Structural analogues of schweinfurthin F: Probing the steric, electronic, and hydrophobic properties of the D-ring substructure

Article abstract of DOI:10.1016/j.bmc.2009.12.063

The natural tetracyclic schweinfurthins are potent and selective inhibitors of cell growth in the National Cancer Institute's 60-cell line screen. An interest in determination of their cellular or molecular target has inspired our efforts to prepare both the natural products and analogues. In this paper, chemical synthesis of analogues modified in different olefinic positions, and preliminary results from studies of their biological activity, are reported.

Full text of DOI:10.1016/j.bmc.2009.12.063

Bioorganic & Medicinal Chemistry 18 (2010) 1676–1683
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Structural analogues of schweinfurthin F: Probing the steric, electronic,
and hydrophobic properties of the D-ring substructure
Natalie C. Ulrich a, John G. Kodet a, Nolan R. Mente a, Craig H. Kuder b, John A. Beutler c, Raymond J. Hohl b,d
,
David F. Wiemer a,b,
*
a Department of Chemistry, University of Iowa, Iowa City, IA 52242-1294, USA
b Department of Pharmacology, University of Iowa, Iowa City, IA 52242-1294, USA
c Molecular Targets Laboratory, Center for Cancer Research, National Cancer Institute, Frederick, MD 21701, USA
d Department of Internal Medicine, University of Iowa, Iowa City, IA 52242-1294, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The natural tetracyclic schweinfurthins are potent and selective inhibitors of cell growth in the National
Cancer Institute’s 60-cell line screen. An interest in determination of their cellular or molecular target has
inspired our efforts to prepare both the natural products and analogues. In this paper, chemical synthesis
of analogues modified in different olefinic positions, and preliminary results from studies of their biolog-
ical activity, are reported.
Received 13 November 2009
Revised 17 December 2009
Accepted 28 December 2009
Available online 4 January 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Schweinfurthin
Stilbene
Synthesis
Anti-proliferative
Bioassay
1. Introduction
the isolation of schweinfurthins E, F (4), G (5), and H by the Kings-
ton group at Virginia Tech followed some years later.6
Glioblastoma multiforme (GBM) is the most common and
aggressive form of central nervous system (CNS) cancer among
adults. Unfortunately, patients undergoing the current standard
of treatment have a median survival rate of only 15 months.1 De-
spite numerous advances in the last several decades in under-
standing the molecular biology of GBM, only modest progress
has been made in improving the prognosis of affected patients,2
making new therapeutic alternatives vital. Fortunately, nature con-
tinues to be a rich source of compounds with chemotherapeutic
potential.3 As part of a continuing mission to obtain anticancer
agents from natural sources, researchers at the National Cancer
Institute (NCI) discovered a family of natural products known as
the schweinfurthins which exhibit potent activity against hu-
man-derived CNS cancer cell lines. Schweinfurthins A and B (SA
and SB, 1 and 2, Fig. 1), along with the less active schweinfurthin
C (SC), were isolated from the African plant Macaranga schweinfur-
thii and displayed potent and selective anti-proliferative activity in
A program called COMPARE has been developed by the NCI to
analyze similarities and differences among drug activity patterns,
OR
3
2
R'
O
A
OH
4'
HO
D
H
OH
1 R = H
R' = OH Schweinfurthin A
2 R = CH3 R' = OH Schweinfurthin B
3 R = CH3 R' = H
OR
3-deoxyschweinfurthin B
O
OH
HO
the NCI’s 60-cell line screen (GI50 = 0.36 lM and 0.81 lM, respec-
H
tively).4 Shortly thereafter, schweinfurthin D was reported,5 and
OH
4 R = CH3 Schweinfurthin F
5 R = H Schweinfurthin G
* Corresponding author. Tel.: +1 319 351 5905; fax: +1 319 335 1270.
E-mail address: david-wiemer@uiowa.edu (D.F. Wiemer).
Figure 1. Selected natural (1–2, 4–5) and synthetic (3) schweinfurthins.
0968-0896/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2009.12.063

N. C. Ulrich et al. / Bioorg. Med. Chem. 18 (2010) 1676–1683
1677
and these analyses can in turn provide insight into the mechanism
R =
of action of the drugs studied in the 60-cell cancer screen.7 Impor-
tantly, the schweinfurthins show no correlation to any clinically
used anti-neoplastic agent, indicating that this family of com-
pounds may act via a novel mechanism or target.8 Only three struc-
turally unrelated families of natural products show any
appreciable correlation to the schweinfurthins: the cephalosta-
tins,9 the stellettins,10 and OSW-1.11 Presumably, a determination
of the molecular target of one of these compounds would aid in
a similar determination with the others, thus increasing under-
standing of their biological activity.
Because of our ongoing interest in the synthesis of prenylated
stilbenes and the unique activity of the schweinfurthins, we under-
took a synthetic effort aimed at these compounds. This endeavor
has led to the total synthesis of SC,12 3-deoxyschweinfurthin B
(3dSB, 3),13 schweinfurthins F and G (4 and 5),14,15 and, most re-
cently, SB (2) and schweinfurthin E.16 Furthermore, we have pre-
pared a number of analogues to illuminate the pharmacophore(s)
responsible for the schweinfurthins’ differential activity.17 First,
based on the relative activity of SA or SB versus SC, it appears that
the left-half hexahydroxanthene substructure is required for po-
tent and selective activity. Second, replacing the phenolic groups
of the right-half resorcinol structure with hydrogen or fluorine
demonstrated that at least one of the phenolic hydroxyl groups is
important for differential activity. Third, the effect of some D-ring
substitutions has been examined. Comparison of the activity of
schweinfurthin F (4), 3dSB (3), and a previously synthesized 3dSB
analogue17 (bearing prenyl, geranyl, and hydroxylated geranyl
chains, respectively) with an analogue which lacks a prenyl chain,
established that the absence of a prenyl chain led to greatly re-
duced activity. Finally, recent attempts at the NCI to obtain addi-
tional amounts of schweinfurthins from a natural source have
resulted in the isolation of compounds tentatively identified as
cis-stilbenes, raising questions about the importance of the central
olefin stereochemistry.
