Synthesis and radioprotective effects of adamantyl substituted 1,4-dihydropyridine derivatives

Article abstract of DOI:10.1016/S0968-0896(98)00017-0

A series of 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid diesters substituted at the N-1 and/or C-4 positions of the dihydropyridine ring was synthesized. The in vitro cytotoxicity and in vitro and in vivo radioprotective efficacy of these agents were evaluated in Chinese hamster (V-79) cells and CD2F1 male mice, respectively. Compounds with at least one adamantyl substituent afforded better radioprotection than those without this substituent. Substitution of an aromatic ring at the C-4 position of the dihydropyridine ring did not enhance the radioprotectant action of the compounds. Copyright (C) 1998 Elsevier Science Ltd.

Full text of DOI:10.1016/S0968-0896(98)00017-0

BIOORGANIC &
MEDICINAL
CHEMISTRY
Bioorganic & Medicinal Chemistry 6 (1998) 563±568
Synthesis and Radioprotective E€ects of Adamantyl Substituted
1,4-Dihydropyridine Derivatives
Isaac O. Donkor,a,* Xiaoxin Zhou,b Je€ery Schmidt,c
Krishna C. Agrawalc and Vimal Kishoreb
aDepartment of Pharmaceutical Sciences, College of Pharmacy, The University of Tennessee, Memphis, TN 38163, USA
bCollege of Pharmacy, Xavier University of Louisiana, New Orleans, LA 70125, USA
cDepartment of Pharmacology, Tulane University School of Medicine, New Orleans, LA 70112, USA
Received 11 August 1997; accepted 7 November 1997
AbstractÐA series of 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid diesters substituted at the N-1 and/or C-4
positions of the dihydropyridine ring was synthesized. The in vitro cytotoxicity and in vitro and in vivo radioprotective
ecacy of these agents were evaluated in Chinese hamster (V-79) cells and CD2F1 male mice, respectively. Compounds
with at least one adamantyl substituent a€orded better radioprotection than those without this substituent. Substitu-
tion of an aromatic ring at the C-4 position of the dihydropyridine ring did not enhance the radioprotectant action of
the compounds. # 1998 Published by Elsevier Science Ltd. All rights reserved.
Introduction
We have synthesized and examined the structure±
activity relationships for introduction of substituents at
the N-1 and C-4 positions of the dihydropyridine ring of
1 (see Chart 1). A 2-chlorophenyl moiety was selected as
the C-4 substituent because Lehuede and coworkers7
have recently demonstrated that incorporation of aro-
matic rings into the dihydropyridine ring increases the
free radical scavenging ability of the compounds. Thus,
the 2-chlorophenyl group could potentially increase the
radioprotective e€ect of 1 by enhancing its free radical
scavenging ability.7 Additionally, the 2-chlorophenyl
moiety has been shown to stabilize dihydropyridines
towards hepatic metabolism.8
Radiation accidents such as the one that occurred at
Chernobyl and increasing use of nuclear techniques in
military and medical settings continue to fuel the need
for safe and e€ective radioprotective agents. Phosphor-
othioate derivatives, such as S-[2-(3-aminopropyl)-amino-
ethyl]phosphorothioic acid ester (WR 2721), have
demonstrated signi®cant radioprotective e€ects.1±3
Although these sulfhydryl-containing compounds are
e€ective radioprotectors, they have a narrow ther-
apeutic index and are plagued by signi®cant side e€ects
even at low doses.4 The search for more e€ective and
less toxic radioprotectants has spurred interest in the
development of nonsulfur-based compounds. Recently,
diadamantyl-2,6-dimethyl-1,4-dihydropyridine-3,5-di-
carboxylic acid diester (1) was reported as a nonsulfur-
based synthetic radioprotective agent.5 The compound
demonstrated low toxicity and high radioprotective
activity against ionizing irradiation in mice and rats.
The adamantyl group has also been shown to enhance
the activity of other radioprotectors, notably the mer-
captoacetamidine phosphorothioates and disul®des.6
Results and Discussion
Chemistry
Synthesis of the key intermediate, adamantyl acet-
oacetate (11), is shown in Scheme 1. Adamantyl acetate
(10) was prepared from 1-adamantanol (8) and acetic
anhydride (9) with zinc chloride as the catalyst. Com-
pound 10 was transformed to 11 in the presence of
sodium and acetic acid. Hantzsch's procedure was
adopted to synthesize the 2,6-dimethyl-1,4-dihydropyr-
idine-3,5-dicarboxylic acid diesters 1±7 (Chart 1).9
Key words: Radioprotectors; adamantyl; dihydropyridine;
radiation; ionizing.
*Corresponding author.
0968-0896/98/$19.00 # 1998 Published by Elsevier Science Ltd. All rights reserved
PII: S0968-0896(98)00017-0

