Alteration of the bis-tetrahydrofuran core stereochemistries in asimicin can affect the cytotoxicity

Article abstract of DOI:10.1021/jm801028c

A systematic analysis using 10 synthetic asimicin stereoisomers revealed that the stereochemistry of the bis-tetrahydrofuran core, including the tetrahydrofuran rings and the adjacent hydroxy functions, had significant effect on its cytotoxicity. Our findings set to rest the highly controversial perception that the stereochemistry of the tetrahydrofuran core has little effect on the activity, which is not true for its cytotoxic effect, and also reinforces the previous conclusion that asimicin is a highly potent anticancer compound.

Full text of DOI:10.1021/jm801028c

J. Med. Chem. 2008, 51, 7045–7048
7045
Alteration of the Bis-tetrahydrofuran Core
Stereochemistries in Asimicin Can Affect the
Cytotoxicity
Subhash C. Sinha,*,† Zhiyong Chen,† Zheng-Zheng Huang,†
Eiko Nakamaru-Ogiso,‡ Halina Pietraszkiewicz,§
Matthew Edelstein,§ and Frederick Valeriote§
The Skaggs Institute for Chemical Biology and the Departments of
Molecular Biology, and Molecular and Experimental Medicine,
The Scripps Research Institute, 10550 North Torrey Pines Road,
La Jolla, California 92037, and Josephine Ford Cancer Center,
Henry Ford Health System, Detroit, Michigan 48202
ReceiVed August 14, 2008
Abstract: A systematic analysis using 10 synthetic asimicin stereoi-
somers revealed that the stereochemistry of the bis-tetrahydrofuran core,
including the tetrahydrofuran rings and the adjacent hydroxy functions,
had significant effect on its cytotoxicity. Our findings set to rest the
highly controversial perception that the stereochemistry of the tetrahy-
drofuran core has little effect on the activity, which is not true for its
cytotoxic effect, and also reinforces the previous conclusion that
asimicin is a highly potent anticancer compound.
Figure 1. Structure of 64 stereoisomeric asimicins arising from six
stereogenic centers of the bis-THF core and a related compound, 27-
hydroxybullatacin.
stereochemistry of the THF core. In addition, it was noted that
a chronic exposure of cancer cells to these compounds could
be essential to achieve any therapeutic effect.
Annonaceous adjacent bis-tetrahydrofuran (bis-THF) aceto-
genins, asimicin (1.1a) and bullatacin (1.1b), are highly potent
cytotoxic molecules.1 Reportedly, they are several orders of
magnitude more cytotoxic than doxorubicin, in particular against
multidrug resistant cell lines. Although the exact mechanism
of action remains unknown, these compounds are believed to
display anticancer activity by inhibiting the mitochondrial
enzyme, complex I, inducing the expression of pro-apoptopic
genes, and arresting cells in multiple phases, including G1 and
G2/M.2 On the basis of a comparison among various acetogenins
and their analogues, it has been shown that the THF core,
including both the THF ring and the neighboring free hydroxyl
functions, are crucial structural elements for their strong complex
I inhibitory effect and high anticancer activitiy.3 Yet, stereo-
chemistry of the THF core is believed to have little effect on
the activity of an acetogenin.1 This would imply that all 64
stereoisomeric asimicins (1.1-1.16)(a-d) with dissimilar ster-
eochemistry in the bis-THF core (Figure 1) would have identical