6
OCH3
O
O
7
8
OH
OH
HO
HO
H
H
R
9
OCH3
OH
OH
10
O
11
12
OCH3
O
O
O
HO
HO
H
H
OH
OCH3
R =
13
OH
R
14
15
OH
OH
OH
OCH3
O
H
2
HO
OH
H
16
Figure 2. Olefin-modified schweinfurthin analogues.
Variations in activity observed through these past studies
prompted investigation into the significance of a hydrophobic sub-
stituent on the D-ring and the stilbene olefin to the schweinfurthin
pharmacophore. Specifically, we wished to explore whether
attaching a simplified tail to the D-ring or altering the electronics
of the stilbene moiety would be tolerated. We therefore targeted
the synthesis of several new schweinfurthin analogues (Fig. 2).
The preparation of these compounds and data on their biological
activity are presented here.
6
OCH3
O
(EtO)2P
O
OMOM
+
O
HO
H
H
OMOM
17
18
Figure 3. A representative retrosynthesis.
2. Synthesis
The total synthesis of SC established an early precedent for a
highly convergent, stereoselective Horner–Wadsworth–Emmons
condensation in formation of the central stilbene moiety,12 a strat-
egy then utilized in the synthesis of analogues such as 3dSB (3,
Fig. 1). Because aldehyde 17 is known,17 the first key intermediates
for preparation of analogues 6–10 were the corresponding phos-
phonates as shown by the representative retrosynthesis depicted
in Figure 3.
1) nBuLi, -20 °C
CuBr DMS, then
OMOM
OMOM
allyl bromide
2) TBAF
TBSO
R
66%
OMOM
OMOM
19
1) TEA, MsCl
2) NaI, Acetone
3) P(OEt)3, reflux
20
18
R = OH
R = P(O)(OEt)2
Benzyl alcohol 20 was prepared from the known arene 1918 by a
directed ortho metallation/transmetallation/alkylation protocol19
and subsequent removal of the silyl protecting group (Scheme 1).
After formation of the mesylate and conversion to the iodide, Arbu-
zov reaction with triethyl phosphite provided phosphonate 18.
Hydroboration/oxidation of compound 18 with 9-BBN and H2O2
gave hydroxylated phosphonate 21, while palladium-catalyzed
hydrogenation of phosphonate 18 produced the n-propyl phospho-
nate 22.
79%
1) 9-BBN
2) H2O, 3N NaOH,
30% H2O2, 50 °C
39%
H2, Pd/C 97%
O
O
OMOM
OMOM
(EtO)2P
(EtO)2P
OH
OMOM
21
OMOM
22
The preparation of isopentyl phosphonate 25 began with known
prenylated arene 2320 (Scheme 2). Hydrogenation of alkene 23
Scheme 1. Synthesis of phosphonates 18, 21, and 22.

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N. C. Ulrich et al. / Bioorg. Med. Chem. 18 (2010) 1676–1683
1) H2, 10% Pd/C
NH4OAc
2) TBAF
deprotection gave the desired analogue 12. When difficulty was
OMOM
OMOM
encountered preparing the phosphonate analogue of the benzofu-
ran alcohol 36, a reversed HWE strategy was explored, based upon
synthesis of the corresponding right-half aldehyde 40 through oxi-
dation of alcohol 36. Condensation of aldehyde 40 with the known
left-half phosphonate 4115 gave the expected trans-stilbene 42,
and deprotection provided the desired benzofuran analogue 11.
To gauge the significance of the trans-stilbene olefin, other ana-
logues were prepared where this moiety was replaced by a simple
alkyl chain or isomerized to the corresponding cis stilbene. For
example, hydrogenation of the known stilbene 4314 over Pd/C gave
the fully saturated analogue 44, and MOM hydrolysis provided the
desired analogue 13 (Scheme 6). Alternatively, selective reduction
of the stilbene moiety in the presence of the isoprenoid olefins23
was accomplished via reaction of compounds 43 and 45 with Mg
and NH4Cl in methanol. Standard deprotection of the products 46
and 47 provided analogues 14 and 15. Finally, the last of our tar-
geted analogues, the cis-stilbene 16, was prepared by irradiation
of 3dSB (3) to promote olefin isomerization, followed by chroma-
tography to isolate the desired cis isomer.
R
TBSO
84%
OMOM
OMOM
23
24
25
R = OH
1) TEA, MsCl
2) NaI, acetone
3) P(OEt)3, reflux
R = P(O)(OEt)2
61%
Scheme 2. Synthesis of phosphonate 25.
over Pd/C in the presence of NH4OAc21 followed by silyl deprotec-
tion provided alkane 24, which was then converted to phosphonate
25 via standard conditions.
Alkynyl phosphonate 29 was obtained via alkylation of known
benzyl alcohol 2618 with 3-(trimethylsilyl)propargyl bromide, con-
version to the phosphonate, and removal of the TMS group
(Scheme 3).
With several of the necessary phosphonates in hand, the Horn-
er–Wadsworth–Emmons condensations were effected in the pres-
ence of NaH and 15-crown-5 (Scheme 4). In all cases, only the
trans-stilbene product was observed. Subsequent hydrolysis of
the MOM protecting groups was carried out in the presence of
TsOH or CSA to provide analogues 6–10 (Table 1).