564
I. O. Donkor et al./Bioorg. Med. Chem. 6 (1998) 563±568
Scheme 1.
Brie¯y, two equivalents of the appropriate alkyl aceto-
acetate were reacted with one equivalent of the appro-
priate aldehyde and one equivalent of ammonium
hydroxide or the appropriate alkylamine in methanol
(Scheme 2). The reaction mixtures were re¯uxed for 6 h
to obtain the corresponding 1,4-dihydropyridine deriva-
tive. Final products were puri®ed by column chroma-
tography and/or recrystallization.
study are shown in Table 1. Compound 1 with a DMF
of 1.71 exhibited the highest radioprotective e€ect.
None of the analogs was as e€ective as 1. Compounds
2±4 demonstrated moderate DMF (1.32 to 1.45) while 5
and 6 had little e€ect. It should be noted that com-
pounds 1±4 have 1 or 2 adamantyl substituents while 5
and 6 lack the same. This observation corroborates
previous reports that adamantyl groups may be impor-
tant in the radioprotective action of 1,4-dihydropyr-
idines.5 Since the position of the adamantyl moiety is
signi®cantly di€erent from each other in compounds 1
and 3, it appears that the lipophilic e€ects of the ada-
mantyl group may be more important than its spatial
location.
Radioprotection evaluation
The cytotoxicity and radioprotective e€ects of the dihy-
dropyridine derivatives were initially determined in vitro
against Chinese hamster (V-97) cells. The results of
these studies are summarized in Table 1. All of the
compounds were essentially nontoxic at the concentra-
tions employed in these experiments against Chinese
hamster (V-79) cells except compound 2 which caused
approximately 28% inhibition in the colony forming
ability of the cells at 0.1 mM. The data indicate that the
substitution of a 2-chlorophenyl group at the C-4 posi-
tion of the dihydropyridine ring and the presence of
adamantyl esters at the 3 and 5 positions (as in com-
pound 2) appear to enhance the cytotoxicity of the
resulting derivative. All the other derivatives which were
either methyl esters (compounds 3±6) or lacked 2-chlor-
ophenyl group at the C-4 position were comparatively
less toxic to the cells at the highest concentration of
0.1 mM than was compound 2.
The compounds were evaluated in vivo for their radio-
protective e€ects using male CD2F1 mice. Thirty day
survival and mean survival times (MST) are reported in
Table 1. In comparison to vehicle treated mice which
had a MST of 7.7 days, all of the compounds except 6
showed a signi®cant increase in MST (from 12.8 days
for 7 to 18.3 days for 2). In comparison to 1, however,
none of the new compounds were signi®cantly more
active. In agreement with the results of the in vitro stu-
dies, the adamantyl group a€orded greater radio-
protective e€ects to the compounds.
The objective of this study was to determine if structural
analogs of 1 would a€ord similar or better radio-
protection to mice. The in vitro and in vivo results
indicate that the structural modi®cations reported in
this study resulted in no signi®cant improvement in the
radioprotective e€ect. The results, however, reveal that
while the position of substitution of the adamantyl
group on the 1,4-dihydropyridine ring is not critical, its
presence does enhance radioprotection in comparison to
In vitro radioprotective e€ects of the compounds were
studied with Chinese hamster (V-79) cells at a nontoxic
dose of 0.05 mM. The dose modifying factor (DMF)
was calculated from the radiation survival curve gener-
ated for each compound tested. The higher the DMF,
the greater the radioprotective e€ect. The results of this

