Platanic Acid-Aryl Enones as Potential Anticancer Compounds: Synthesis and Biological Profiling against Breast, Prostate and Lung Cancer Cell Lines

Article abstract of DOI:10.1002/cbdv.202100292

A series of rationally designed platanic acid-based compounds derived from naturally occurring betulinic acid were synthesized through a sequence of Lemieux-Johnson oxidation and Aldol condensation reaction. All the compounds were screened for cytotoxicity against a panel of human cancer and normal cell lines using MTT assay. From the biological data, it was observed that some of these semi-synthetic congeners exhibited potent biological profiles compared to platanic acid. One of the compounds with the p-tolyl substitution was found to be most active in this study, and its cytotoxicity against two of the cell lines, MDA-MB 231 and A-549 were in tune with the standard compound, 5-fluorouracil.

Full text of DOI:10.1002/cbdv.202100292

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FULL PAPER
Platanic Acid-Aryl Enones as Potential Anticancer Compounds:
Synthesis and Biological Profiling against Breast, Prostate and Lung
Cancer Cell Lines
Bilal Ahmad Ganaie,a, b Mir Shahid,b, c Auqib Rashid,b Tabassum Ara,a Javid Ahmad Banday,a
Fayaz Malik,b, c and Bilal A. Bhat*b, c
a
National Institute of Technology, Hazratbal, Srinagar, 190006, India
b
CSIR-Indian Institute of Integrative Medicine, Jammu & Kashmir, 190005, India, e-mail: bilal@iiim.res.in
c
Academy of Scientific & Innovative Research (AcSIR), Ghaziabad, 201002, India
A series of rationally designed platanic acid-based compounds derived from naturally occurring betulinic acid
were synthesized through a sequence of Lemieux-Johnson oxidation and Aldol condensation reaction. All the
compounds were screened for cytotoxicity against a panel of human cancer and normal cell lines using MTT
assay. From the biological data, it was observed that some of these semi-synthetic congeners exhibited potent
biological profiles compared to platanic acid. One of the compounds with the p-tolyl substitution was found to
be most active in this study, and its cytotoxicity against two of the cell lines, MDA-MB 231 and A-549 were in
tune with the standard compound, 5-fluorouracil.
Keywords: platanic acid, arylenones, cytotoxicity, Aldol condensation, Lemieux-Johnson oxidation.
Introduction
tumors.[12–16] The mechanism of action involves
Natural products and their derived semi-synthetic mitochondrial membrane permeabilization with the
congeners act as a source of many drugs and drug release of factors like cytochrome-c, Smac, or AIF in a
candidates.[1,2] Among the natural products, pentacy- permeability transition pore-dependent manner, acti-
clic triterpenes are regarded as an important class of vating caspases and nuclear fragmentation and also in
compounds due to their unique biological certain cases inducing apoptosis.[5,17–20] The antitumor
potentials.[3,4] For example, betulinic acid (1), a lupane- properties of betulinic acid motivated chemists to
type triterpene isolated from various plant sources, access its structurally modified analogs and studies
had been extensively studied for its anticancer related to its structure-activity relationship have been
potential against a range of tumors and tumor cell explored for the past several years quite thoughtfully.
