Synthesis and cytotoxic evaluation of a series of γ-substituted γ-aryloxymethyl-α-methylene-γ-butyrolactones against cancer cells

Article abstract of DOI:10.1023/A:1007534416561

Purpose. The main objective of this investigation was to explore the cytotoxic structure-activity relationships of γ-substituted γ-aryloxy-methyl-α-methylene-γ-butyrolactones against cancer cells. Methods. The target compounds were synthesized in two step

Full text of DOI:10.1023/A:1007534416561

Pharmaceutical Research, Vol. 17, No. 6, 2000
Research Paper
reported that some natural ␣-methylene-␥-butyrolactone bear-
ing butanolides, which was isolated from Litsea akoensis, also
have significant cytotoxicity (7). Due to the unique structural
feature as well as interesting biological activities of ␣-methyl-
ene-␥-butyrolactones, their synthesis has attracted renewed
attentions (8–10). A number of possible drug candidates bearing
this versatile functionality have also been synthesized with the
aim of finding effective clinical drugs (11–14). Over the past
few years, we were particularly interested in synthesizing ␣-
methylene-␥-butyrolactones (I) and evaluated for their cardio-
vascular activities (15–18). Although the enone (O ϭ C–C ϭ
CH2) component in this type of lactone is essential for their
biological activities, by acting as an alkylating agent through
a Michael-type reaction with bionucleophiles or sulfhydryl-
containing enzymes (19), the substituent at ␥-position of the
lactone also played an important role for their pharmacological
properties. For example, a phenyl group at ␥-position contrib-
Synthesis and Cytotoxic Evaluation of
a Series of ␥-Substituted ␥-
Aryloxymethyl-␣-methylene-␥-
butyrolactones Against Cancer Cells
Cheng-Chyi Tzeng,1,4 Kuan-Han Lee,2 Tai-Chi
Wang,2 Chein-Hwa Han,3 and Yeh-Long Chen1
Received December 22, 1999; accepted February 29, 2000
Purpose. The main objective of this investigation was to explore the
cytotoxic structure-activity relationships of ␥-substituted ␥-aryloxy-
methyl-␣-methylene-␥-butyrolactones against cancer cells.
Methods. The target compounds were synthesized in two steps com-
mencing with aryl-OH which was treated with a bromomethyl ketone uted more antiplatelet actitities than a methyl substituent, while
followed by the Reformatsky-type condensation.
a biphenyl counterpart is relatively inactive as a vasorelaxing
agent (15–18). Recently, we have reported certain ␥-aryloxy-
methyl-␣-methylene-␥-phenyl-␥-butyrolactones (I, R ϭ phe-
nyl) as potential anticancer agents (20). To explore the effect
of ␥-substitution with respect to cytotoxicities of the ␣-methyl-
ene-␥-butyrolactones, we report herein the preparation and eval-
Results. Seven types of ␣-methylene-␥-butyrolactones were evaluated
in vitro against 60 human cancer cell lines derived from nine cancer
cell types. The average values of log GI50 indicated that for the aryl
portion, potencies of these ␣-methylene-␥-butyrolactones are in a
decreasing order of quinolin-2(1H)-one (or 2-hydroxyquinoline, 21,
Ϫ5.89) Ͼ quinoline (19, Ϫ5.79) Ͼ 2-methylquinoline (20, Ϫ5.69)
Ͼ 8-hydroxyquinoline (17, Ϫ5.64) Ͼ 2-naphthalene (16, Ϫ5.59) Ͼ
benzene (15, Ϫ4.90). The same order was obtained for both log TGI
and log LC50. However, for the ␥-substituent, the potencies are in a
decreasing order of biphenyl (16f–21f ) Ͼ phenyl and 4-substituted
phenyl (16b-e–21b-e) Ͼ methyl (16a–21a).
uation of
a series of ␥-substituted ␥-aryloxymethyl-␣-
methylene-␥-butyrolactones. Their structure-activity relation-
ships are also described.