anticancer activity. This is an unlikely assumption from a historic
perspective of medicinal chemistry. Although one could cite
the famous example of bullatacin being more than a billion times
more potent than asimicin and trilobacin (1.13a) in MCF-7 cells,
in spite of the fact that these molecules differ from one other at
only one stereogenic center in the THF core,4 the results could
not be corroborated in later studies.5 Therefore, we prepared
several asimicin stereoisomers, including 1.1a-d and 1.4a-d,
and using these compounds as well as the previously described
asimicin stereoisomers, 1.6a and 1.8a,6 we determined both their
anticancer activities and the complex I inhibitory effects. On
the basis of the results of these studies, we report here that both
the cytotoxic activity, and to a lesser extent the complex I
inhibitory effect of acetogenins, do indeed depend upon the
Synthesis of compounds 1.1a-d and 1.4a-d was achieved
by starting with the bis-THF intermediates 5.1 and 5.4, re-
spectively, by modifying the general strategy that we recently
used in the synthesis of 27-hydroxybullatacin, 2 (Figure 1).7
The new strategy, especially that used in the synthesis of 1.4’s,
was different from any previous strategies by being more
versatile, as this yielded the desired stereoisomeric asimicins
rapidly using simple processes and fewer number of intermedi-
ates, steps, and chromatography.8,9 This strategy may also be
applied to the asimicin library and analogues’ syntheses using
the appropriate bis-THF intermediates. Compounds 5.1 and 5.4
were prepared from 3.2 and 3.1, via 4.2 and 4.1, respectively,
in four easy steps, including mesylation, Sharpless asymmetric
dihydroxylation with AD-mix-ꢀ, Williamson-type etherification
and monobenzoylation. Compounds 5.1 and 5.4 were oxidized
using Swern reaction, and the resulting aldehydes, 6.1 and 6.4,
were alkynylated with 1-decyne using Carreira’s enantioselective
alkynylation10 to give both threo and erythro products. The
alkynylated products were hydrogenated over Pd-C, and the
resulting saturated compounds 7.1a,b and 7.4a,b were converted
to alcohols 8.1a,b and 8.4a,b. We applied two alternative
strategies to convert alcohol 8’s to the target compound 1’s. In
one strategy, alcohols 8.1a,b were oxidized and the resulting
aldehydes were allylated using Brown’s method11 with (+)- and
(-)-Ipc2B-allyl, affording compound pairs, 9.1a/9.1c (from 8.1a)
and 9.1b/9.1d (from 8.1b), respectively. These alkenes were
cross-metathesized12 with butenolide 107a using Grubbs’ cata-
lyst,13 and the resulting products 11.1a-d were hydrogenated
and deprotected to afford 1.1a-d, as described for compound
2.7a In an alternative approach, aldehyde products from alcohols
8.4a,b were reacted with 12 under Carreira’s asymmetric
alkynylation conditions using (+)- or (-)-NME and Zn(OTf)2
to give 13.4a/13.4c and 13.4b/13.4d. These products were
hydrogenated and deprotected as above affording compounds
1.4a-d.
* To whom correspondence should be addressed. Phone: (858) 784-8512.
Fax: (858) 784-8732. E-mail: subhash@scripps.edu.
†
The Skaggs Institute for Chemical Biology, TSRI.
Department of Molecular and Experimental Medicine, TSRI.
Josephine Ford Cancer Center.
‡
§
10.1021/jm801028c CCC: $40.75
2008 American Chemical Society
Published on Web 11/01/2008