To examine the impact of a benzofuran or dihydrobenzofuran
system as an E-ring, the key intermediate 36 was prepared from
the known benzofuran core 3522 through MOM-protection and
reduction as shown in Scheme 5. Hydrogenation of compound 36
occurred smoothly upon treatment with hydrogen and Pd/C, to af-
ford the reduced compound 37. Conversion to the phosphonate 38
took place under standard conditions, and the HWE condensation
with aldehyde 17 occurred smoothly as well (Scheme 5). Final
3. Biological results and discussion
As presented above, the schweinfurthins exhibit potent and dif-
ferential cytotoxicity in the NCI’s 60-cell cancer screen. Of the cell
lines tested in the NCI assay, the human-derived glioblastoma cell
line SF-295 is one of the most sensitive to the growth inhibitory ef-
fects of the schweinfurthins, while the human-derived lung adeno-
carcinoma cell line A549 displays only moderate sensitivity to the
schweinfurthins. Based on this difference in antiproliferative activ-
ities, a two-cell line screen was developed to determine whether
synthetic analogues of the schweinfurthins exhibit the same basic
pattern of cytotoxicity as the natural compounds. Within this test-
ing scheme, all of the prepared compounds display schweinfur-
thin-like activity, but the observed potencies vary greatly.
One subset of these analogues can be viewed as the group with
small alkyl substituents on the D-ring, compounds 6–10. All five of
these compounds showed anti-proliferative effects in the low or
sub-micromolar range when tested against SF-295 cells (Table 2),
and substantially less activity when tested in the A549 cells. The
most potent compound in this set was the isopentyl compound
9, indicating that the presence of an olefin at this position is unnec-
essary for activity in the SF-295 cell assay, and this compound
showed approximately 10-fold lower potency against the A549
cells. Comparison of the Clog P values of compounds 7, 8, and 9 re-
veals a tentative correlation between hydrophobicity and cytotoxic
activity. The hydroxyl moiety in analogue 8 leads to a decrease in
activity in the sensitive cell line, while the presence of hydrophobic
methyl groups in analogue 9 appears to contribute to slightly in-
creased anti-proliferative activity.
nBuLi
OMOM
OMOM
CuBr DMS
HO
R
R'
TMS
Br
22%
OMOM
26
OMOM
R = OH, R' = TMS
27
28
1) TEA, MsCl; LiBr
2) P(OEt)3, reflux
R = P(O)(OEt)2, R' = TMS
R = P(O)(OEt)2, R' = H
TBAF
70%
29
Scheme 3. Synthesis of phosphonate 29.
OCH3
O
(EtO)2P
O
OMOM
R
+
O
HO
Compared to the first set of compounds, the two heterocyclic
compounds, benzofuran 11 and its dihydro analogue 12, showed
somewhat less potency against the SF-295 cell line, although dihy-
drofuran 12 was more active than its benzofuran counterpart. This
result is in agreement with findings observed in a similar study.24
Assays on the final compounds suggest that reduction of the
trans-stillbene olefin diminishes activity (e.g., 13–15 vs 9). Isomer-
H
17
H
OMOM
18, 21, 22, 25, 29
NaH
15-crown-5
OCH3
O
OMOM
R
ization of 3dSB (3, EC50’s of 0.5 and 6.4 lM, respectively, in this as-
HO
H
say) to the cis olefin 16 has an even greater negative impact. This
outcome is interesting given the varied potencies observed in cis
and trans analogues of medicinally important stilbenes such as res-
veratrol25 and combretastatin.26
30- 34
OMOM
TsOH or
CSA
Of the 11 compounds tested in the two-cell assay, compound 9
demonstrated the greatest potency against SF-295 cells, along with
a 10-fold difference in activity in the two-cell assays. When this
6-10
Scheme 4. Synthesis of analogues 6–10.

N. C. Ulrich et al. / Bioorg. Med. Chem. 18 (2010) 1676–1683
1679
O
O
1) MOMCl
DIPEA
O
O
O
EtO
HO
H
MnO2
95%
2) LiAlH4
78%
OH
35
OMOM
OMOM
40
36
H2, Pd/C
NH4OAc
NaH
15-Crown-5
95%
OCH3
O
O
R
O
P(OEt)2
MOMO
H
OMOM
37 R = OH
R = P(O)(OEt)2
41
1) LiBr, NEt3, MsCl
2) P(OEt)3, reflux
OCH3
38
O
55%
NaH, 15-Crown-5
52%
O
RO
17
H
OMe
42 R = MOM
11 R = H
TsOH, MeOH
23%
O
OR
O
HO
H
39
12
R = MOM
R = H
OR
TsOH
MeOH
45%
Scheme 5. Synthesis of analogues 11 and 12.
was ꢀ33 nM, making this one of the most potent schweinfurthin
analogues to date. Its potency in the 60-cell line screen exceeds
that of several of the natural products (e.g., SA and SB), which will
encourage additional efforts to improve the activity of schweinfur-
thin analogues. Furthermore, the GI50 values varied over the 60-
cell lines examined by more than three orders of magnitude (cf.
