as a potent
Table 1
Inhibitory activity against the biotransformation of 7-benzyloxyquinoline by cDNA-
expressed human CYP3A4
Compound
Ki (
lM)
pKia (M)
18
19
20
21
26
27
28
29
na
0.17
na
na
na
0.03
1.55
0.32
0.58
0.07
1.01
0.03
—
6.78 ( 0.05)
—
—
—
7.50 ( 0.10)
5.81 ( 0.09)
6.50 ( 0.05)
6.24 ( 0.10)
7.15 ( 0.02)
5.99 ( 0.03)
7.48 ( 0.02)
30
31
32
Ketoconazole
a
Values are means of three experiments, standard deviation is given in paren-
theses (na = not active at 10 M).
l
goals and proved crucial to our unraveling of two potent inhibitors
of CYP3A4, with activities similar to the clinical antifungal cyto-
chrome inhibitor ketoconazole.
This fully controlled approach is outlined in Scheme 3. Activa-
tion of 3,4-methylenedioxyphenylacetic acid 8 with pivaloyl chlo-
ride under basic conditions gave the mixed anhydride 9 which was
reacted further without purification with the lithium salt of (R)-
(+)-oxazolidinone 10 providing chiral imide 11 in 84% yield. Evans’
MgCl2-catalyzed aldol process9 was next invoked to couple imide
inhibitor of CYP3A4 (Ki 0.17 lM). These results are consistent with
and extend our previous findings in the lycorine derivatives7 for
which CYP3A4 inhibition required a free hydroxyl group or a small
acyl group (acetate but not benzoate) at C3 (C1 in the lycoranes),
enhanced by lipophilic substitution at C4 (C2 in the lycorane ser-
ies). This is consistent with the C3 substituent functioning as an
H-bond acceptor, subject to moderate steric interactions with the
enzyme. The present results indicate that CYP3A4 inhibition is en-
hanced by lipophilic substituents at positions 4, 5 and 6 (corre-
sponding to C2, C3 and C4 in the lycoranes), given the lack of
inhibitory activity of derivative 21.
11 with L-threose aldehyde 12 (derived in four steps from L-tartaric
acid), leading to the non-Evans anti-adduct 13 as the major diaste-
reomer (95:5) in 95% yield.1f,g This single step is remarkable in that
it connects the ring A aromatic moiety with the nascent ring B frag-
ment and, notably, sets the stereochemistry at two (C1 and C10b)
of the six contiguous stereocentres in pancratistatin 5, with a fur-
ther two (C2 and C3) preset by chiron 12. The selective formation
of the non-Evans anti-adduct 13 is mechanistically of significance
as it indicates that the facial selectivity of the chiral auxiliary has
an overriding influence on the stereochemical outcome of this
reaction, overcoming any Felkin-Ahn bias on the part of the alde-
hyde.1f Furthermore, the efficiency of the reaction conducted with
enolizable aldehyde 12 under the conditions outlined in Scheme 3
(step c) is remarkable as we readily confirmed1f that enolizable ali-
phatic aldehydes in general suffer from low conversions as noted
Our next goal was to probe these CYP3A4 SAR studies further by
extension of the substituent at C3 (C1 in the lycorane series) to a
conformationally flexible H-bond acceptor for which we selected
a methoxymethyl (MOM) substituent. We also wished to be able
to differentially functionalize the amino group in these seco-ana-
logs to circumvent the O- to N-benzoyl migration on reduction of
azide 18 (Scheme 2). The new synthetic approach outlined in
Scheme 3 was developed that allowed us to achieve both of these

5610
J. McNulty et al. / Bioorg. Med. Chem. Lett. 19 (2009) 5607–5612
O
N
H
O
N
O
OH
O
10
O
O
O
O
O
O
O
a
O
O
11
O
O
b
9
8
O
O
O
O
12
O
TMSO
TMSO
O
OTBS
OTBS
OTBS
O
O
O
O
O
O
d
13
O
+
O
c
N
N
O
O
O
95 : 5
13
14
O
O
O
O
O
O
MOMO
HO
MOMO
OTBS
OTBS
OTBS
O
O
O
O
O
O
O
g
e
f
O
O
OH
N
N
O
O
O
24
22
23
O
O
O
O
O
O
MOMO
MOMO
MOMO
OTBS
OTBS
h
OTBS
O
O
O
O
O
j
i
N3
Br
HN
O
25
26
27
O
OH
l
k
4
3
HO
OH
5
1
2'
2
O
O
O
O
6OH
O
3'
O
O
1'
MOMO
MOMO
OTBS
OH
HN
m
6'
4'
5'
O
O
O
O
1"
2"
6"
5"
HN
O
HN
3"
29
28
O
4"
20
O
o
n
O
O
O
O
O
O
MOMO
MOMO
MOMO
OAc
OTBDPS
OTos
O
O
O
O
O
HN
HN
HN
O
32
30
31
O
O
O
Scheme 3. Evans’ catalytic anti-aldol reaction as key step in the synthesis of seco-pancratistatin analogs. Reagents and conditions: (a) PivCl, TEA, DEE, À78 °C to rt, 2 h; (b)
LiHMDS, THF, À78 °C to rt, 6 h, 84%; (c) MgCl2, TEA, TMSCl, EtOAc, rt, 12 h, 95%; (d) HOAc (cat), MeOH, rt, 4 h, 96%; (e) DIPEA, MOMCl, DCM, 0 °C to rt, 10 h, 92%; (f) LiBH4, THF/
MeOH (1:1), 0 °C to rt, 2 h, 90%; (g) NBS, PPh3, TEA, DCM, 0 °C to rt, 5 h, 85%; (h) NaN3, DMF, rt, 5 h, 91%; (i) (i) 5% Pd/C, H2, THF, rt, 3 h; (ii) BzCl, TEA, DCM, rt, 2 h, 98%; (j) 2 M
HCl, THF, rt, 2 h, 88%; (k) TBAF, THF, rt, 1 h, 97%; (l) (i) 5% Pd/C, H2, THF, rt, 3 h; (ii) Boc2O, TEA, DCM, rt, 2 h, 98%; (m) TBDPSCl, py, DCM, rt, 7 h, 98%; (n) TosCl, py, DCM, rt, 5 h,
98%; (o) Ac2O, py, DCM, rt, 4 h, 98%.