MATERIALS AND METHODS
Conclusions. Unlike cardiovascular activities of ␣-methylene-␥-butyr-
olactones in which a ␥-methyl substituent is necessary for vasorelaxing
effect while a phenyl or a halogen-substituted phenyl is prefer for the
antiplatelet activities, a ␥-biphenyl substituent proved to be the best
for their cytotoxicities against various cancer cell lines tested.
Melting points were determined on an Yanaco micromelt-
ing-point apparatus and are uncorrected. Proton nuclear mag-
netic resonance (1H NMR) spectra were obtained with a Varian
Gemini-200, spectrometer. Chemical shifts were expressed in
parts per million (␦) with TMS as an internal standard. Thin-
layer chromatography (TLC) was run on precoated (0.2 mm)
silica gel 60 F-254 plates manufactured by EM Laboratories,
Inc., and short wave UV light (254 nm) was used to detect the
UV-absorbing spots. Elemental analyses were carried out on a
Heraeus CHN-O-Rapid elemental analyzer and the results were
within Ϯ0.4% of theoretical values.
KEY WORDS: ␣-methylene-␥-butyrolactones; cytotoxicity; quino-
lin-2(1H)-one; quinoline.
INTRODUCTION
The ␣-methylene-␥-butyrolactone moiety is a characteris-
tic component of a large number of natural products, especially
the sesquiterpene lactones, which possess wide-ranging biologi-
cal activities, including antitumor, bactericidal, fungicidal, anti-
biotic, and anthelmintic properties (1–3). However, the
biological activity of ␣-methylene-␥-butyrolactones is not only
confined to the complex polyfunctional sesquiterpene lactones.
For example, the parent ␣-methylene-␥-butyrolactone
(tulipaline A), first isolated from Erythronium americanum in
1946, was identified as a substance with allergenic, antibiotic,
and fungitoxic activities (4–6). Recently, it has also been
2-(Naphthalen-2-yloxy)-1-(4-Fluorophenyl)ethan-1-one
(9c)
2-Naphthol (2; 1.44 g, 10 mmol), K2CO3 (1.52 g, 11,
mmol), and dry DMF (20 ml) were stirred at r.t. for 30 min.
2-Bromo-4Ј-fluoroacetophenone (2.39 g, 11 mmol) in dry DMF
(10 ml) was added to this solution. The resulting mixture was
stirred for 24 h (TLC monitoring), then poured into ice-water
(100 ml), and extracted with CHCl3 (3 ϫ 20 ml). The organic
phase was washed with H2O, dried (Na2SO4), and evaporated
and the crude oil submitted to column chromatography (silica
gel, EtOAc/hexane 1:9): 9c (1.99 g, 71%). mp 81–82ЊC. Anal.
1
(C18H13FO2) C,H,N. H-NMR (CDCl3) ␦: 5.33 (2H, s), 7.12–
1 School of Chemistry, Kaohsiung Medical University, Kaohsiung,
8.14 (11H, m).
Taiwan.
2 Department of Pharmacy, Tajen Institute of Technology, Pingtung,
Taiwan.
2-(Naphthalen-2-yloxy)-1-(4-Chlorophenyl)ethan-1-one
(9d)
3 Department of Pharmacy, Chia Nan College of Pharmacy and Science,
Tainan, Taiwan.
From 2 and 2-bromo-4Ј-chloroacetophenone as described
for 9c: 73% yield. mp 110–111ЊC. Anal. (C18H13ClO2) C,H,N.
1H-NMR (CDCl3) ␦: 5.32 (2H, s), 7.11–8.02 (11H, m).
4 To whom correspondence should be addressed. (e-mail:
tzengch@cc.kmu.edu.tw)
715
0724-8741/00/0600-0715$18.00/0 ᭧ 2000 Plenum Publishing Corporation

716
Tzeng et al.
