New derivatives of 11-keto-β-boswellic acid (KBA) induce apoptosis in breast and prostate cancers cells

Article abstract of DOI:10.1080/14786419.2019.1593165

A series of new 11-keto-β-boswellic acid were partially-synthesized by modifying the hydroxyl and carboxylic acid functional groups of ring A. The structures of the new analogs were confirmed by detailed spectral data analysis. Compounds 4, 5 and 9 exhibi

Full text of DOI:10.1080/14786419.2019.1593165

Natural Product Research
Formerly Natural Product Letters
ISSN: 1478-6419 (Print) 1478-6427 (Online) Journal homepage: https://www.tandfonline.com/loi/gnpl20
New derivatives of 11-keto-β-boswellic acid (KBA)
induce apoptosis in breast and prostate cancers
cells
Asma Bani Araba, Najeeb Ur Rehman, Amna Al-Araimi, Sulaiman Al-Hashmi,
Sulaiman Al-Shidhani, Rene Csuk, Hidayat Hussain, Ahmed Al-Harrasi &
Fahad Zadjali
To cite this article: Asma Bani Araba, Najeeb Ur Rehman, Amna Al-Araimi, Sulaiman Al-Hashmi,
Sulaiman Al-Shidhani, Rene Csuk, Hidayat Hussain, Ahmed Al-Harrasi & Fahad Zadjali (2019):
New derivatives of 11-keto-β-boswellic acid (KBA) induce apoptosis in breast and prostate cancers
cells, Natural Product Research, DOI: 10.1080/14786419.2019.1593165
To link to this article: https://doi.org/10.1080/14786419.2019.1593165
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NATURAL PRODUCT RESEARCH
https://doi.org/10.1080/14786419.2019.1593165
New derivatives of 11-keto-b-boswellic acid (KBA)
induce apoptosis in breast and prostate
cancers cells
a
b
a
b
Asma Bani Araba , Najeeb Ur Rehman , Amna Al-Araimi , Sulaiman Al-Hashmi ,
b
c
b
b
Sulaiman Al-Shidhani , Rene Csuk , Hidayat Hussain , Ahmed Al-Harrasi and
a
Fahad Zadjali
a
Biochemistry Department, College of Medicine and Health Science, Sultan Qaboos University,
b
Muscat, Oman; Natural and Medical Sciences Research Center, University of Nizwa, Nizwa,
Sultanate of Oman; Organic Chemistry, Martin-Luther-University Halle-Wittenberg,
c
Halle (Saale), Germany
ABSTRACT
ARTICLE HISTORY
A series of new 11-keto-b-boswellic acid were partially-
synthesized by modifying the hydroxyl and carboxylic acid
functional groups of ring A. The structures of the new
analogs were confirmed by detailed spectral data analysis.
Compounds 4, 5 and 9 exhibited potent anti-cancer results
against two human tumor cancer cell lines having IC50
value of MCF-7 (breast) and LNCaP (prostate): 123.6, 9.6
and 88.94 lM and 9.6, 44.12 and 12.03 lM, respectively.
Additionally, a maximum nuclear fragmentation was observed
for 4 (78.44%) in AKBA treated cells after 24 hr followed by 5
and 9 with (74.25 and 66.9% respectively). This study sug-
gests that the presence of hydrazone functionality (4 and 9)
has effectively improved the potency of AKBA. Interestingly,
compound 5 with a lost carboxylic acid group of ring A
showed comparable potent activity. Highly selective AKBA
requires further modification to improve its bioavailability
and solubility inside the cancer cells.
Received 20 January 2019
Accepted 3 March 2019
KEYWORDS
Boswellia sacra; 3-acetyl-
1
1
1-Keto-b-boswellic acid;
1-keto-b-boswellic acid;
breast cancer cell lines;
prostate cancer cell lines;
normal cell lines
CONTACT Fahad Zadjali
fahadz@squ.edu.om; Ahmed Al-Harrasi
aharrasi@unizwa.edu.om; Hidayat Hussain
hidayat110@gmail.com
Supplemental data for this article is available online at https://doi.org/10.1080/14786419.2019.1593165.
ß 2019 Informa UK Limited, trading as Taylor & Francis Group