7046 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 22
Scheme 1. Total Synthesis of Eight Stereoisomeric Asimicinsa
Letters
a Key: (a) (i) MsCl, Et3N, CH2Cl2, 0 °C; (ii) AD-mix-ꢀ, tert-BuOH/H2O, 0 °C, then Na2SO3. (b) (i) Pyridine, reflux; (ii) BzCl, Et3N, CH2Cl2, 0 °C. (c)
Oxalyl chloride, DMSO, CH2Cl2, then Et3N. (d) (i) Zn(OTf)2, (+)- or (-)-NME, DIPEA, toluene; (ii) H2, Pd/C, EtOAc. (e) (i) TBSOTf, 2,6-lutidine,
CH2Cl2; (ii) LiOH, MeOH, THF, H2O. (f) (+)- or (-)-Ipc2B-allyl, Et2O. (g) Grubbs catalyst [(PCy3)2RudCHPh]Cl2, CH2Cl2, syringe pump. (h) (i) TsNHNH2,
AcONa, DME/H2O, syringe pump; (ii) 5%HF, CH2Cl2, CH3CN.
While numerous studies have been directed to an understand-
ing of the activity relationships among various types of ac-
etogenins and their analogues, either obtained from natural
sources or prepared synthetically,14 no efforts have been made
to elucidate the stereochemistry-activity relationships, espe-
cially in relation to the THF cores.15 Therefore, to understand
this relationship, we determined the inhibitory effect of com-
pounds 1.1a-d, 1.4a-d, 1.6a, and 1.8a on both tumor cell
proliferation and the complex I activity. These complementary
studies were necessary to make comparison between the two
activity data sets, which previously have been found by others
not to correlate for many acetogenin analogues. The complex I
activity was determined using bovine heart submitochondrial
particles (SMPa),16 as described earlier.7a Briefly, compound
1’s at various concentrations were added to 15 µg of SMPs/
mL containing 0.25 M sucrose, 1 mM MgCl2, and 50 mM
phosphate buffer (pH 7.5), and mixed. After 5 min equilibration
of SMP with inhibitors, the reaction was started using 150 µM
NADH, and progress of reaction determined spectrophotometri-
cally at 340 nm. The results (IC50 of the compounds) are shown
in Table 1. All compounds possessed comparable IC50 values,
suggesting that the stereochemistry of both the bis-THF rings
and the adjacent hydroxyl functions in stereoisomeric asimicins
may have only little effect on the complex I activities.
cells (H125). Murine and human leukemia (L1210 and CCRF-
CEM) cells were used as the reference tumors of the assay. A
normal granulocyte/ macrophage committed progenitor cell from
the marrow (CFU-GM), which represents the target for the most
common chemotherapeutic toxicity in vivo, myelosuppression,
were used to determine their selectivity to tumor cells vs normal
cells. Such comprehensive tests allow us not only to elucidate
the structure-activity relationship but also to identify com-
pounds that could be advanced to further pharmacological
studies. The anticancer activities of 1.1a-d, 1.4a-d, 1.6a, and
1.8a were determined using both the disk diffusion and cell
proliferation assays, as described earlier.17
Briefly, for the disk diffusion assay, a volume of 15 µL of
each sample was dropped onto a 6.5 mm filter disk and allowed
to dry overnight. Cells were plated in soft agar in 60 mm tissue
culture dishes, and the disk was placed close to the edge of the
dish. The dishes were incubated for 7-10 days, and the zone
of inhibition from the edge of the filter disk to the beginning of
normal-sized colony formation was measured. The diameter of
the filter disk, 6.5 mm, was arbitrarily taken as 200 units. Any
excessively toxic sample at the first concentration was diluted
by 1:4 or 1:10 decrements, and the experiments were repeated.
At some dilution, quantifiable cytotoxicity (zone of inhibition
<750 units) was invariably obtained (see Supporting Informa-
tion for the data). A difference in the sensitivity of the tumor
cells versus either the normal or leukemia cells to a compound,
Next, we evaluated the cytotoxic activities of compounds
1.1a-d, 1.4a-d, 1.6a, and 1.8a using murine and human cancer
cell lines, including colon cells (Colon38 and H116), and lung
is presented in Table 2 as HCT-116∆CEM ) n, indicating that there
was an “n” unit zone differential between the tumor (human
colon HCT-116) and leukemeia (human CEM). For differential
values g250 units between solid tumor cells and either normal
a Abbreviations: DIPEA, diisopropylethylamine; Ipc2B-allyl, allyl di-
isopino-campheylborane; SMP; submitochondrial particles; NADH, nico-
tinamide adenine dinucleotide.