2,3,4,5-Tetrahydro-4-Methylene-5-oxo-2-Phenoxymethyl-
2-Phenylfuran (15b)
1
Yield 82%. mp 60-62ЊC. Anal. (C18H16O3) C,H,N. H-
NMR (CDCl3) ␦: 3.19 (1H, dt, J ϭ 16.8, 2.9), 3.67 (1H, dt,
J ϭ 16.8, 2.4), 4.10, 4.18 (2H, AB, J ϭ 10.1), 5.67 (1H, t,
J ϭ 2.6), 6.29 (1H, t, J ϭ 2.9), 6.81–7.49 (10H, m).
2,3,4,5-Tetrahydro-2-Methyl-4-Methylene-2-
[(Naphthalen-2-yloxy)methyl]-5-Oxofuran (16a)
1
Yield 76%. mp 88–89ЊC. Anal. (C17H16O3) C,H,N. H-
NMR (CDCl3) ␦: 1.60 (3H, s), 2.78 (1H, dt, J ϭ 17.1, 2.8),
3.23 (1H, dt, J ϭ 17.1, 2.6), 4.03, 4.12 (2H, AB, J ϭ 9.7), 5.67
(1H, t, J ϭ 2.5), 6.30 (1H, t, J ϭ 2.9), 7.09–7.79 (7H, m).
2-(Naphthalen-2-yloxy)-1-(4-Methoxyphenyl)ethan-1-
one (9e)
From
2
and 2-bromo-4Ј-methoxyacetophenone as
2,3,4,-5-Tetrahydro-4-Methylene-2-[(Naphthalen-2-
described for 9c: 87% yield. mp 93–94ЊC. Anal. (C19H16O3)
C,H,N. H-NMR (CDCl3) ␦: 3.87 (3H, s), 5.31 (2H, s), 6.95–
8.06 (11H, m).
yloxy)methyl]-5-oxo-2-Phenylfuran (16b)
1
1
Yield 89%. mp 84-86ЊC. Anal. (C22H18O3) C,H,N. H-
NMR (CDCl3) ␦: 3.23 (1H, dt, J ϭ 16.8, 2.9), 3.71 (1H, dt, J
ϭ 16.8, 2.5), 4.22, 4.30 (2H, AB, J ϭ 10.1), 5.70 (1H, t, J ϭ
2.5), 6.33 (1H, t, J ϭ 2.9), 7.06–7.74 (12H, m).
2-(Naphthalen-2-yloxy)-1-[(1,1Ј-Biphenyl-4-yl]ethan-1-
one (9f)
2-(4-Fluorophenyl)-2,3,4,5-Tetrahydro-4-Methylene-2-
[(Naphthalen-2-yloxy)methyl]-5-Oxofuran (16c).
From 2 and 2-bromo-4’-phenylacetophenone as described
for 9c: 68% yield. mp 125–126ЊC. Anal. (C24H18O2)C,H,N.
1H-NMR (CDCl3) ␦: 5.40 (2H, s), 7.15–8.15 (16H, m).
Yield 74%. mp 126–127ЊC. Anal. (C22H17FO3) C,H,N.
1H-NMR (CDCl3) ␦: 3.19 (1H, dt, J ϭ 16.8, 2.9), 3.69 (1H,
dt, J ϭ 16.8, 2.4), 4.19, 4.27 (2H, AB, J ϭ 10.1), 5.71 (1H, t,
J ϭ 2.4), 6.34 (1H, t, J ϭ 2.8), 7.06–7.78 (11H, m).
2-(Naphthalen-1-yloxy)-1-(4-Methoxyphenyl)ethan-1-
one (11e)
From naphthalen-1-ol (4) and 2-bromo-4Ј-methoxyaceto-
phenone as described for 9c: 77% yield. mp 90–91ЊC. Anal.
(C19H16O3) C,H,N. 1H-NMR (CDCl3) ␦: 3.87 (3H, s), 5.36 (2H,
s), 6.76–8.38 (11H, m).
2-(4-Chlorophenyl)-2, 3, 4,-5-Tetrahydro-4-Methylene-2-
[(Naphthalen-2-yloxy)methyl]-5-Oxofuran (16d)
Yield 91%. mp 110–111ЊC. Anal. (C22H17ClO3) C,H,N.