I. O. Donkor et al./Bioorg. Med. Chem. 6 (1998) 563±568
565
similar compounds lacking this group. This ®nding is in
agreement with earlier reports that the adamantyl moi-
ety enhances the radioprotective e€ects of potential
radioprotectants.5,6 Our results are however, at odds
with an earlier report7 which indicated that substitution
of aromatic rings in dihydropyridines increases their free
radical scavenging ability. Based on the earlier report,7
we introduced a 2-chlorophenyl moiety at the 4-position
of the dihydropyridine ring of 1 (as in compound 2) but
did not observe enhancement in the radioprotective
e€ect of 1 with respect to 30-day survival.
The recognized mechanism of action of dihydropyridine
calcium channel blockers is the inhibition of the entry of
calcium ions across the cell membrane. The mechanism
of action of these compounds as radioprotective agents
has not been fully investigated. However, it has been
suggested that this class of agents may interfere with the
damaging e€ects of intracellular in¯ux of calcium after
membrane injury by radiation-induced free radicals.10
Alternatively, the calcium antagonists may also directly
inactivate free radicals.11
Experimental
All chemicals were purchased from Aldrich Chemical
Company (Milwaukee, WI, USA.). Solvents were dried
prior to use when necessary. Tetrahydrofuran was
freshly distilled from sodium and benzophenone. Melt-
ing points were determined on a HAAKE micromelting
point apparatus and are uncorrected. Proton NMR
spectra were recorded on a 500 MHz GE NMR Spec-
trometer, and values are reported in parts per million
(ppm) from Me4Si. Thin layer chromatography (TLC)
was performed on precoated silica gel plates (Sigma
Chemical Company, St. Louis, MO, USA.). The com-
pounds were visualized at 254 nm under an UV lamp.
Column chromatography was performed with silica gel
60 A (230±400 mesh, Aldrich, Milwaukee, WI). Ele-
mental analyses (C,H,N) were performed at M-H-W
Laboratories (Phoenix, AZ, USA.) and are within 0.4%
of the theoretical values.
Chart 1.
Adamantyl acetate (10). A mixture of 1-adamantanol
(7.6 g, 50 mmol), acetic anhydride (50 mL) and zinc
Scheme 2.

566
I. O. Donkor et al./Bioorg. Med. Chem. 6 (1998) 563±568
Table 1. Cytotoxicity and radioprotective e€ects of dihydropyridine derivatives
Compound
Cytotoxicity
Conc. (mM)
Survival (%)
In vitro DMFa
Doseb
200
In vivo survivorsc
MSTc
T/C%d
pe
Control
WR2721
NAf
0.1
NA
1.40
0/10
8/10
7.7‹0.9
27.4‹1.8
NA
263
Ð
<0.001
100.0
2.0
0.0
0.5
1.0
1
2
3
4
5
6
7
0.01
0.05
0.1
91.6
83.5
90.0
86.1
79.3
72.2
91.8
93.3
90.0
87.8
86.9
85.4
95.4
85.0
83.0
96.1
91.9
90.5
NDf
ND
ND
1.71
1.35
1.45
1.32
1.13
1.02
ND
23.3
28.9
18.6
24.2
16.8
17.5
18.9
3/10
2/10
3/10
1/10
1/10
0/10
0/10
19.1‹2.6
18.3‹3.1
17.9‹2.6
14.0‹1.9
13.3‹2.0
9.1‹1.1
248
238
286
182
173
118
166
0.002
0.005
0.004
0.012
0.039
>0.1
0.070
0.01
0.05
0.1
0.1
0.05
0.1
0.01
0.05
0.1
0.01
0.05
0.1
0.01
0.05
0.1
0.01
0.05
0.1
12.8‹2.4
aDose modifying factor (DMF) was determined by dividing the Do value (the radiation dose required to reduce the survival by a factor
of 0.37 in the exponential region of the curve) obtained from the radiation survival curve in the presence of a radioprotective agent by
the Do value obtained from the control radiation survival curve. The drug concentration used in radioprotective activity study on
Chinese hamster (V-79) cells was 0.05 mM.
bThe dose is in mg/kg and was based on 0.05 mmol/kg for all the compounds except for WR2721, which was based on 1 mmol/kg.
c30-Day survival and mean survival time (MST)‹S.E.M. were evaluated at 10 Gy. Mice surviving more than 30 days were counted as
30 day survivors in the calculation of MST.
dT/C%=MST of treated mice (T) divided by MST of control mice (C) multiplied by 100.
ep value for a two-sample t-test with unequal variances.
fnd=not determined; na=not applicable.
chloride (0.1 g) was re¯uxed with stirring for 4 h. The
reaction mixture was allowed to cool to room tempera-
ture and the pH was adjusted to 10 with 6 N potassium
carbonate followed by extraction with ethyl acetate
(3Â30 mL). The combined organic extracts were dried
over sodium sulfate and evaporated to dryness. The
resulting residue was puri®ed by column chromato-
graphy with methylene chloride as the eluant to give
6.6 g (68%) of 10 as a colorless liquid. 1H NMR
(CDCI3) d 1.65 (m, 6H, adamantyl), 1.95 (s, 3H, CH3),
2.08 (d, 6H, adamantyl), 2.14, (br. s, 3H, adamantyl).
and the mixture was extracted with ethyl acetate
(3Â20 mL). The combined extracts were dried over
sodium sulfate and evaporated to dryness. The resulting
residue was puri®ed by column chromatography using
methylene chloride as an eluant to give 0.78 g (22%) of
11 as a colorless liquid. H NMR (CDCI3) d 1.64±2.15
(m, 15H, adamantyl), 2.22 (s, 3H, CH3), 3.33 (s, 2H,
CH2).
1
General procedure for the preparation of 2,6-dimethyl-
1,4-dihydropyridine-3,5-dicarboxylates (1±7). A mixture
of the appropriate alkyl acetoacetate (12, 2.2 mmol), the
appropriate aldehyde (13, 1 mmol), and concentrated
ammonium hydroxide or the appropriate amine (14,
1 mmol) in methanol (100 mL) was re¯uxed for 6 h. The
mixture was allowed to cool to room temperature and
the resulting solid was ®ltered and puri®ed by either
Adamantyl acetoacetate (11). A mixture of adamantyl
acetate (10, 6 g, 31 mmol) and sodium metal (0.36 g,
15 mmol) cut into small pieces were gently heated and
stirred under nitrogen until the mixture solidi®ed. After
cooling, 20 mL of 50% aqueous acetic acid was added