2
A. BANI ORABA ET AL.
1. Introduction
Number of annual deaths due to cancer is dramatically increasing worldwide despite
the advances in the treatment strategies. Natural compounds or their derivatives are
major sources of anticancer drugs and it has been reported that over 150 natural
products-derived drugs are amiable in market between 1981 and 2014 (Baskar et al.
2
012). Evidences from tissue culture, animal, and clinical studies suggest that more
than 20,000 natural triterpenoids have the potential ability to limit the development
and severity of certain cancers (Newman and Cragg 2016; Laszczyk 2009) Pentacyclic
triterpenes such as ursane and oleanane-type play an important role in cancer treat-
ment with different modes of action (Sun et al. 2006). These triterpenes exhibit signifi-
cant antitumor activity and the chemical modification of these triterpenes results in
enhancing anti-tumor activities (Csuk et al. 2015; Kumar et al. 2016)
Various triterpenes have been reported from the resins of Boswellia species (frankin-
cense). Boswellic acids are either oleanane or ursane-type having carboxylic acid at C-
4. They demonstrated antimicrobial, antidiabetic, antiviral, antipruritic and anti-inflam-
matory activity (Kumar et al. 2016). The family consists of b-boswellic acid (b-BA), a
pentacyclic triterpenic acid, and its natural derivatives: 3-acetyl-b-BA (b-ABA), 11-keto-
b-BA, and 3-acetyl-11-keto-b-BA (Kumar et al. 2016; Raja et al. 2011; Safayhi et al.
1992; Hamidpour et al. 2013). AKBA suppresses NF-jB signaling and to noncompeti-
tively inhibit 5-lipoxygenase, topoisomerase and leukocyte elastase (Csuk et al. 2015).
AKBA has also shown to exert apoptotic actions on various cancer cell lines through
induction of caspase-3 and caspase-8 as well as with poly(ADP)ribose polymerase
(PARP) cleavage (Lu et al. 2008). The anticancer activity of AKBA remains in micro

NATURAL PRODUCT RESEARCH
3
molar with IC50 dose 10–100 lM (Yuan et al. 2008; Park et al. 2002; Siddiqui 2011; Liu
et al. 2013; Jing et al. 1999).
The current study aims to increase the potency of AKBA via modification of ring A
and synthesis of heterocyclic analogs. This project begins with structure–activity rela-
tionship (SAR) studies in which various functional groups of the small molecule of
interest are added or removed to determine the derivative that increases potency and
selectivity of AKBA. Triterpenoids with 30 carbon atoms derived from cyclization of
squalene, oleanane and ursane type of triterpenoids that exhibit antitumor activity by
the substitution of cinnamoyl moiety in their structures (Sun et al. 2006). Saponin is well
known triterpene, amide substitution at C-28 of saponin results in highly cytotoxic
derivatives for specific tumor cell lines, and also leads to an increase in the antitumor
selectivity of b-hederin (Thakur et al. 2011). Further incorporation of carbonyl group at
C-16, additional sugar unit viz., L-rhamnose at C-3 and acetyl group at C-6 of the D-glu-
cose in various saponins lead to a significant increase of the cytotoxic activity against
various cancer cells (Mu et al. 2013). Synthetic addition of 13,28-epoxy, 16 a-hydroxy,
and C-30 methyl moieties in the saponins selectively inhibited the growth of liver cancer
(
(
Bel-7402 and HepG-2) cells without affecting the survival of normal liver (HL-7702) cells
Li et al. 2012). Hydrazone represents an important class of compounds with broad spec-
trum of pharmacological activities with a highly reactive group (CO-NH-N¼ CH) (Verma
et al. 2014).
2. Results and discussion
2.1. Chemistry
2.1.1. The preparation of 11-keto-b-boswellic acid (KBA)
Boswellic acids were extracted from Omani frankincense tree (B. sacra) using
the protocol described earlier (Csuk et al. 2015). The concentration of BA, KBA,
ABA and AKBA vary significantly depending on the Boswellia species as well as on
the environmental factors within the same species (Al-Harrasi et al. 2018). In order to
enrich the content of KBA, we followed Jauch and Bergmann focused approach
(Jauch and Bergmann 2003) and converted AKBA to KBA and ABA into BA via deacety-
lation. This is followed by conversion of BA to KBA employing allylic photo-oxidation
which introduced carbonyl group at C-11 (Jauch and Bergmann 2003) (Scheme 1).
2.1.2. The preparation of new derivatives of KBA
In order to synthesize different derivatives of KBA, the carboxyl group in KBA was
protected using benzyl bromide in the presence potassium carbonate which afforded
ketone in 1a in 91% yield. This was followed by oxidation of the hydroxyl group at C-
3
using Jones reagent which furnished 3-keto derivative 2 in 86% yield. Similarly, the
natural 3-epi-a-amyrin 6 was oxidized to a-amyrenone 7 using Jones reagent. This was
followed by treating 7 with phenylhydrazine to give the indole derivatives 8 in 67%
yield. Interestingly when compound 2 was treated with 2,4-dinitrophenylhydrazine
under identical conditions described for synthesis of 8, the expected indole derivative
was not formed, instead hydrazone 4 was isolated in 73% yield. This is likely due

