Synthesis and in vitro antitumor activity of 4(3H)-quinazolinone derivatives with dithiocarbamate side chains

Article abstract of DOI:10.1016/j.bmcl.2005.01.083

A series of 4(3H)-quinazolinone derivatives with dithiocarbamate side chains were synthesized and tested for their in vitro antitumor activity against human myelogenous leukemia K562 cells. Among them, (3,4-dihydro-2-methyl-4- oxoquinazolin-6-yl)methyl 4-(4-fluorophenyl)piperazine-1-carbodithioate 8q exhibited significant inhibitory activity against K562 cells with IC ₅₀ value of 0.5 μM.

Full text of DOI:10.1016/j.bmcl.2005.01.083

Bioorganic & Medicinal Chemistry Letters 15 (2005) 1915–1917
Synthesis and in vitro antitumor activity of
(3H)-quinazolinone derivatives with dithiocarbamate side chains
4
a,
Sheng-Li Cao, Yu-Ping Feng, Yu-Yang Jiang, Shi-Ying Liu,
b
b
b
*
b
Guo-Yu Ding and Run-Tao Li
c
a
Department of Chemistry, Capital Normal University, Beijing 100037, China
b
Department of Chemistry, Tsinghua University, Beijing 100084, China
School of Pharmaceutical Sciences, Peking University, Beijing 100083, China
c
Received 22 August 2004; revised 29 January 2005; accepted 31 January 2005
Abstract—A series of 4(3H)-quinazolinone derivatives with dithiocarbamate side chains were synthesized and tested for their in vitro
antitumor activity against human myelogenous leukemia K562 cells. Among them, (3,4-dihydro-2-methyl-4-oxoquinazolin-6-yl)-
methyl 4-(4-fluorophenyl)piperazine-1-carbodithioate 8q exhibited significant inhibitory activity against K562 cells with IC50 value
of 0.5 lM.
Ó 2005 Elsevier Ltd. All rights reserved.
Structure modification of folic acid led to the discovery
of a number of antifolates as efficient anticancer agents.
For example, Methotrexate (1) (Fig. 1), an inhibitor of
dihydrofolate reductase, has been used clinically for
the treatment of leukemia and solid tumors in children
by mutation, and toxicity to the host, which is due to
4
unnecessarily long retention inside normal cells. One
strategy to overcome these shortcomings is to design
nonclassical lipophilic inhibitors of folate requiring en-
zymes by deleting or modifying L-glutamic acid compo-
1
2,3
5,6
and adults for several decades. Raltitrexed (2) (Fig.
), which is an inhibitor of thymidylate synthase has
nent from the folate analogues.
1
7
been registered widely for the first-line treatment of ad-
vanced colorectal cancer. However, these so-called clas-
sical antifolates containing L-glutamic acid moiety in the
molecule have shortcomings such as drug resistance,
which have originated from the defective cell transport
Recently, Brassinin (3) (Fig. 1), a dithiocarbamate iso-
lated from cabbage, was reported to have cancer chemo-
preventive activity, and its structural modification led to
the design and synthesis of a potential cancer chemopre-
8
ventive agent Sulforamate (4) (Fig. 1). More recently, a
Figure 1. Structures of Methotrexate (1), Raltitrexed (2), Brassinin (3), and Sulforamate (4).
Keywords: 4 ( 3H )-Quinazolinone; Dithiocarbamate; Antitumor activity; K562 cells.
*
Corresponding author. Tel.: +86 10 6890 2974; fax: +86 10 6890 2493; e-mail: caoshengli@tsinghua.org.cn
0
960-894X/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2005.01.083