Letters
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 22 7047
Table 1. Inhibitory Effect of the Stereoisomeric Asimicins and Their
Analogues on Complex I Activity
compd
IC50 (nM)
compd
IC50 (nM)
1.1a
1.1c
1.4a
1.4c
1.6a
1.2
3.3
7.5
2.5
2.0
1.1b
1.1d
1.4b
1.4d
1.8a
2.5
9.0
3.0
5.0
3.0
Table 2. Cytotoxicity and Selectivity of Asimicin Stereoisomers
Determined by Disk Diffusion Assay
compd
µg/disk
∆
∆
∆
∆
C38 L1210
C38 CFU
H116 CEM
H125 CEM
1.1a
15
1
400
550
500
450
500
600
400
550
300
400
100
300
150
300
350
600
350
400
300
400
500
500
550
600
400
600
500
600
350
450
650
200
650
400
100
550
550
150
0
1.1b
1.1c
1.1d
1.4a
1.4b
1.4c
1.4d
1.6a
1.8a
60
1
60
3.8
15
1
15
1
Figure 2. In vitro therapeutic effect of asimicin to HCT-116 colon
cancer cells.
15
1
results are significant because it was believed that the stereo-
chemistry of THF rings and the hydroxy functions in the central
region had no effect on their activity. Evidently, the cytotoxicity
of asimicin depends highly upon the bis-THF core stereochem-
istry. This result also complements the previous findings that
the alkyl chain and methylene bridge length, and the butenolide
surrogates, all influence the anticancer activities of a bis-THF
acetogenin.
60
3.8
15
1
30
0.3
30
0.3
Finally, we determined the cytotoxicity of asimicin to HCT-
116 cells at various concentrations and incubation durations.
Cells were incubated with asimicin at 0.001, 0.01, 0.1, 1, and
10 µg/mL for either 2 h, 24 h, or continuously (for 168 h), and
the number of surviving clonogenic cells determined. The results
are shown in Figure 2. In this analysis, 90% cell killing or 10%
survival (S10) was selected for the comparison of activities.
Neither 2 nor 24 h were sufficient durations of exposure even
at the highest concentration (10 µg/mL) of asimicin to yield
10% survival. In contrast, for the 7-day (168 h) exposure du-
ration, the S10 was less than 1 ng/mL. This implies that chronic
exposure of asimicin is necessary for any therapeutic effect and
that continuous levels of at least 1 ng/mL (in the serum) would
be sufficient for a therapeutic effect.
0
Table 3. Anticancer Activity of the Stereoisomeric Asimicins to Human
Colon Cancer, HCT-116
compd
1.1a 1.1b 1.1c 1.1d 1.4a 1.4b 1.4c 1.4d
1.4 27 0.45 18 0.22 5.6 0.69
IC50 (nM) 0.51
or leukemia cells defines solid tumor selective compounds in
our assay and these values are bolded in Table 2. All com-
pounds were more sensitive to Colon38 cells compared to
either HCT-116 or H-125 cells by 15- to 100-fold depending
upon the compound. They were also selective for Colon38
against both L1210 and CFU-GM. Selectivity was also de-
monstrated for all compounds for HCT-116 (and usually for
H125 also) compared to CEM (Table 2). Further, some com-
pounds were more sensitive than others to the same cell lines.
For example, compounds 1.1c and 1.4c were 10-fold less
cytotoxic to Colon38 than compounds 1.6a and 1.8a. Com-
pounds 1.1a, 1.1d, and 1.4b were more cytotoxic than com-
pounds 1.1c or 1.4c against HCT-116 cells.
The difference in anticancer activity of various stereoiso-
meric asimicins was further confirmed by determining their
IC50 against HCT-116 cells using the cell proliferation assay.
In this assay, cells were incubated with various concentration
of 1.1a-d and 1.4a-d, and their effect on cell proliferation
was determined. As shown in Table 3, several compounds
possessed subnanomolar anticancer activities, but at least two
compounds, 1.1c and 1.4a, were as much as two logs of mag-
nitude less potent than the most potent isomer, 1.4b. These
In conclusion, by synthesizing and evaluating ten synthetic
asimicin stereoisomers, we have shown that the anticancer
activity of the bis-THF acetogenins depends upon the stereo-
chemistry of the THF core, including the both THF rings and
the central hydroxyl functions. A chronic exposure of tumor
cells to asimicin at 1 ng/mL is predicted to be therapeutically
significant in vivo. To fully understand the relationship between
the anticancer activity and the bis-THF/hydroxy functions in
the central region, synthesis of a complete library of all 64
stereoisomeric asimicins seems essential.
Acknowledgment. We thank the Skaggs Institute for Chemi-
cal Biology and National Institute of Health for the financial
support. We are also thankful to Professor Takao Yagi for pro-
viding us the SMPs.

7048 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 22
Supporting Information Available: Typical experimental pro-
Letters
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cedure, analytical and biological data, and of H and 13C NMR
spectra for selected compounds. This material is available free of
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JM801028C