4
A. BANI ORABA ET AL.
Scheme 1. Jauch and Bergmann (2003) ‘Focusing’ approach to large-scale synthesis of KBA (2).
Reagents and conditions: (i) 0.5 N KOH in iPrOH, reflux, 15 hr; (ii) NBS/CaCO /H O, dioxane, hm,
3
2
rt, 10 hr.
to the presence of two electron withdrawing nitro groups at positions 2 and 4.
In a similar manner, hydrazone 9 was obtained from the reaction of 2 with hydrazine.
Brominated derivative 3 was obtained in 81% yield by reaction of diketone 2 with
CuBr which upon treatment with Li CO and LiCl, decarboxylated derivative 5 was
2
2
3
isolated in relatively low yield (Scheme 2).
2.2. Biological assays
2.2.1. Cytotoxicity of natural compounds of boswellic acids
Cytotoxic effects of boswellic acid derivatives were studied against two human cancer
cell lines: human breast cancer (MCF-7) and human prostate cancer (LNCaP) using
doxorubicin as positive control. The effects were also studied on normal human nasal
epithelial cell line (RPMI2650). Analysis of the two natural triterpenes derivatives of
boswellic acid, KBA and AKBA, showed that AKBA showed more potent inhibition of
cellular survival with IC50 dose of 75.4 mM and 21.0 mM on MCF-7 and LNCaP cell lines,
respectively, Figure S1A and B. Breast adenocarcinoma MCF-7 cell lines were more
pre-apoptotic-sensitive with AKBA with pre-apoptosis EC50 dose of 2.4 mM compared
to LNCaP cell lines with EC dose of 21 mM, Figure S1A and B. The IC50 of KBA was 3.7
fold less effective on MCF-7 compared to AKBA. Cytotoxic effects of both AKBA and
KBA were induced at higher dose when normal human cell lines were used, Figure
S1C. This shows less cytotoxic effects on normal cell line compared to breast and pros-
tate cancer cell lines. Figure S1D shows an example of flow cytometry scatter plot live,
dead and preapoptotic cells.
2.2.2. Derivatives with no enhanced potency compared to AKBA
Some of the AKBA derivatives showed lower activity compared to the natural AKBA,
Table 1, and Figure S3. Loss of acetyl group as in 1 and 2 (line b and c in Figure S2)
showed reduced cytotoxicity with IC50 dose of 107 mM and 181.3 mM on MCF-7 cell
lines respectively. On the other hand, MCF-7 cell lines underwent pre-apoptosis with
these two derivatives at EC50 value of 5.2 mM and 6.3 mM, respectively. Prostate cancer
cell lines (LNCaP) exhibited more sensitivity against these two derivatives with IC50
dose of 25.62 mM and 98.6 mM respectively. Loss of carboxylic group in KBA as in 6