I. O. Donkor et al./Bioorg. Med. Chem. 6 (1998) 563±568
567
recrystallization or column chromatography to yield the
corresponding 1,4-dihydropyridine derivative (15).
obtained in 34% yield after recrystallization from
methylene chloride:methanol (1:1). Melting point 134 ꢀC
(dec.). H NMR (CDCI3) d 1.56 (s, 3H, CH3), 1.80 (s,
1
Diadamantyl-2,6-dimethyl-1,4-dihydropyridine-3,5-dicar-
boxylate (1). Compound 1 was obtained in 45% yield
after recrystallization from methylene chloride/metha-
nol mixture. Melting point 216 ꢀC (dec.). 1H NMR
(CDCI3) d 1.62±2.22 (m, 30H, adamantyl), 2.25 (s, 6H,
2,6-dimethyl), 2.78 (s, 2H, CH2), 4.82 (br. s 1H, NH).
Anal. calcd for C29H39NO4: C, 74.80; H, 8.40; N, 3.01.
Found: C, 74.60; H, 8.04; N, 2.94.
3H, CH3), 3.00 (s, 3H, N-CH3), 3.50 (s, 3H, COOCH3),
3.73 (s, 3H, COOCH3), 6.26 (s, 1H, 4-CH), 7.03±7.34
(m, 4H, aromatic). Anal. calcd for C18H20ClNO4: C,
61.80; H, 5.76; N, 4.00. Found: C, 62.08; H, 5.79; N, 3.99.
Diethyl-2,6-dimethyl-N-methyl-4-(2-chlorophenyl)-1,4-
dihydropyridine-3,5-dicarboxylate (7). Compound 7 was
obtained in 40% yield after recrystallization from
methylene chloride:methanol (1:1). Melting point 128±
129 ꢀC. 1H NMR (CDCI3) d 1.20 (t, 6H, CH3 of 3,5-
diCOOCH2CH3), 2.41 (s, 6H, 2,6-dimethyl), 3.21 (s,
3H, N-CH3), 4.05±4.14 (m, 4H, CH2 of 3,5-di-
COOCH2CH3), 5.56 (s, 1H, 4-CH), 7.06±7.25 (m, 4H,
aromatic). Anal. calcd for C20H24ClNO4: C, 63.57; H,
6.40; N, 3.71. Found: C, 63.70; H, 6.39; N, 3.71.
Diadamantyl-2,6-dimethyl-4-(2-chlorophenyl)-1,4-dihydro-
pyridine-3,5-dicarboxylate (2). Compound
2
was
obtained in 31% yield after puri®cation by column
chromatography with methylene chloride as the eluant.
Melting point 135 ꢀC (dec.). H NMR (CDCI3) d 1.64±
1
2.16 (m, 30H, adamantyl), 2.27 (s, 6H, 2,6-dimethyl),
5.36 (s, 1H, 4-CH), 5.53 (s, 1H, NH), 7.17±7.41 (m, 4H,
aromatic). Anal. calcd for C35H42ClNO4: C, 72.96; H,
7.35; N, 2.43. Found: C, 72.74; H, 7.16; N, 2.32.
Evaluation of in vitro radioprotective e€ects
The cytotoxicity and radioprotective ecacy of the
dihydropyridine derivatives were determined using
asynchronous exponentially growing monolayer cul-
tures of Chinese hamster (V-79) cells. The methods of
culturing and measuring cell survival by colony forma-
tion were reported previously by Agrawal et al.12 V-79
cells were grown in Eagle's minimum essential medium
(MEM) with 15% fetal bovine serum. For cytotoxicity
studies, approximately 250 cells were plated in petri
dishes (60Â15 mm) containing 3 mL of medium and were
allowed to attach for 2 h. The medium was then removed
by aspiration and replaced with 3 mL of medium with-
out drug (controls) or containing the various concentra-
tions of the drugs. The plates were incubated for 2 h at
37 ꢀC. At the end of a 2 h period, the medium containing