by Evans et al.9 As mentioned above, single-crystal X-ray structure
of benzylidene 16 (Fig. 1),1f derived from 13 via 1,3-diol 15
(Scheme 2), confirmed the aldol adduct as the desired non-Evans
anti-diastereomer.
Interestingly, the minor adduct 14 was shown by us to be the
Evans anti-diastereomer.1f At this stage, the two synthetic strate-
gies (Schemes 2 and 3) diverged. With adduct 13 in hand, chemo-
selective removal of the TMS group with a catalytic amount of
acetic acid afforded hydroxyimide 22 which was subsequently
protected as the MOM ether 23. Cleavage of the chiral auxiliary
with lithium borohydride in THF/MeOH gave hydroxy-MOM ether
24 in 90% isolated yield. Nucleophilic bromination with NBS/tri-
phenylphosphine then converted the primary hydroxyl group in
24 to bromide 25 which underwent smooth SN2 displacement with
sodium azide to give the MOM-azide 26. Palladium on carbon
reduction of azide 26 and subsequent benzoylation of the free
amine afforded MOM-benzamide 27. A full set of physical data
for 27 is provided in the accompanying supplementary section of

J. McNulty et al. / Bioorg. Med. Chem. Lett. 19 (2009) 5607–5612
5611
this article. Similarly, the amine derived from 26 was also con-
verted to Boc-derivative 29 in 98% yield by reaction with Boc-
anhydride. Securing the MOM-azide 26 allowed us to circumvent
the O- to N-acyl migration that compromised the prior reduction
of azidobenzoate 18 in Scheme 2.1g Desilylated hydroxybenzamide
28 was obtained almost quantitatively from MOM-benzamide 27
by reaction with tetrabutylammonium fluoride (TBAF). A series
of 6-substituted analogs 30–32 were efficiently prepared (Scheme
2, steps m, n and o) directly from hydroxybenzamide 28. Straight-
forward global deprotection of 27 with 2 M HCl then led to the
3,4,5,6-tetrahydroxyhexyl-1-benzamide 20.
The library comprising compounds 18–21 (Scheme 2) as well as
26–32 (Scheme 3) was screened for CYP3A4 inhibitory activity via
kinetic monitoring of the conversion of 7-benzyloxyquinoline (BQ)
to 7-hydroxyquinoline (HQ) by fluorometric measurement of emis-
sion at 538 nm after excitation at 410 nm (see Supplementary
data), utilizing ketoconazole as control (Table 1).7
pounds 27 and 31 and the lesser active compounds shown here al-
low three major conclusions to be drawn. (i) Significant
interactions with the cytochrome CYP3A4 involve an H-bond
acceptor region at C3 (C1 in the alkaloid series). A small substituent
such as hydroxyl and acetoxy contributes to this cytochrome inter-
action. Compounds with a benzoyl group were less potent, while
the flexible MOM H-bond acceptor showed strong interaction. (ii)
The cytochrome interaction is enhanced when a bulky lipophilic
substituent is placed at C3 or C6 (C2 or C4 alkaloid numbering),7
indicating a strong interaction with a large hydrophobic binding
pocket in the cytochrome active site. Both activities are additive
in that the most potent cytochrome inhibitors have both a small,
flexible H-bond acceptor at C3 and a lipophilic substituent at C3
or C6. (iii) Lastly, a double bond between C1-C10b elicits strong
interaction with the cytochrome alone, as evidenced by the previ-
ous results contrasting the potency of narciclasine 6 with pancrat-
istatin 5. It is noteworthy that both pancratistatin 5 and B,C-seco-
pancratistatin 20 are inactive against CYP3A4, while narciclasine
The MOM-benzamide derivative 27 (Ki 0.03 lM) was shown to
be a powerful inhibitor with a potency equal to that of ketocona-
6 exhibits good activity (Ki 0.63 l
M).7 The present results are fully
zole. Removal of the MOM ether group results in a ꢀ6-fold drop
in accord with our earlier structure–activity CYP3A4 mapping con-
ducted in the lycorane series.7 Overall, these studies provide valu-
able insight into regions of the amaryllidaceae anticancer
pharmacophore likely to interact with CYP3A4. Recent studies
have focused on both narciclasine derivatives,2a–c,s and C1 ben-
zoyl2q and other1g,2r derivatives. The present results highlight re-
gions in the pancratistatin series that may affect the
bioavailability of the compounds, their capacity to elicit significant
drug–drug interactions and their inhibition of other crucial oxida-
tive processes carried out by this important enzyme. Compounds
that demonstrate ketoconazole-like activity may also contribute
to hepatic toxicity. Lastly, we have identified two derivatives 27
and 31 that exhibit CYP3A4 inhibitory activity at the nanomolar le-
vel, similar to the known inhibitor ketoconazole. Extension of these
leads towards the synthesis of potent, selective antifungal agents
and further extension of the CYP3A4 studies are ongoing in our
laboratories.