1H-NMR (CDCl3) ␦: 3.17 (1H, dt, J ϭ 16.9, 2.9), 3.69 (1H,
dt, J ϭ 16.9, 2.6), 4.18, 4.26 (2H, AB, J ϭ 10.1), 5.71 (1H, t,
J ϭ 2.4), 6.33 (1H, t, J ϭ 2.8), 7.05–7.78 (11H, m).
2-(Naphthalen-1-yloxy)-1-[(1,1Ј-Biphenyl-4-yl]ethan-1-
one (11f)
From 4 and 2-bromo-4Ј-phenylacetophenone as described
for 9c: 88% yield. mp 125–126ЊC. Anal. (C24H18O2) C,H,N.
1H-NMR (CDCl3) ␦: 5.45 (2H, s), 6.79–8.40 (16H, m).
2,3,4,-5-Tetrahydro-2-(4-Methoxphenyl)-4-Methylene-2-
[(Naphthalen-2-yloxy)methyl]-5-Oxofuran (16e)
1
Yield 86%. mp 99–100ЊC. Anal. (C23H20O4) C,H,N. H-
NMR (CDCl3) ␦: 3.19 (1H, dt, J ϭ 16.8, 2.9), 3.67 (1H, dt,
J ϭ 16.9, 2.4), 3.83 (3H, s), 4.17, 4.27 (2H, AB, J ϭ 10.2),
5.69 (1H, t, J ϭ 2.4), 6.31 (1H, t, J ϭ 2.9), 6.94–7.77 (11H, m).
2,3,4,5-Tetrahydro-2-Methyl-4-Methylene-5-oxo-2-
Phenoxymethylfuran (15a)
To a solution of 1-phenoxypropan-2-one (8a, 0.15 g, 1
mmol) in dry THF (20 ml) were added activated zinc powder
(85 mg, 1.3 mmol), hydroquinone (2 mg), and ethyl 2-(bromo-
methyl)acrylate (0.26 g, 1.3 mmol). The mixture was refluxed
under N2 for 4 h (TLC monitoring). After cooling, it was poured
into an ice-cold 5% HCl solution (100 ml) and extracted with
CH2Cl2 (3 ϫ 50 ml). The CH2Cl2 extracts were combined and
washed with brine, dried (Na2SO4), and evaporated to give a
white solid which was crystallized from EtOAc: 15a (0.21 g,
94%). white crystalline solid. mp 71–72ЊC. Anal. (C13H14O3)
2-(1,-1Ј-Biphenyl-4-yl)-2,3,4,5-Tetrahydro-4-Methylene-2-
[(Naphthalen-2-yloxy)methyl]-5-Oxofuran (16f)
Yield 72%. mp 172–173ЊC. Anal. (C28H22O3) C,H,N. 1H-
NMR (CDCl3) ␦: 3.27 (1H, dt, J ϭ 17.1, 2.9), 3.74 (1H, dt,
J ϭ 17.1, 2.4), 4.29, 4.37 (2H, AB, J ϭ 10.1), 5.72 (1H, t,
J ϭ 2.4), 6.35 (1H, t, J ϭ 2.7), 7.12–7.76 (16H, m).
2,3,4,-5-Tetrahydro-2-(4-Methoxphenyl)-4-Methylene-2-
[(Naphthalen-1-yloxy)methyl]-5-Oxofuran (18e)
1
C,H,N. H-NMR (CDCl3) ␦: 2.09 (3H, s), 3.28 (1H, dt, J ϭ
17.2, 2.9), 3.72 (1H, dt, J ϭ 17.2, 2.5), 4.46, 4.55 (2H, AB,
J ϭ 9.7), 6.20 (1H, t, J ϭ 2.5), 6.82 (1H, t, J ϭ 2.9), 7.40–7.87
(5H, m).