the drug was removed and replaced with 3 mL of fresh
medium. The cultures were then incubated for 6 days at
37 ꢀC in an atmosphere of 95% air and 5% CO2. The
resulting colonies were ®xed in absolute ethanol, stained
with methylene blue, and counted.
Dimethyl-2,6-dimethyl-N-(1-adamantylmethyl)-1,4-di-
hydropyridine-3,5-dicarboxylate (3). Compound 3 was
obtained in 69% yield after puri®cation by column
chromatography with ethyl acetate:hexane (1:4) as the
eluant. Melting point 78±84 ꢀC (dec.). 1H NMR
(CDCI3) d 1.52±1.98 (m, 15H, adamantyl), 1.88 (s, 6H,
2,6-dimethyl), 2.83 (s, 2H, 4-CH2), 3.62 (s, 6H, 3,5-
diCOOCH3), 4.41 (s, 2H, N-CH2). Anal. calcd for
C22H31NO4: C, 70.75; H, 8.37; N, 3.75. Found: C,
70.46; H, 8.37; N, 3.86.
Dimethyl-2,6-dimethyl-N-(1-adamantylmethyl)-4-(2-chloro-
phenyl)-1,4-dihydropyridine-3,5-dicarboxylate (4). Com-
pound 4 was obtained in 65% yield after recrystallization
from methylene chloride/methanol mixture. Melting
point 148±151 ꢀC. 1H NMR (CDCI3) d 1.55±2.03
(m, 15H, adamantyl), 1.80 (s, 6H, 2,6-dimethyl), 3.01
(m, 2H, N-CH2), 3.52 (s, 3H, COOCH3), 3.70 (s, 3H,
COOCH3), 6.23 (s, 1H, 4-CH), 7.09±7.28 (m, 4H, aro-
matic). Anal. calcd for C28H34ClNO4: C, 69.47; H, 7.08;
N, 2.89. Found: C, 69.62, H, 6.86, N, 2.82.
To determine in vitro radioprotective activity, varying
numbers of cells were plated to provide approximately
200 colonies after exposure to various doses of irradia-
tion (Gammacell 40 irradiator containing Cs-137
source, Nordion International, Ontario, Canada). The
cell survival curves were generated for each compound
after exposing the cells to 0.05 mM concentration of
each drug under aerobic conditions at the radiation
doses of 2 to 14 Gy. The Do value (the radiation dose
required to reduce the survival by a factor of 0.37 in the
exponential region of the curve) was calculated for each
compound, and the ratio of the Do value of drug treated
cells to the Do value of the control cells provided the
dose modifying factor (DMF) for each compound. The
Dimethyl-2,6-dimethyl-4-(2-chlorophenyl)-1,4-dihydropyr-
idine-3,5-dicarboxylate (5). Compound 5 was obtained
in 60% yield after recrystallization from methylene
chloride/methanol. Melting point 192±193 ꢀC. 1H NMR
(CDCI3) 2.31 (s, 6H, 2,6-dimethyl), 3.60 (s, 6H, 3,5-
diCOOCH3), 5.29 (s, 1H, 4-CH), 5.64 (br. s, 1H, NH),
7.03±7.36 (m, 4H, aromatic). Anal. calcd for
C17H18ClNO4: C, 60.81; H 5.40; N, 4,17. Found: C,
61.00; H, 5.42; N, 4.56.
Dimethyl-2,6-dimethyl-N-methyl-4-(2-chlorophenyl)-1,4-
dihydropyridine-3,5-dicarboxylate (6). Compound 6 was

568
I. O. Donkor et al./Bioorg. Med. Chem. 6 (1998) 563±568
Do value for the control cells under these conditions
was 2.3 Gy.
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