Supplementary data). This large range is indicative of selective tox-
icity. Conversely, compound 15 proved to be one of the least active
compounds tested in the two-cell assay. When this compound was
Table 1
HWE condensations and hydrolysis reactions
Phosphonate
R
Stilbene Yield (%) Target Yield (%) (TsOH)
18
22
21
25
29
Allyl
n-Propyl
3-Propanol 32
Isopentyl
Propynyl
30
31
70
75
65
—
6
7
8
9
67
73
74
33
34
73 (CSA) (two steps)
26 (two steps)
—
10
tested in the NCI’s 60-cell line assay, its average GI50 was 4.9 lM,
suggesting a weakly toxic compound, and it exhibited virtually
no differential activity across the 60 cell lines (cf. Supplementary
data). Taken together with the results obtained from testing com-
compound was tested in the 60-cell line assay at the NCI, it also
showed significant potency. In this assay, the average GI50 across
the 60 cell lines was 0.29
lM, and the GI50 in the SF-295 cell line
OCH3
O
OMOM
HO
H
Mg
NH4Cl
MeOH
43 R = Prenyl
45 R = Ger-OH
R
OMOM
OCH3
O
94%
H2, Pd/C
OCH3
OMOM
HO
H
O
R
46 R = Prenyl
47 R = Ger-OH
OMOM
OR
HO
TsOH
MeOH
H
14 R = Prenyl (70%)
15 R = Ger-OH (70%)
44 R = MOM
13 R = H
TsOH
MeOH
OR
41%
hv (365 nm)
3
16
52%
Scheme 6. Synthesis of analogues 13–16.

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N. C. Ulrich et al. / Bioorg. Med. Chem. 18 (2010) 1676–1683
otherwise noted. The 31P chemical shifts were reported in ppm rel-
Table 2
Activity of synthetic schweinfurthins in a two-cell screen
ative to 85% H3PO4 (external standard). High resolution mass spec-
tra were obtained at the University of Iowa Mass Spectrometry
Facility, and elemental analyses were obtained at Atlantic Microl-
abs, Inc. Silica gel (60 Å, 0.040–0.063 mm) was used for flash chro-
matography. Most of the analogues were prepared using left-half
aldehyde 17 with an ee of 90%, as determined by HPLC.
Compound
Clog P
SF-295 EC50
(
lM)
A549 EC50 (lM)
6
7
8
5.75
6.05
4.62
6.79
5.16
5.11
4.84
6.98
6.58
6.95
8.04
1.7
0.9
2.5
0.4
1.3
4.8
2.9
2.8
2.9
>10
>10
>10
>10
>10
4.2
>10
>10
>10
>10
>10
>10
>10
9
10
11
12
13
14
15
16
5.2. Benzyl alcohol 20
To a solution of known silyl protected benzyl alcohol 1918
(634 mg, 1.9 mmol) in THF (12 mL) at ꢁ20 °C was added n-BuLi
(0.9 mL, 2.4 M in hexane, 2.2 mmol), and the reaction was allowed
to warm to 0 °C over 1 h. The solution was then cooled to ꢁ20 °C,
CuBrꢂDMS (380 mg, 1.9 mmol) was added in one portion, and the
resulting solution was allowed to stir for 1 h. To the solution was
added allyl bromide (0.2 mL, 2.1 mmol) and the resulting solution
was allowed to stir for 2 h. After the reaction was quenched by
addition of NH4Cl (satd), the aqueous layer was extracted with
EtOAc, dried (MgSO4), and concentrated in vacuo. The resulting
oil was dissolved in THF (10 mL) at rt, TBAF (1.5 mL, 1.0 M in
THF, 1.5 mmol) was added, and the reaction was allowed to stir
for 2 h. Once TLC analysis indicated complete consumption of the
starting material, the reaction was quenched by addition of H2O
and the aqueous layer was extracted with EtOAc. The combined or-
ganic layers were washed with brine, dried (MgSO4), and concen-
trated in vacuo. The resulting oil was purified by column
chromatography (60% EtOAc/hexanes) to afford compound 20
(329 mg, 66%) as a colorless oil: 1H NMR d 6.77 (s, 2H), 5.97–5.91
(m, 1H), 5.17 (s, 4H), 5.00–4.91 (m, 2H), 4.59 (s, 2H), 3.45 (s, 6H),
3.40–3.37 (m, 2H); 13C NMR d 155.7 (2C), 140.6, 136.6, 117.3,
114.2, 106.3 (2C), 94.3 (2C), 65.2, 56.0 (2C), 27.5; HRMS (EI+) calcd
for C14H20O5 [M+] 268.1311; found 268.1309.
pound 9, this suggests that the two-cell line assay is an effective
means for rapidly screening analogues.
4. Conclusions
In conclusion, these studies have led to the preparation of a set
of eleven new schweinfurthin analogues with variations in the nat-
ure of the stilbene olefin and the substituent at C-40 of the D-ring.
The paucity of functionality in the side chain of the most potent
compound, the isopentyl analogue 9, may suggest that increasing
hydrophobicity is more important than interaction with a specific
functional group. Given this perspective, the activity observed in
the heterocyclic compounds 11 and 12 encourages exploration of
other heterocyclic systems, especially if they can be prepared with
an additional alkyl substituent in the E-ring. Finally, either reduc-
tion of the stilbene olefin (e.g., 13–15) or isomerization from the
trans stereochemistry to the cis (16) diminishes activity in the
SF-295 cell line.
The two-cell assay for screening synthetic analogues has proven
quite effective in quickly identifying potent and selective com-
pounds. In this study, all eleven new schweinfurthin analogues
were pre-screened in the two-cell assay. After the most potent
compound of the set was identified, confirmation of this analogue’s
activity was obtained via the NCI’s 60-cell line assay. As a proof of
concept, one of the least active of the analogues in the two-cell as-
say also was tested in the 60-cell assay and displayed both reduced
cytotoxicity and lessened differential activity. Thus it appears rea-
sonable to use this facile screening process for more efficient test-
ing of future synthetic analogues.