Yield 79%. mp 132–133ЊC. Anal. (C23H20O4) C,H,N. 1H-
NMR (CDCl3) ␦: 3.28 (1H, dt, J ϭ 16.9, 2.9), 3.75 (1H, dt,
The same procedure was used to convert 8b to 15b, 9a- J ϭ 16.9, 2.2), 3.84 (3H, s), 4.23, 4.31 (2H, AB, J ϭ 10.1),
f to 16a-f, and 11e-f to 18e-f, respectively. 5.76 (1H, t, J ϭ 2.6), 6.42 (1H, t, J ϭ 2.9), 6.69–8.10 (11H, m).

Cytotoxic Evaluation of ␣-methylene-␥-butyrolactones
717
Table 1. Inhibition of In Vitro Cancer Cell Lines by Quinolin-2(1H)-
one ␣-Methylene-␥-butyrolactones [Log GI50 (M)]a
2-(1,1Ј-Biphenyl-4-yl)-2,3,4,5-Tetrahydro-4-Methylene-2-
[(Naphthalen-1-yloxy)methyl]-5-Oxofuran (18f)
Yield 84%. mp 161–162ЊC. Anal. (C28H22O3) C,H,N. 1H-
NMR (CDCl3) ␦: 3.34 (1H, dt, J ϭ 17.0, 2.9), 3.81 (1H, dt,
J ϭ 17.0, 2.2), 4.31, 4.39 (2H, AB, J ϭ 10.1), 5.79 (1H, t, J
ϭ 2.6), 6.45 (1H, t, J ϭ 2.9), 6.72–8.12 (16H, m).
Cell Line
Leukemia
RPMI-8226
HL-60 (TB)
21a
21b
21c
21d
21e
21f
Ϫ5.85 Ϫ6.76 Ϫ7.03b Ϫ6.91b ϽϪ8.00b Ϫ7.61b
Ϫ6.06b Ϫ6.92b Ϫ6.60 Ϫ6.76
Ϫ7.98 Ϫ7.61
Non-Small Cell Lung Cancer
NCI-H322M Ϫ4.83 Ϫ4.90c Ϫ4.78c Ϫ4.91c Ϫ4.92c Ϫ5.53c
RESULTS AND DISCUSSION
HOP-62
Colon Cancer
COLO 205
SW-620
CNS Cancer
SF-295
SNB-19
Melanoma
LOX IMVI
MALME-3M Ϫ6.28 Ϫ6.91 Ϫ5.76 Ϫ6.82
Ovarian Cancer
IGROV1
SK-OV-3
Renal Cancer
ACHN
Ϫ5.11 Ϫ5.29 Ϫ4.94 Ϫ5.38
Ϫ5.31 Ϫ5.87
Preparation of the ␣-methylene-␥-butyrolactones is illus-
trated in Scheme 1. Alkylation of phenol with bromoacetone
under basic conditions provided 1-phenoxypropan-2-one (8a)
(21) which was then reacted with ethyl 2-(bromomethyl)acry-
late and zinc powder in dry tetrahydrofuran (THF) (Reformat-
sky-type condensation) to afford 2,3,4,5-tetrahydro-2-methyl-4-
methylene-5-oxo-2-phenoxymethylfuran (15a) in 73% overall
yield. The same synthetic procedure was applied for the synthe-
sis of 15b, 16a-f, and 18e-f from their respective ketone precur-
sors (22–24). Synthesis of compounds 17a-f, 18b, 19a-f, 20a-
f, and 21a-f were previously reported (15–18).
Ϫ5.68 Ϫ5.97 Ϫ5.76 Ϫ5.92
Ϫ5.69 Ϫ6.10 Ϫ5.63 Ϫ5.98
Ϫ6.50 Ϫ6.35
Ϫ6.88 Ϫ6.91
Ϫ4.87 Ϫ4.96 Ϫ4.90 Ϫ4.99
Ϫ4.80c Ϫ5.19 Ϫ5.43 Ϫ5.16
Ϫ5.34 Ϫ5.89
Ϫ5.35 Ϫ5.82
Ϫ5.56
6.53 Ϫ5.81 Ϫ6.42
Ϫ6.71 Ϫ6.91
Ϫ7.96 Ϫ7.14
Ϫ4.97 Ϫ5.82 Ϫ5.78 Ϫ5.79
Ϫ4.81 Ϫ5.00 Ϫ4.82 Ϫ5.08
Ϫ5.88 Ϫ5.88
Ϫ5.23 Ϫ5.63
All these compounds were evaluated in vitro against 60
human cancer cell lines derived from nine cancer cell types.