in activity as shown for hydroxybenzamide 19 with Ki 0.17 lM. A
pronounced reduction (ꢀ50-fold) in activity is observed in going
from MOM-benzamide 27 to desilylated analogue 28 (Ki
1.55 lM). Cleavage of both MOM and TBS groups from 19 produced
inactive 3,6-diol 21 while removal of all protecting groups gave the
3,4,5,6-tetrahydroxyhexylbenzamide 20 which also exhibited no
inhibition. Azides 18 and 26 were void of activity while replace-
ment of the benzamide moiety in 27 with a t-butyl carbamate re-
sulted in
a 10-fold decrease in activity as evident for 29.
Substitution of the 6-TBS group in 27 with other protecting groups
had effects on inhibitory activity to varying degrees; tosylate 31
was highly active (Ki 0.07
less active than 27 while acetate 32 was mildly active with Ki
1.01 M. The above activity data highlight several core pharmaco-
lM), TBDPS-benzamide 30 was 20-fold
l
logical elements of the potent CYP3A4 inhibitor 27. First, the 1-
benzamide functionality is essential as azides 18 and 26 were inac-
tive and since there is a ten fold difference in activity between
MOM-1-benzamide 27 and MOM-1-carbamate 29. This suggests
that this part of the molecule must occupy a fairly bulky, polar
pocket within the enzyme active site. There is a ꢀ6-fold modula-
tion in activity between hydroxybenzamide 19 and MOM-benzam-
ide 27, consistent with our earlier hypothesis that a relatively
small hydrogen bond acceptor is required at C3. The effect of the
silyl group on inhibition is observed to be dramatic as seen for
27 versus 28, pointing at a lipophilic binding site within the en-
zyme. Again, these results are fully consistent with the pronounced
CYP3A4 inhibitory effects of TBS-substituted derivatives of lycorine
4.7 Absence of both 3-MOM and 6-TBS groups results in complete
lack of activity as evident with 3,6-diol 21, while a further loss of
the 3,4-isopropylidene group also produces inactive tetra-
hydroxyhexylbenzamide 20. The effect of the isopropylidene group
is seen to serve as an anchor within a more rigid portion of the en-
zyme. The bulkiness of the 6-TBDPS group in 30 is somewhat det-
rimental to inhibition while introduction of a small, polar group
such as an acetate, as in 32, results in further loss of activity. Inter-
estingly, inhibition is sustained with the introduction of an O-tos-
ylate group at C6 as in 31 (Ki 0.07 lM), also highlighting the
requirement for heteroatom-containing functional groups (27, 30,
31 vs 32).
In conclusion, a more comprehensive view of the cytochrome
P450 3A4 inhibitory pharmacophore has been developed through
SAR studies with flexible, differentially functionalized pancratista-
tin analogs. This pharmacophore is worthy of significant consider-
ation, given the intensive efforts to advance a viable narciclasine 6
or pancratistatin 5 analog into clinical development. The results
detailed in our earlier report7 and the structural features of com-
Acknowledgments
We thank NSERC and McMaster University for financial support
of this work. We are grateful to Dr. D. Hughes for obtaining high
field NMR data.
Supplementary data
CCDC file 654288 contains the supplementary crystallographic
data for 16. These data can be obtained free of charge from The
Cambridge Crystallography Data Centre via www.ccdc.cam.ac.uk/
data_requestcif.html. Supplementary data associated with this
article can be found, in the online version, at doi:10.1016/
j.bmcl.2009.08.032.
References and notes
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Med. Chem. Lett. 2001, 11, 169; (c) Hudlicky, T.; Rinner, U.; Gonzales, D.; Akgun,
H.; Schilling, S.; Siengalewicz, P.; Martinot, T. A.; Pettit, G. R. J. Org. Chem. 2002,
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R. Bioorg. Med. Chem. Lett. 2004, 14, 2911; (e) McNulty, J.; Larichev, V.; Pandey, S.
Bioorg. Med. Chem. Lett. 2005, 15, 5315; (f) McNulty, J.; Nair, J. J.; Sliwinski, M.;
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