NATURAL PRODUCT RESEARCH
5
Scheme 2. Reagents and conditions: (i) BnBr, K CO , DMF, rt, 12 hr, 1 (91%), 7 (84%); (ii) Jones
2
3
reagent, rt, 2 hr, 2 (86%) (iii) Phenylhydrazine, AcOH, reflux, 6h, 8 (67%) (iv) 1-(2,4-dinitrophenyl)
hydrazine, AcOH, reflux, 6 hr, 4 (73%); (v) CuBr , CH Cl -EtOAc, reflux, 3 hr, 3 (81%); (vi) Hydrazine,
2
2 2
AcOH, reflux, 48 hr, 9 (64%) (vii) Li CO , LiCl, DMF, reflux, 8 hr, 5 (48%).
2
3
decreased the potency with IC50 dose of 114.9 mM and 133.7 mM on MCF-7 and LNCaP
cell lines, respectively, Figure S2 (line d). Indole derivatives are important structures of
antitumor drug design; however, this moiety in 8 did not show enhanced anti-cancer
activity with IC50 of 294.5 mM on MCF-7 cell line (Figure S3 line e). Likewise, addition of
bromo-group in 3 did not improve the cytotoxic activity on breast cancer cells where
IC50 dose was 123.6 mM, Figure S2 line f.
2.2.3. Derivatives with enhanced potency compared to AKBA
Survival and pre-apoptosis data revealed that structure-activity relationships (SAR) play
a crucial role in the cytotoxic activity of AKBA analogs. As illustrated in Figure S3,
hydrazone 4 demonstrated increased anticancer activity in LNCaP with IC50 of 9.6 lM
when compared to AKBA (21 lM) (Figure S3B). MCF-7 cell lines were less sensitive to
hydrazone analog (4) with IC50 of 123.6 lM (Figure S3A) compared to AKBA.
Hydrazide-hydrazone derivatives containing a highly reactive group (CO-NH-N ¼ CH)
are reported to be good candidates for development of a new drugs (El-Faham et al.

6
A. BANI ORABA ET AL.

NATURAL PRODUCT RESEARCH
7
2
015). In addition, their anti-cancer activity has been reported (Terzioglu and G u€ rsoy
2003; Boga et al. 2009; el-Sabbagh and Rady 2009) and are considered one of the
most efficacious low-molecular drugs for the treatment of breast cancer (Biersack and
Schobert 2012; Sidhu et al. 2015). Compound 5 demonstrated better anticancer effects
towards MCF-7 and LNCaP cell lines with IC50 value of 44 lM and 9.6 lM, respectively.
In addition, compound 5 started to induce pre-apoptosis at extremely low dose with
EC50 of 0.09 lM on MCF-7 cell lines. More activity was observed on LNCaP cell line
than MCF-7 with IC50 dose of 12.03 lM and 88.94 lM, respectively.
One of the greatest challenges in cancer drug discovery is the selective killing of
cancer cells. Natural products are gaining a great attention to act as promising cancer-
specific cytotoxicity. It is worth noting that AKBA reflected a remarkable selectivity
where IC50 and EC50 values on normal cell lines (RPMI2650) were 1014 lM and
1006 lM, respectively (Figure S3C). On the other hand, the potent compounds (4, 5
and 9) showed cytotoxicity on normal cells as illustrated in Figure S3C. This finding
suggests that AKBA is a promising anticancer drug that may provide an alternative to
chemo and radiotherapy.
2.2.4. Chromatin condensation assay using Hoechst 33342 stain
To gain further insight into the cytotoxic effect of the compounds, we investigated
the nuclear changes and condensation using Hoechst 33342 stain on MCF-7 cells.
Apoptosis is morphologically characterized by cell shrinkage, chromatin condensation
and nuclear fragmentation. The results of this assay revealed that potent compounds
inducing apoptosis in MCF-7 cells and the effect was found to be increased with
increasing doses of the compounds (Table 2). Fragmentation of nuclei, a characteristic
feature of apoptosis, was observed in compounds-treated cells after staining with
Hoechst. Maximum nuclear fragmentation occurred in AKBA treated cells for 24 hr fol-
lowed by compound 5 and 9 with percentage 78.25, 74.25 and 66.9% respectively.
2.2.5. Effect of potent compounds on cellular signaling
Different signaling apoptotic pathways were investigated for the effects of AKBA and
its potent derivatives. AKBA treatment showed reduction in levels of caspase-3 and
PARP, Figure S4. Western blot data indicate inhibition of PARP1 in cells treated by
potent derivatives (4, 5 and 9), thereby initiating the apoptosis pathway in both cell
lines. Protein levels of pro and active PARP1 were strongly reduced by these deriva-
tives making them future candidate of PARP inhibition. Several PARP inhibitors are in
advanced stages of clinical development for several tumor types. In breast and ovarian
cancer clinical trials, PARP inhibitors showed increased activity in platinum-sensitive
Table 2. Nuclear fragmentation percentage of the potent AKBA derivatives.
Nuclear Fragmentation (%)
Compounds
0 hr
9 hr
12 hr
24 hr
AKBA
30.5 ± 3.06
32.93 ± 8.89
32.28 ± 7.37
28.5 ± 2.65
54.25 ± 1.53
54.8 ± 4.04
40.75 ± 3.06
53.26 ± 5.03
63.0 ± 2.89
59.99 ± 1.53
56.5 ± 8.14
63.4 ± 6.11
78.25 ± 2.65
70.49 ± 2.08
74.25 ± 4.16
66.9 ± 9.88
4
5
9
Experiments were performed in triplicate in three separate experiments and results are expressed as mean ± stan-
dard deviation (mean ± SD).