At this time, the mode of action and/or molecular target of the
schweinfurthins remain unknown. Given the preservation of activ-
ity despite variations in the alkyl chains at C-40, this position ap-
pears to be a reasonable site for preparation of biotinylated
derivatives. Preparation of such compounds is underway and will
be reported in due course.
5.3. Phosphonate 18
Methanesulfonyl chloride (0.1 mL, 1.6 mmol) was added drop-
wise to a solution of alcohol 20 (329 mg, 1.2 mmol) and Et3N
(0.3 mL, 1.8 mmol) in THF (7 mL) at 0 °C, and the solution was al-
lowed to stir for 1 h. The resulting precipitate was dissolved by
addition of H2O, and the aqueous layer was extracted with EtOAc,
washed with brine, dried (MgSO4), and concentrated in vacuo. The
resulting residue was dissolved in acetone (10 mL), and NaI
(670 mg, 4.5 mmol) was added in one portion. After the mixture
was allowed to stir for 24 h, it was quenched by addition of H2O
and extracted with EtOAc. The combined extracts were washed
with Na2S2O3 (satd) until the color had disappeared, dried (MgSO4),
and concentrated in vacuo. The resulting yellow oil was added to a
solution of triethyl phosphite (0.2 mL, 1.4 mmol) in THF (3 mL),
and the solution was heated at reflux overnight. After concentra-
tion in vacuo, the resulting oil was purified by column chromatog-
raphy (2% MeOH/CHCl3) to yield phosphonate 18 (375 mg, 79%) as
a pale oil: 1H NMR d 6.70 (d, JPH = 2.5 Hz, 2H), 6.01–5.86 (m, 1H),
5.18 (s, 4H), 5.00–4.90 (m, 2H), 4.09–3.99 (m, 4H), 3.45 (s, 6H),
3.44–3.40 (m, 2H), 3.08 (d, JPH = 21.5 Hz, 2H), 1.38–1.32 (m, 6H);
13C NMR d 155.6 (d, JCP = 2.6 Hz, 2C), 142.4, 136.7 (d, JCP = 1.8 Hz),
116.8, 114.1, 109.5 (d, JCP = 6.8 Hz, 2C), 94.4 (2C), 62.0 (d,
JCP = 6.6 Hz, 2C), 56.0 (2C), 33.0 (d, JCP = 137.0 Hz), 27.5, 16.4 (d,
JCP = 7.2 Hz, 2C); 31P NMR d 26.9; HRMS (EI+) calcd for C18H29O7P
[M+] 388.1651; found 388.1655.
5. Experimental procedures and methods
5.1. General experimental conditions
Tetrahydrofuran was freshly distilled from sodium/benzophe-
none. Methylene chloride and triethylamine were distilled from
calcium hydride prior to use. Solutions of butyl lithiums were pur-
chased from a commercial source and titrated with diphenyl acetic
acid prior to use. All other reagents and solvents were purchased
from commercial sources and used without further purification.
All reactions in nonaqueous solvents were conducted in flame-
dried glassware under a positive pressure of argon and with mag-
netic stirring. NMR spectra were obtained at 300 MHz for 1H, and
75 MHz for 13C with CDCl3 as solvent, and (CH3)4Si (1H,
5.4. Phosphonate 21
To a solution of phosphonate 18 (101 mg, 0.3 mmol) in THF
(1 mL) at 0 °C was added 9-BBN (2.0 mL, 0.5 M in THF, 1.0 mmol),
and the solution was allowed to warm to rt and stirred overnight.
0.00 ppm) or CDCl3 (
13C, 77.0 ppm) as internal standards unless

N. C. Ulrich et al. / Bioorg. Med. Chem. 18 (2010) 1676–1683
1681
To the solution was added H2O (0.1 mL), 2 N NaOH (0.8 mL), and
30% H2O2 (0.4 mL), and the reaction was heated at 50 °C for 2 h,
then allowed to cool to rt and stirred for 2 days. After the resulting
solution was extracted with EtOAc, washed with brine, dried
(MgSO4), and concentrated in vacuo, the remaining oil was purified
by flash column chromatography (2% MeOH/CHCl3) to afford com-
pound 21 (41 mg, 39%) as a colorless oil: 1H NMR d 6.66 (s, 2H),
5.11 (s, 4H), 3.99–3.94 (m, 4H), 3.47 (t, J = 6.0 Hz, 2H), 3.40 (s,
6H), 3.01 (d, JPH = 21.4 Hz, 2H), 2.70 (t, J = 7.1 Hz, 2H), 2.10 (br s,
1H), 1.76–1.68 (m, 2H), 1.20 (t, JPH = 5.9 Hz, 6H); 13C NMR d
155.8 (d, JCP = 3.4 Hz, 2C), 130.7 (d, JCP = 8.9 Hz), 118.1, 109.5 (d,
JCP = 6.7 Hz, 2C), 94.6 (2C), 62.0 (d, JCP = 6.8 Hz, 2C), 61.6, 56.1
(2C), 33.8 (d, JCP = 138.2 Hz), 31.7, 18.8, 16.3 (d, JCP = 6.1 Hz, 2C);
31P NMR d 26.7; HRMS (EI+) calcd for C18H31O8P [M+] 406.1757;
found 406.1761.
122.6, 120.6, 117.5, 114.2, 106.8, 105.9 (2C), 94.4 (2C), 77.9, 77.1,
56.0 (2C), 55.9, 46.7, 38.4, 37.7, 29.2, 28.3, 27.7, 27.3, 23.1, 19.9;
HRMS (EI+) calcd for C32H42O7 [M+] 538.2931; found 538.2930.