For each compound, dose-response curves for each cell line
Ϫ5.55 Ϫ5.83 Ϫ5.79 Ϫ5.87
Ϫ5.40 Ϫ5.75 Ϫ5.72 Ϫ5.79
Ϫ6.14 Ϫ6.19
Ϫ5.81 Ϫ5.92
TK-10
were measured with five different drug concentrations, and the Prostate Cancer
PC-3
Ϫ4.90 Ϫ5.67 Ϫ5.80 Ϫ5.41
Ϫ5.11 Ϫ5.75 Ϫ5.31 Ϫ5.75
Ϫ5.41 Ϫ5.81
Ϫ5.84 Ϫ6.04
molar concentration causing 50% cell growth inhibition (GI50),
total cell growth inhibition (TGI, 0% growth), and 50% cell
death (LC50, Ϫ50% growth) compared with the control was
calculated (25). The cytotoxicity of 21a-f against representative
cancer cells is outlined in Table 1. Comparison of the mean
log GI50 values of 21a-f, 8-{[2-(1,1Ј-biphenyl-4-yl)-2,3,4,5-
tetrahydro-4-methylene-5-oxofuran-2-yl]methoxy}-quinolin-
2(1H)-one (21f ), and its 2-(4-methoxyphenyl) analogue 21e,
having a mean log GI50 of Ϫ6.27 and Ϫ6.15, respectively, are
more active than their 2-phenyl, 2-(4-fluorophenyl) and 2-(4-
chlorophenyl) counterparts (21b-d) which in turn are more
active than 2-methyl derivative, 21a. This finding is interesting,
because earlier studies on ␣-methylene-␥-butyrolactones indi-
cated these compounds also have antiplatelet and vasorelaxing
activities, with the ␥-phenyl lactones being better antiplatelet
agents than their corresponding ␥-methyl counterparts and the
␥-biphenyl lactones being relatively inactive as vasorelaxing
agents (18). Therefore, compounds 21e and 21f may be useful
in developing ␣-methylene-␥-butyrolactones anticancer agents
that do not have vasorelaxing side effects. Results in Table 1
DU-145
Breast Cancer
MCF7
Ϫ5.52 Ϫ5.96 Ϫ6.00 Ϫ6.20
Ϫ6.70 Ϫ6.55
Ϫ6.31 Ϫ6.56
Ϫ6.15 Ϫ6.27
MDA-MB-435 Ϫ5.44 Ϫ5.93 Ϫ5.77 Ϫ5.95
Meand
Ϫ5.35 Ϫ5.91 Ϫ5.75 Ϫ5.89
1.26 2.02 2.25 2.00
Rangee
3.08
2.08
a
Data obtained from NCI’s in vitro disease-oriented tumor cells screen.
GI50: Drug molar concentration causing 50% cell growth inhibition.
The most sensitive cell.
b
c
d
The least sensitive cell.
Mean values over all cell lines tested. These cell lines are: leukemia
(CCRF-CEM, HL-60 (TB), K-562, MOLT-4, PRMI-8226, and SR);
non-small cell lung cancer (A549/ATCC, EKVX, HOP-62, HOP-92,
NCI-H226, NCI-H23, NCI-H322M, and NCI-H522); colon cancer
(COLC 205, HCC-2998, HCT-116, HCT-15, HT29, KM12, and SW-
620); CNS cancer (SF-268, SF-295, SF-539, SNB-19, SNB-75, and
U251); melanoma (LOX IMVI, MALME-3M, M14, SK-MEL-2, SK-
MEL-28, SK-MEL-5, and UACC-257); ovarian cancer (IGROV1,
OVCAR-3, OVCAR-4, OVCAR-5, OVCAR-8, and SK-OV-3); renal
cancer (786-0, A498, ACHN, CAKI-1, RXF 393, SN12C, TK-10,
and UO-31); prostate cancer (PC-3 and DU-145); and breast cancer
(MCF7, MCF7/ADR-RES, MDA-MB-231/ATCC, HS 578T, MDA-
MB-435, MDA-N and T-47D).