lines.[5–8] Additionally, this compound also exhibited It is to note that many betulinic acid derived
other pharmacological properties like anti-HIV, anti- derivatives have been prepared, and some of them
inflammatory, antibacterial, antimalarial, antitrypano- exhibited increased cytotoxicity potential.[21–23] One of
somal, and analgesic activity.[9–11] The action of its products, platanic acid (3β-hydroxy-20-oxo-30-nor-
betulinic acid against a range of tumor cell lines has lupan-28-oic acid (2) is also naturally produced 30-
attracted considerable traction among medicinal norlupane, demonstrating potential antitumor
chemists. This compound is active in micromolar activity.[24–26] In the literature, platanic acid had
concentrations with a high degree of selectivity attracted more attention as a new scaffold for the
against the melanoma cells and malignant synthesis of novel biologically potent molecules with a
potential in drug discovery.[27–29] Though there are
limited reaction sites in platanic acid for chemical
modification due to the lack of functional groups that
tolerate substitutions, but the derivatives displaying
Supporting information for this article is available on the
WWW under https://doi.org/10.1002/cbdv.202100292
Chem. Biodiversity 2021, 18, e2100292
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interesting biological potential could however be
In continuation of our deep interests in natural
tactfully accessed. In the literature, a number of products total synthesis,[34–39] and their exploitation in
potential anticancer congeners from betulinic acid medicinal chemistry,[40,41] platanic acid derived from
were accessed by structural tweaking at only specific betulinic acid was taken as a starting point for
positions keeping in consideration its SAR. As a result, structural reformations. Based on the literature prece-
derivatives that bear substitutions at C-3 and C-2 dence, structural analoguing was executed on the side
positions of ring A (3 and 4, respectively), carboxylic chain which is considered as one of the molecule’s hot
acid group derived compounds like BA-amide deriva- spots. In this communication, we report the synthesis
tive 5 and BA-ester derivative with side chain of a battery of new arylenone compounds from
modification congener (6) have been obtained (Fig- platanic acid in order to increase their cytotoxic
ure 1).[30–33] This information of betulinic acid struc- potential with the target proteins and screened them
tural reformations could act as a platform to access for cytotoxic activity against a panel of human cancer
novel platanic acid-based scaffolds.
cell lines.
Figure 1. Betulinic acid, platanic acid and its structurally modified potent cytotoxic analogs.
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(Table 1, compound 7). Keeping in mind the stability of
aldehyde derivative, 7, we were tempted to target a
Results and Discussion
Keeping in mind the biological profile with respect to range of arylenone based congeners. In this connec-
the cytotoxic background of betulinic acid and its tion, we first converted betulinic acid into platanic
structural analogous reported, we initially attempted acid by Lemieux-Johnson oxidation. The reaction of
allylic oxidation of its side chain with SeO2 to generate platanic acid with a range of aldehydes in the
an enal-derivative 7 (Scheme 1).[42] The biological presence of a strong base, sodium hydride under
activity of this compound against a panel of human anhydrous conditions furnished a series of arylenone
cancer cell lines indicated that this type of modifica- congeners (8–26) in an expeditious fashion. With the
tion significantly enhanced its cytotoxic potential help of this protocol, a wide range of compounds
Scheme 1. Synthesis of platanic acid analogs.
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Table 1. IC50 (μM) values of all compounds against various cell lines.[a]