5.8. Analogue 6
To a solution of stilbene 30 (37 mg, 0.07 mmol) in MeOH (2 mL)
at rt was added TsOH (60 mg, 0.3 mmol) and the solution was al-
lowed to stir for 18 h. The reaction was quenched by addition of
NaHCO3 (satd) and extracted with EtOAc. The combined organic
extracts were washed with brine, dried (MgSO4), concentrated in
vacuo, and purified by flash column chromatography (50% EtOAc/
hexanes) to afford analogue 6 (21 mg, 67%) as a yellow oil: 1H
NMR d 6.83–6.65 (m, 4H), 6.49 (s, 2H), 5.99–5.88 (m, 1H), 5.14–
5.03 (m, 2H), 3.79 (s, 3H), 3.41–3.33 (m, 3H), 2.65–2.62 (m, 2H),
2.07–2.02 (m, 1H), 1.82–1.51 (m, 4H), 1.14 (s, 3H), 1.02 (s, 3H),
0.89 (s, 3H); 13C NMR d 155.3 (2C), 148.8, 142.7, 137.4, 136.1,
128.8, 128.6, 125.8, 122.7, 120.7, 115.8, 111.4, 107.0, 106.1 (2C),
78.1, 77.2, 56.0, 46.7, 38.4, 37.6, 29.2, 28.2, 27.6, 27.3, 23.1, 19.8;
HRMS (EI+) calcd for C28H34O5 [M+] 450.2406; found 450.2408.
5.5. Phosphonate 22
To a solution of phosphonate 18 (69 mg, 0.2 mmol) in MeOH
(3 mL) was added 10% Pd–C (67 mg, cat.) and an excess of H2,
and the mixture was agitated overnight. Following filtration
through Celite, the resulting solution was concentrated in vacuo
to afford compound 22 (67 mg, 97%) as a colorless oil: 1H NMR d
6.63 (s, 2H), 5.10 (s, 4H), 3.99–3.94 (m, 4H), 3.39 (s, 6H), 3.02 (d,
JPH = 21.6 Hz, 2H), 2.54 (t, J = 7.5 Hz, 2H), 1.48–1.40 (m, 2H), 1.19
(t, JPH = 6.9 Hz, 6H), 0.86 (t, J = 7.2 Hz, 3H); 13C NMR d 155.7 (d,
JCP = 3.3 Hz, 2C), 129.9 (d, JCP = 9.2 Hz), 119.5 (d, JCP = 4.2 Hz),
109.2 (d, JCP = 6.7 Hz, 2C), 94.3 (2C), 62.0 (d, JCP = 6.7 Hz, 2C), 55.8
(2C), 33.7 (d, JCP = 137.7 Hz), 25.1, 22.6 (d, JCP = 2.4 Hz), 16.2 (d,
JCP = 6.1 Hz, 2C), 14.1; 31P NMR d 27.0; HRMS (EI+) calcd for
C18H31O7P [M+] 390.1807; found 390.1811.
5.9. Benzyl alcohol 36
To a solution of known ester 3522 (202 mg, 1.0 mmol) in CH2Cl2
(10 mL) at 0 °C was added DIPEA (0.4 mL, 2.3 mmol). After stirring
for 30 min, MOMCl (0.2 mL, 2.6 mmol) was added. The reaction
was allowed to warm to rt, stirred for 12 h, then quenched by addi-
tion of H2O and extracted with EtOAc. The organic layers were
combined and washed with brine, dried (MgSO4), filtered, and con-
centrated in vacuo. To a solution of the crude ester dissolved in THF
(20 mL) at 0 °C was added LiAlH4 (276 mg, 7.3 mmol), and the reac-
tion was allowed to warm to rt and stirred for 4 h. The reaction was
quenched by the addition of H2O and extracted with EtOAc. The or-
ganic layers were combined, washed with brine, dried (MgSO4), fil-
tered, and concentrated in vacuo to afford alcohol 36 (155 mg, 78%
over two steps) as an off-white solid: 1H NMR d 7.54 (d, J = 2.2 Hz,
1H), 7.20 (m, 1H), 6.91 (m, 1H), 6.85 (dd, J = 2.2, 1.0 Hz, 1H), 5.30 (s,
2H), 4.74 (s, 2H), 3.52 (s, 3H), 1.97 (br s, 1H); 13C NMR d 156.4,
150.9, 144.1, 138.7, 117.8, 106.3, 104.1, 103.9, 94.7, 65.6, 56.2;
HRMS (EI+) calcd for C11H12O4 [M+] 208.0736; found 208.0733.
5.6. Benzyl alcohol 27
To a solution of benzyl alcohol 26 (203 mg, 0.9 mmol) in THF
(10 mL) at ꢁ20 °C was slowly added n-BuLi (0.8 mL, 2.2 M in hex-
ane, 1.8 mmol), and the reaction was allowed to warm to 0 °C over
1 h. The solution was then cooled to ꢁ20 °C, CuBrꢂDMS (390 mg,
1.9 mmol) was added in one portion, and the resulting solution
was allowed to stir for 1 h. To this solution was added 3-(trimeth-
ylsilyl)propargyl bromide (0.2 mL, 1.2 mmol), and the resulting
solution was allowed to warm to rt and stirred for 2 h. After the
reaction was quenched by addition of NH4Cl (satd), extracted with
EtOAc, washed with brine, dried (MgSO4), and concentrated in va-
cuo, final purification by column chromatography (35% EtOAc/hex-
anes) provided alcohol 27 (66 mg, 22%) as a colorless oil: 1H NMR d
6.74 (s, 2H), 5.18 (s, 4H), 4.54 (s, 2H), 3.59 (s, 2H), 3.45 (s, 6H), 2.99
(br s, 1H), 0.06 (s, 9H); 13C NMR d 155.2 (2C), 141.4, 114.4, 106.3
(2C), 105.5, 94.0 (2C), 82.0, 64.7, 55.8 (2C), 14.1, ꢁ0.1 (3C); HRMS
(EI+) calcd for C17H26O5Si [M+] 338.1550; found 338.1548.