e
Difference in log GI50 value for the least sensitive cell and the most
sensitive cell.
also show the quinolin-2(1H)-one substituted derivatives have
a strong growth inhibiting activities against leukemia cell lines,
with a log GI50 of less than Ϫ8.00 (GI50 value of less than 0.01
␮M) for compound 21e against RPMI-8226 cell. However,
these compounds are relatively inactive against non-small cell
lung cancer and CNS cancer cell lines.
The log GI50, log TGI, and log LC50 of different compounds,
expressed in the form of mean graph midpoint values, are listed
in Table 2. Comparison of the log GI50 mean graph midpoints
of 16a-f shows the ␥-substituted biphenyl compound, 2-(1,1Ј-
biphenyl-4-yl)-2,3,4,5-tetrahydro-4-methylene-2-[(naphthalen-2-
yloxy)methyl]-5-oxofuran (16f), with a GI50 of Ϫ5.72, is more
active than its 2-phenyl analogues 16b-e which in turn are more

718
Tzeng et al.
Table 2. Mean Values of the ␣-Methylene-␥-butyrolactones in the In
Vitro Disease-Oriented Anticancer Screena
The observed higher potency of quinoline derivatives than their
naphthalene counterparts is probably due to a higher affinity of
quinoline with DNA strands, an action of mechanism similar to
that of antimalarial chloroquine whose activity was attributed by
the intercalation of quinoline portion into DNA (26). Under such
circumstances, the quinoline became a carrier of the alkylating
␣-methylene-␥-butyrolactone, thus reducing the chance of its
reaction with other cell components and resulted in the enhance-
ment of the anticancer potency. The present results also show
that the constitutional isomers 16b,e,f and 18b,e,f respectively,
also possess comparable cytotoxicity. The selective cytotoxicity
of the compounds being evaluated in the present study (as repre-
sented by their average range of log GI50 values) show in a
decreasing order of 8-hydroxyquinoline (17, 2.45) Ͼ quinolin-
2(1H)-one (21, 2.12) Ͼ 2-methylquinoline (20, 1.98) Ͼ quinoline
(19, 1.90) Ͼ 2-naphthalene (16, 1.60) Ͼ benzene (15, 1.06).
Compd.
Log GI50
Log TGI
Log LC50
Range
15a
15b
Average
16a
16b
16c
16d
16e
16f
Average
17a
17b
17c
17d
17e
17f
Average
18b
18e
18f
Average
19a
19b
19c
19d
19e
19f
Average
20a
20b
20c
20d
20e
20f
Average
21a
21b
21c
21d
Ϫ4.48
Ϫ5.32
Ϫ4.90
Ϫ5.37
Ϫ5.48
Ϫ5.54
Ϫ5.61
Ϫ5.63
Ϫ5.72
Ϫ5.59
Ϫ5.52
Ϫ5.75
Ϫ5.66
Ϫ5.60
Ϫ5.58
Ϫ5.75
Ϫ5.64
Ϫ5.50
Ϫ5.77
Ϫ5.73
Ϫ5.67
Ϫ5.44
Ϫ5.84
Ϫ5.74
Ϫ5.83
Ϫ5.93
Ϫ5.93
Ϫ5.79
Ϫ5.44
Ϫ5.71
Ϫ5.62
Ϫ5.72
Ϫ5.77
Ϫ5.88
Ϫ5.69
Ϫ5.35
Ϫ5.91
Ϫ5.75