Compound
MDA MB231
(breast)
MCF 7
(breast)
FR2
(normal breast
cell lines)
PC3
(prostate)
RWPE1
(normal prostate
cell lines)
A549
(lung)
HBEC3-KT
(normal lung
cell lines)
2
7
8
9
28�0.6
20�0.9
24�0.8
24�1.0
19�0.3
25�0.5
20�0.4
21�0.7
20�0.3
25�0.3
20�0.6
16�0.4
27�0.4
26�1.0
19�0.6
22�0.4
19�1.1
26�1.2
20�0.9
28�0.8
19�1.0
15�0.8
28�0.5
18�0.5
22�0.9
21�0.2
17�0.6
22�0.9
18�0.6
22�0.8
19�0.8
24�1.0
19�0.8
18�0.6
24�0.4
22�0.5
20�0.9
25�1.0
21�0.8
25�0.8
20�0.7
26�0.9
22�0.4
6.5�0.3
38�0.7
34�0.3
25�0.4
43�0.1
35�0.6
32�0.5
31�0.9
34�0.5
36�0.6
35�0.6
37�0.7
45�0.8
35�0.7
45�0.9
30�0.9
46�0.4
38�0.9
33�0.2
28�0.3
33�0.9
39�0.1
17�0.3
31�0.6
17�0.7
21�0.7
21�0.9
18�0.5
23�0.5
20�0.4
20�0.4
21�0.5
22�1.0
19�1.1
18�0.8
23�0.7
21�0.9
18�0.6
18�0.7
20�0.4
23�0.5
18�0.6
22�0.5
19�0.9
07�0.4
37�0.6
33�0.3
36�0.8
37�0.6
34�0.7
39�0.2
34�0.9
33�0.5
37�0.8
34�0.6
35�0.8
38�0.4
36�0.2
34�0.8
34�0.8
33�0.5
38�0.6
34�0.4
36�0.3
35�0.5
37�0.8
20�0.4
32�0.6
20�0.6
22�0.5
22�0.4
19�0.4
20�0.5
23�0.7
20�0.4
21�0.8
23�0.9
22�0.8
17�0.7
22�0.5
22�0.4
18�0.9
21�0.8
21�0.7
22�0.9
19�0.8
25�0.5
20�0.5
17�0.7
41�0.5
38�0.4
38�0.4
36�0.3
37�0.9
35�0.6
38�0.8
36�0.6
33�0.8
42�0.6
38�0.7
39�0.8
38�0.9
41�0.6
35�0.9
43�0.6
40�0.9
38�0.9
34�0.2
41�0.8
35�0.4
25�0.6
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
5-FU[b]
[a] All experiments were carried out in triplicates; [b] 5-FU=5-flourouracil; � =SD.
containing electron rich and electron deficient aro- (b) After the structural reformation of platanic acid to
matics, heteroaromatics and polyaromatics were ob-
tained in decent yields and their structures were
aryl-enones, some of these modified analogs
exhibited enhanced cytotoxic activity selectively
against the certain cancer cell lines in contrast to
normal cell lines like FR2, RWPE1 and HBEC3-KT.
1
secured through H-NMR and 13C-NMR data analysis.
From their 1H-NMR data, we observed two clear
doublets of trans-alkenes and its associated aromatic (c) Aromatic substituted compounds with p-nitro
ring proton signals in the aromatic region, which was
also supported by its carbon framework through 13C-
NMR data (see SI).
All these compounds (2, 7–26) were screened for
cytotoxic activity against four human cancer cell lines,
substitution (10), p-OMe and o-OMe substitution
(12 and 14, respectively), m-CH3 and p-CH3 (16
and 17, respectively) and p-Br or o-Br substitutions
(20 and 22) exhibited better activity than platanic
acid.
MDA-MB 231 (breast), MCF-7 (breast), PC-3 (prostate) (d) Among hetero-aromatics and polyaromatic com-
and A-549 (lung), and three normal cell lines, FR2
(normal breast cell lines), RWPE1 (normal prostrate cell
lines) and HBEC3-KT (normal lung cell lines) using MTT
pounds with 3-thiophenyl and naphthyl substitu-
tions (24 and 26) were better than the platanic
acid.
assay.[43] These cell lines were treated with different (e) Compound 17 with p-tolyl substitution exhibited
concentrations (10, 20, 30 and 60 μM) of compounds
and the results are reported in terms of IC50 values
(Table 1). From the results, it was observed that:
the better cytotoxic activity against all the tested
cancer cell lines compared to normal cell lines.
Among all these compounds it was observed that
(a) Compared with the standard compound, 5-fluo- the compound 17 was most potent. It is noteworthy
rouracil (5-FU), platanic acid has lower cytotoxic that the cytotoxic potential of compounds 17 against
activity against all the cancer and normal cell lines. two cell lines MDA-MB 231 and A-549 were in tune
However, after allylic oxidation of betulinic acid to with the standard compound, 5-FU. Additionally, its
furnish betulinic acid-derived enal analog-7 were IC50 value against the corresponding normal cell lines,
more active than parent platinic acid.
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