5.10. Benzyl alcohol 37
To a solution of benzofuran 36 (387 mg, 1.9 mmol) in MeOH
(2 mL) at rt was added NH4OAc (72 mg, 0.9 mmol), 10% Pd–C
(40 mg, cat.), and excess H2, and the resulting mixture was agitated
for 12 h. The reaction mixture then was filtered through Celite,
washed with EtOAc, and concentrated in vacuo to afford compound
37 (373 mg, 95%) as a light yellow oil: 1H NMR d 6.57 (s, 1H), 6.45
(s, 1H), 5.15 (s, 2H), 4.56 (t, J = 8.7 Hz, 2H), 4.53 (s, 2H), 3.45 (s, 3H),
3.20 (br s, 1H), 3.13 (t, J = 8.7 Hz, 2H); 13C NMR d 161.5, 153.8,
142.9, 114.1, 105.1, 102.0, 94.1, 71.6, 65.0, 55.9, 27.0; HRMS (EI+)
calcd for C11H14O4 [M+] 210.0892; found 210.0895.
5.7. Stilbene 30
To a mixture of NaH (28 mg, 0.8 mmol) and 15-crown-5 (1 drop,
cat.) in THF (5 mL) at 0 °C was added a solution of phosphonate 18
(38 mg, 0.1 mmol) and aldehyde 17 (29 mg, 0.1 mmol) in THF
(1 mL), and the reaction was allowed to stir for 1 h at 0 °C. The
reaction mixture was then quenched via dropwise addition of
H2O, extracted with ether, washed with brine, dried (MgSO4),
and concentrated in vacuo. The resulting oil was purified by flash
column chromatography (45% EtOAc/hexanes) to afford stilbene
30 (37 mg, 70%) as a colorless oil: 1H NMR d 6.91–6.79 (m, 6H),
5.90–5.85 (m, 1H), 5.16 (s, 4H), 4.95–4.85 (m, 2H), 3.82 (s, 3H),
3.42 (s, 6H), 3.38–3.37 (m, 3H), 2.65–2.56 (m, 2H), 2.07–2.02 (m,
1H), 1.81–1.52 (m, 4H), 1.18 (s, 3H), 1.03 (s, 3H), 0.81 (s, 3H); 13C
NMR d 155.9 (2C), 148.9, 142.6, 137.1, 136.6, 128.8, 128.4, 126.3,
5.11. Phosphonate 38
To a solution of alcohol 37 (187 mg, 0.9 mmol) in THF (10 mL)
was added NEt3 (0.5 mL, 3.6 mmol) and LiBr (460 mg, 5.3 mmol),
and the reaction was cooled to 0 °C. After 10 min, MsCl (0.2 mL,
2.2 mmol) was added slowly and the mixture was allowed to stir
for 1 h. Additional LiBr (200 mg, 2.3 mmol) was added and the
reaction mixture was allowed to stir for 45 min, then poured into
Et2O. The reaction mixture was quenched by addition of NH4Cl
(satd) and extracted with Et2O. After the combined organic layers
were washed with brine, dried (MgSO4), filtered, and concentrated
in vacuo, the resulting oil was dissolved in P(OEt)3 (2 mL) and

1682
N. C. Ulrich et al. / Bioorg. Med. Chem. 18 (2010) 1676–1683
heated at reflux overnight. The reaction was then allowed to cool
to rt, poured into Et2O, quenched by addition of H2O, and extracted
with Et2O. After the combined organic extracts were washed with
brine, dried (MgSO4), and concentrated in vacuo, final purification
by flash column chromatography (2–3% MeOH/Et2O) afforded
phosphonate 38 (160 mg, 55%) as a light yellow solid: 1H NMR d
6.53 (m, 1H), 6.44 (m, 1H), 5.17 (s, 2H), 4.57 (t, J = 8.7 Hz, 2H),
4.04 (qd, J = 7.8, 7.1 Hz, 4H), 3.47 (s, 3H), 3.14 (dt, J = 8.8, 3.3 Hz,
2H), 3.07 (d, JPH = 21.4 Hz, 2H), 1.28 (t, J = 7.0 Hz, 6H); 13C NMR d
161.5 (d, JCP = 3.0 Hz), 153.7 (d, JCP = 3.2 Hz), 132.7 (d, JCP = 9.2 Hz),
113.7 (d, JCP = 3.7 Hz), 108.2 (d, JCP = 6.7 Hz), 105.0 (d, JCP = 6.7 Hz),
94.3, 71.6, 61.9 (d, JCP = 6.9 Hz, 2C), 55.9, 33.8 (d, JCP = 138.1 Hz),
27.1 (d, JCP = 1.0 Hz), 16.2 (d, JCP = 6.2 Hz, 2C); 13P NMR d 26.2;
HRMS (EI+) calcd for C15H23O6P [M+] 330.1232; found 330.1224.
2.07–1.92 (m, 6H), 1.83–1.77 (m, 1H), 1.75 (s, 3H), 1.73–1.66 (m,
2H), 1.64 (s, 3H), 1.58 (s, 3H), 1.18 (s, 3H), 1.06 (s, 3H), 0.85 (s,
3H); 13C NMR (CD3OD) d 157.1 (2C), 149.0, 143.0, 137.7, 134.8,
132.0, 130.5, 130.0, 129.7, 125.5, 124.6, 124.4, 123.4, 115.4,
111.3, 108.0 (2C), 78.7, 78.1, 56.0, 48.5, 41.1, 39.5, 38.9, 29.0,
27.9, 27.8, 25.9, 24.0, 23.1, 20.2, 17.7, 16.3, 14.8; HRMS (EI+) calcd
for C35H46O5 [M+] 546.3345; found 546.3351.