Ϫ5.89
Ϫ6.15
Ϫ6.27
Ϫ5.89
Ϫ4.05
Ϫ4.82
Ϫ4.44
Ϫ4.84
Ϫ5.00
Ϫ5.01
Ϫ5.05
Ϫ5.18
Ϫ5.23
Ϫ5.05
Ϫ4.98
Ϫ5.32
Ϫ5.22
Ϫ5.05
Ϫ4.97
Ϫ5.19
Ϫ5.12
Ϫ4.98
Ϫ5.30
Ϫ5.33
Ϫ5.20
Ϫ4.89
Ϫ5.29
Ϫ5.36
Ϫ5.42
Ϫ5.23
Ϫ5.50
Ϫ5.28
Ϫ4.91
Ϫ5.30
Ϫ5.06
Ϫ5.14
Ϫ5.35
Ϫ5.47
Ϫ5.21
Ϫ4.86
Ϫ5.54
Ϫ5.35
Ϫ5.48
Ϫ5.59
Ϫ5.78
Ϫ5.43
Ϫ4.01
Ϫ4.34
Ϫ4.18
Ϫ4.37
Ϫ4.52
Ϫ4.45
Ϫ4.54
Ϫ4.79
Ϫ4.68
Ϫ4.56
Ϫ4.37
Ϫ4.72
Ϫ4.56
Ϫ4.59
Ϫ4.47
Ϫ4.77
Ϫ4.58
Ϫ4.59
Ϫ4.66
Ϫ4.71
Ϫ4.65
Ϫ4.24
Ϫ4.53
Ϫ4.89
Ϫ4.87
Ϫ4.61
Ϫ4.91
Ϫ4.68
Ϫ4.30
Ϫ4.63
Ϫ4.54
Ϫ4.60
Ϫ4.79
Ϫ5.06
Ϫ4.65
Ϫ4.32
Ϫ5.07
Ϫ4.52
Ϫ4.98
Ϫ5.03
Ϫ5.26
Ϫ4.86
1.05
1.06
1.06
1.01
1.10
2.68
1.73
1.55
1.55
1.60
2.07
3.01
2.31
2.57
2.48
2.26
2.45
1.84
2.00
1.81
1.88
1.74
2.87
1.95
1.65
1.59
1.61
1.90
1.52
3.23
1.71
1.52
1.95
1.92
1.98
1.26
2.02
2.25
2.00
3.08
2.08
2.12
CONCLUSIONS
We have synthesized certain ␥-substituted ␥-aryloxy-
methyl-␣-methylene-␥-butyrolactones and evaluated for their
cytotoxicities. These compounds demonstrated a strong growth
inhibitory activity against leukemia cell lines but are relatively
inactive against non-small cell lung cancers and CNS cancers.
The ␣-methylene-␥-butyrolactone moiety may be considered
as the determinant pharmacophore for their activities, while the
substituents which included both aryl group and ␥-substituent,
are important and play a modulatory role in which the aryl
group is prefer to be quinolin-2(1H)-one and ␥-substituent
prefer to be a biphenyl. Among these ␣-methylene-␥-butyrolac-
tones, 8-{[2-(1,1Ј-biphenyl-4-yl)-2,3,4,5-tetrahydro-4-methyl-
ene-5-oxofuran-2-yl]methoxy}quinolin-2(1H)-one (21f ) is the
most potent with a mean log GI50 value of Ϫ6.27. The relatively
low activity of 21f as a vasorelaxing agent compared to that
of their ␥-methyl and ␥-phenyl counterparts (21a and 21b)
(18) can be advantageous because vasorelaxing effects will
otherwise become side effects when these compounds are used
as anticancer agents.
ACKNOWLEDGMENTS
21e
21f
Average
We gratefully acknowledge the National Science Council
of the Republic of China for financial support and the National
Cancer Institute (NCI) of the U.S. National Institute of Health
for anticancer screening.
a
GI50: Drug molar concentration causing 50% cell growth inhibition.
TGI: Drug concentration causing total cell growth inhibition (0%
growth). LC50: Drug concentration causing 50% cell death (Ϫ50%).
The concentration shown are mean values of the average sensitivity
of 60 cell lines toward the test agent.
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