Bioorganic & Medicinal Chemistry Letters
Amino(oxo)acetate moiety: A new functional group to improve the
cytotoxicity of betulin derived carbamates
a
a
a
b
a,
⇑
Lucie Heller , Vincent Perl , Jana Wiemann , Ahmed Al-Harrasi , René Csuk
a
Martin-Luther-University Halle-Wittenberg, Organic Chemistry, Kurt-Mothes-Str. 2, D-06120 Halle (Saale), Germany
University of Nizwa, Chair of Oman’s Medicinal Plants and Marine Natural Products, PO Box 33, Birkat Al-Mauz, Nizwa, Oman
b
a r t i c l e i n f o
a b s t r a c t
Article history:
While 3-O-acetylated betulin derivatives carrying a carbamate moiety at position C-28 are of rather low
Received 4 March 2016
Revised 17 April 2016
Accepted 20 April 2016
Available online xxxx
cytotoxicity for human tumor cell lines, the corresponding C-3 amino(oxo) acetates show good cytotox-
icity. For example, an EC50 as low as 2.0
29)-en-3-yl amino(oxo)acetate (16) employing the ovarian cancer cell line A2780.
Ó 2016 Elsevier Ltd. All rights reserved.
lM was found for (3b) 28-{[(hexylamino)carbonyl]oxy}lup-20
(
Keywords:
Betulin
Cytotoxicity
Triterpene
Cancers are a family of diseases, and one of the hallmarks of
cancer is a continuous and unregulated growth of cells leading
either to a solid tumor or to diffusely spread cells. In Europe, North
America and parts of Asia nearly half of people diagnosed with
cancer and receiving a treatment die of cancer or because of the
treatment. Cancer can be treated and even cured either by surgery,
application of radiation, immunotherapy or by chemotherapy.
Although it is indisputable that notable progress and major
achievements in the therapy of all kinds of cancer have been made
by chemotherapy, but there remains the need to search for new
chemotherapeutics. Starting several decades ago, natural product
derived compounds made their way into modern anticancer
chemotherapy, and nowadays they play a major role in developing
new cytotoxic agents. Among these natural products, many
Figure 1. Structure of betulin (BN) and betulinic acid (BA).
1
–8
terpenoids
finding new therapeutic drugs
preventive agents
have shown to act as excellent starting points for
2,3,5,6,8
and even as potential chemo-
During our search for new cytotoxic
1
,4–7
obtain in huge amounts from extracting birch bark, and it is an
interesting scaffold for accessing derivatives displaying various
biological properties. For example, in HeLa cancer cells BN, unlike
BA, seems to trigger apoptosis through an intrinsic pathway by a
sequential activation of caspase-9 and caspase 3/-7 and the cleav-
compounds derived from secondary natural products, we became
9
interested in triterpenoic acids (cf. betulinic acid (BA), boswellic
1
0,11
12
13
14
acid,
glycyrrhetinic acid, maslinic acid, oleanolic acid,
1
4
15
ursolic acid, tormentic acid and others) and other triterpenes
2
6
age of poly-(ADP-ribose)-polymerase. Recently, BN derived car-
(
cf. betulin, BN, Fig. 1). Interestingly enough, while there are many
16–22
bamates came into the focus of scientific interest because of their
reports on the cytotoxicity of BA or derivatives,
BN is of
2
7–31
increased cytotoxic activity
and an improved therapeutic
reduced cytotoxicity, and the number of betulin derived cytotoxic
3
0,32
derivatives remained limited.2
3–25
index. Hence, we decided to have a closer look onto this class
of compounds, and to explore their cytotoxic properties.
3
2
Apart from the fact that BN is a cheap, renewable resource usu-
ally obtained from agro-industrial waste. Thus, BN is easily to
Following well known procedures, BN was acetylated and diac-
etate 1 was obtained in excellent yields (Scheme 1). A regioselective
and partial deacetylation of 1 with KOH in a mixture of THF and
⇑
Corresponding author.
960-894X/Ó 2016 Elsevier Ltd. All rights reserved.
0