5.15. Cell culture
Cells were cultured in RPMI 1640 (SF-295) or F-12 (A549) media
containing 10% fetal bovine serum, penicillin–streptomycin,
amphotericin B, and -glutamine at 37 °C in the presence of 5% CO2.
L
5.16. Cytotoxicity assay
5.12. Aldehyde 40
SF-295 and A549 cells were grown to 60% confluency before
treatment with indicated compound concentrations. After 44 h,
the media was aspirated and changed to RPMI 1640 without phenol
red (SF-295) or F-12 (A549) with 0.06 mg/mL MTT salt (Calbiochem,
San Diego, CA, USA). MTT stop solution (10% 1 N HCl, 10% triton X-
100, and isopropyl alcohol) was added after 4 h of incubation with
MTT containing media. Plates were wrapped and incubated over-
night at 37 °C with gentle agitation. The optical density of each con-
dition was determined spectrophotometrically at 540 nm and
650 nm. EC50 values were calculated using Calcusyn (Biosoft, Cam-
bridge, UK).
Alcohol 36 (121 mg, 0.6 mmol) was dissolved in CH2Cl2 (15 mL),
and MnO2 (980 mg, 11.3 mmol) was added. The reaction was al-
lowed to stir for 5 h at rt, and then filtered through Celite and the
pad was washed with CH2Cl2. The solvent was removed in vacuo to
yield aldehyde 40 (114 mg, 95%) as a white solid: 1H NMR d 10.0 (s,
1H), 7.75 (d, J = 2.2 Hz, 1H), 7.70 (m, 1H), 7.45 (d, J = 1.1 Hz, 1H),
6.96 (dd, J = 2.2, 1.0 Hz, 1H), 5.37 (s, 2H), 3.54 (s, 3H); 13C NMR d
191.5, 155.8, 151.3, 147.4, 134.3, 124.4, 108.9, 106.5, 104.7, 94.8,
56.4. Anal. Calcd for C11H10O4: C, 64.07; H, 4.89. Found: C, 63.69;
H, 4.95.
5.13. Analogue 14
Acknowledgments
Toa solutionof knownstilbene4314 (23 mg, 0.04 mmol) in MeOH
(2 mL) at rt was added freshly ground Mg (50 mg, 0.9 mmol) and
NH4Cl (50 mg, 0.9 mmol). The reaction was allowed to stir until all
theMg had dissolved. Once TLCanalysis indicated thedisappearance
of starting material, the reaction mixture was poured into NH4Cl
(satd), and EtOAc was added. The aqueous layer was acidified with
1 M HCl until the precipitate dissolved, and then was extracted with
EtOAc. The combined organics extracts were washed with NaHCO3
(satd) and brine, dried (MgSO4), filtered, and concentrated in vacuo.
To a solution of the resulting oil in MeOH (3 mL) was added TsOH
(20 mg, 0.1 mmol), the reaction was allowed to stir for 2 days, and
then was quenched by addition of NaHCO3 (satd) and extracted with
EtOAc. After the combined organic layers were dried (MgSO4), fil-
tered, and concentrated in vacuo, final purification by flash column
chromatography (40% EtOAc/hexanes) afforded analogue 14
(14 mg, 70% over two steps) as a yellow oil: 1H NMR d 6.53 (d,
J = 1.6 Hz, 1H), 6.49 (d, J = 1.6 Hz, 1H), 6.26 (s, 2H), 5.28–5.24 (m,
1H), 3.79 (s, 3H), 3.45–3.38 (m, 3H), 2.80–2.72 (m, 4H), 2.69–2.66
(m, 2H), 2.13–2.09 (m, 1H), 1.89–1.58 (m, 5H), 1.82 (s, 3H), 1.75 (d,
J = 0.9 Hz, 3H), 1.23 (s, 3H), 1.09 (s, 3H), 0.87 (s, 3H); 13C NMR d
154.8 (2C), 148.4, 141.7, 140.7, 135.1, 132.8, 122.4, 121.8, 121.0,
110.9, 109.7, 108.3 (2C), 78.1, 56.0, 46.8, 38.4, 37.7, 37.7, 37.2, 28.3,
27.4, 25.8, 23.1, 22.3, 19.8, 17.9, 14.3; HRMS (EI+) calcd for
C30H40O5 [M+] 480.2876; found 480.2885.
We thank Dr. David G. Covell, NCI-Frederick, for helpful discus-
sions. This project was supported at the UI by the Roy J. Carver
Charitable Trust as a Research Program of Excellence, the Roland
W. Holden Family Program for Experimental Cancer Therapeutics,
and the NIH through R41CA126020-01 to Terpenoid Therapeutics,
Inc. This research at the NCI was supported by the Intramural Re-
search Program of the NIH, National Cancer Institute, Center for
Cancer Research; we thank the Developmental Therapeutics Pro-
gram in the Division of Cancer Treatment and Diagnosis of the Na-
tional Cancer Institute, for 60-cell testing.
Supplementary data
Supplementary data (spectroscopic data and experimental con-
ditions for preparation of compounds 7–13, 15, 24, 25, 29, 31, 32,
39, and 44 are provided, along with the two-cell data for com-
pounds 6–16 and the 60-cell data for compounds 9 and 15) associ-
ated with this article can be found, in the online version, at
doi:10.1016/j.bmc.2009.12.063.
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