1916
S.-L. Cao et al. / Bioorg. Med. Chem. Lett. 15 (2005) 1915–1917
series of dithiocarbamate compounds have been synthe-
sized and found to possess in vitro and in vivo antitumor
leukemia K562 cells by MTT (3-(4,5-dimethylthiazo-2-yl)-
2,5-diphenyl-tetrazolium bromide) assay. The assays
were performed in 96-well plates as described in the lit-
erature. The IC50 value represents the concentration,
which results in a 50% decrease in cell growth after
24h incubation.
9
,10
activity.
In an effort to look for the possible nonclas-
1
3
sical antifolates acting as antitumor agents, we were
interested in the incorporation of dithiocarbamate moi-
ety with 4(3H)-quinazolinone. Herein, we report the
synthesis of 4(3H)-quinazolinone derivatives with dithio-
carbamate side chains and their in vitro antitumor
activity against human myelogenous leukemia K562
cells.
The inhibitory activity of the synthesized compounds
against K562 cells is summarized in Table 1. Methotrex-
ate (1) and Brassinin (3) were used for comparison. The
results demonstrated that compounds 8a–q exhibited
potent cytotoxicity and are more potent than Metho-
trexate and Brassinin in inhibiting K562 cell growth
with IC50 values from 0.5 to 31.0 lM. Comparing com-
pounds 8a,d with 8b, 8c, and 8e, it can be seen that com-
pounds containing secondary amine moiety have
stronger activities than those containing primary amine
moiety. However, compounds containing benzyl or fur-
furyl primary amine moiety (8f,g) have strong activities.
Furthermore, compounds 8i,j have stronger activities
than 8h, also suggesting that the introduction of an aryl
group into amino moiety resulted in the enhancement of
anti-K562 cell activity. When the oxygen atom was
introduced into the piperidine ring, the resulting com-
pounds 8k,l were more active than parent compound
8h. As shown in Table 1, compounds 8o, 8p, and 8q hav-
ing aryl or arylalkyl group at the 4-position of piper-
azine ring have stronger activities than 8n with methyl
at 4-position of piperazine ring, moreover, introduction
The procedure for the synthesis of compounds 8a–q is
outlined in Scheme 1. Heating 2-amino-5-methylbenzoic
1
1
acid with thioacetamide yielded 2,6-dimethyl-4(3H)-
quinazolinone (5), which was converted to 6-bromo-
methyl-2-methyl-4(3H)-quinazolinone (6) by brominat-
ing with N-bromosuccinimide in the presence of
(
od for dithiocarbamates, compounds 8a–q were ob-
PhCO) O . According to the improved synthetic meth-
2 2
1
2
tained by the reaction of 6-bromomethyl-2-methyl-
4
in the presence of anhydrous K PO . For the prepara-
(3H)-quinazolinone with CS and various amines (7)
2
3
4
tion of compounds 8e and 8o, 1-adamantylamine hydro-
chloride and N-benzylpiperazine hydrochloride was
used, respectively, without previous neutralization by
the tertiary amine.
The synthesized compounds 8a–q were tested for their in
vitro antitumor activity against human myelogenous
Scheme 1. Synthesis of compounds 8a–q. Reagents and conditions: (a) CH
3
CSNH
2
2 2
, 135–150 °C, 2 h, 73%; (b) N-bromosuccinimide, (PhCO) O ,
3 2 3 4
CHCl , reflux 3 h, 77%; (c) CS , K PO , DMF, rt, 2 h, 51–94%.

S.-L. Cao et al. / Bioorg. Med. Chem. Lett. 15 (2005) 1915–1917
1917
Table 1. In vitro cytotoxicity of compounds 1–4, 8a–q against K562
cells
(Grant No 2002KJ091) and the Ministry of Education,
China.
Compd
IC50 (lM)
1
2
3
4
419
NA
a
References and notes
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f
4.4
25.6
31.0
7.6
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3.7
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4.3
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of fluorine atom into the aromatic ring obviously en-
hanced the activity and resulted in the compound 8q
possessing the strongest inhibitory activity against
K562 cells.
0
1
1
004, 9, 59.
In summary, we have designed and synthesized a series
of 4(3H)-quinazolinone derivatives with dithiocarba-
mate side chains. The preliminary in vitro antitumor
activity tests indicated that among the synthesized com-
pounds, 8q exhibited significant inhibitory activity
against K562 cells in culture.
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Chin. Sci. Bull. 2003, 48, 869.
1
1
4. Selected data for compound 8q: mp 246–248 °C; H NMR
(
200 MHz, CDCl
N(CH ), 4.13 (br s, 2H, NCH
.74 (s, 2H, CH S), 6.94(m, 4H , Ph–H), 7.63 (d, 1H,
J = 8.5 Hz, quinazolinone 8-H), 7.82 (dd, 1H, J = 8.5 and
.1 Hz, quinazolinone 7-H), 8.26 (d, 1H, J = 2.1 Hz,
3
) d 2.56 (s, 3H, CH
3
), 3.2 (t, 4H,
2
)
2
2
), 4.42 (br s, 2H, NCH
2
),
4
2
Acknowledgements
2
+
This research was financially supported by the Natural
Science Foundation of Beijing City (Grant No 7002006
and 7042006), the Education Committee of Beijing City
quinazolinone 5-H); ESIMS m/z 429.3 (MH ). Anal.
Calcd for C H FN OS : C 58.86%, H 4.94%, N
13.07%. Found: C 58.84%, H 4.99%, N 12.93%.
2
1
21
4
2