8
A. BANI ORABA ET AL.
tumors, making PARP an attractive candidate in cancer therapy (Lu et al. 2008). We
only detected expression of pro-caspase-3 without the cleaved active form. Absence
of active caspase-3 levels may suggest non-classical AKBA-induced apoptosis. Such
apoptotis is present in normal oral epithelium, keratinocytes and squamous cell carcin-
oma (Gandarillas et al. 1999; Hague et al. 2004; Lippens et al. 2000). All these data
suggests that the potent derivatives of AKBA may act as future candidate for anti-can-
cer drug development. Although multiple signaling pathways are affected, with pro-
found effect on PARP and STAT3 signaling, it yet unclear about the cellular target of
AKBA. Future proteomic profiling and drug-protein binding assays are warranted.
3. Conclusion
Natural products are gaining a lot of interest due to their affectivity and selectivity. In this
study, eight AKBA derivatives were synthesized as anticancer drugs. The anti-proliferative
effects of these compounds were determined in breast and prostate cancer cell lines
(MCF-7 and LNCaP), and the structure-activity relationships (SAR) were analyzed.
Synthetic efforts were mainly directed toward the modification in ring A and C-24 carb-
oxyl group with different substituents to evaluate the effects of functional groups on
anti-proliferation activities. Moreover, among all tested compounds, three compounds (4,
5
and 9) exhibited the best potency. Despite of potency of the derivatives, the natural
AKBA showed greater selectivity on cancer cells over the normal cell line (RPMI2560). This
feature of AKBA overcomes the adverse effect of chemo and radiotherapy on normal
cells. For instance, Doxorubicin exhibits very low IC50 value of 0.164 lM compared to
1
-
014 lM of AKBA on normal nasal cell line (RPMI2560) (Drug: Doxorubicin - Cancerrxgene
Genomics of Drug Sensitivity in Cancer). However, AKBA displays drawback in its poor
oral bioavailability due to its high lipid solubility, rapid phase-1 metabolism and poor
intestinal permeability (Miller et al. 2016; Bhardwaj et al. 2016). Future research is
required to improve AKBA bioavailability and solubility through different drug delivery
system nanoparticles (Ding et al. 2016), nanomicelles (Goel et al. 2010), liquisolid systems
(Mostafa, Nagwa, Abd El-Alim, et al. 2015), new water soluble glycosides (Manjunath
et al. 2018), and transdermal microemulsions (Mostafa, Nagwa, Mona, et al. 2015).
Acknowledgement
The authors would like to thank The Oman Research Council (TRC) for the generous support
through the project ORG/HSS/14/004.
Disclosure statement
The authors declare no conflict of interest with respect to this study.
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