Anti-proliferative evaluation of monoterpene derivatives against leukemia

Article abstract of DOI:10.1016/j.ejmech.2016.02.034

The cure rate of pediatric acute lymphoblastic leukemia (ALL) has significantly improved in the past thirty years, however not all patient cohorts respond well to current chemotherapy regimens. Among the high risk patient cohort is infants with MLL-rearranged (MLL-r) B-ALL, which remains dismal with an overall survival rate <35%. Our program is interested in identifying new molecular scaffolds to better understand the underlying mechanisms and ultimately provide new targeted treatments. Based on a phenotypic screen, phenolic natural products were identified as promising scaffolds for further chemical evaluation. Herein we disclose the effects of a potent anti-proliferative compound 31 against human ALL leukemia cellular models.

Full text of DOI:10.1016/j.ejmech.2016.02.034

Accepted Manuscript
Anti-proliferative Evaluation of Monoterpene Derivatives against Leukemia
Lekh Nath Gautam, Taotao Ling, Walter Lang, Dr. Fatima Rivas
PII:
S0223-5234(16)30114-3
10.1016/j.ejmech.2016.02.034
EJMECH 8385
DOI:
Reference:
To appear in: European Journal of Medicinal Chemistry
Received Date: 17 December 2015
Revised Date: 11 February 2016
Accepted Date: 12 February 2016
Please cite this article as: L.N. Gautam, T. Ling, W. Lang, F. Rivas, Anti-proliferative Evaluation of
Monoterpene Derivatives against Leukemia, European Journal of Medicinal Chemistry (2016), doi:
10.1016/j.ejmech.2016.02.034.
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Anti-proliferative Evaluation of Monoterpene Derivatives against Leukemia
Lekh Nath Gautam, Taotao Ling, Walter Lang and Fatima Rivas*
a Department of Chemical Biology and Therapeutics, St. Jude Children’s Research Hospital,
Memphis, Tennessee 38105-3678 USA.
*Corresponding author:
Dr. Fatima Rivas
Department of Chemical Biology and Therapeutics
St. Jude Children’s Research Hospital
262 Danny Thomas Place
Memphis, TN 38105-3678, USA
Phone: 901-595-6504, Fax: 901-595-5715, e-mail: Fatima.rivas@stjude.org

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Abstract
The cure rate of pediatric acute lymphoblastic leukemia (ALL) has significantly improved in the past
thirty years, however not all patient cohorts respond well to current chemotherapy regimens. Among the
high risk patient cohort is infants with MLL-rearranged (MLL-r) B-ALL, which remains dismal with an
overall survival rate <35%. Our program is interested in identifying new molecular scaffolds to better
understand the underlying mechanisms and ultimately provide new targeted treatments. Based on a
phenotypic screen, phenolic natural products were identified as promising scaffolds for further chemical
evaluation. Herein we disclose the effects of a potent anti-proliferative compound 31 against human
ALL leukemia cellular models.
.

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Introduction
Natural products (NPs) are an integral component of drug discovery programs and have been
successfully implemented in the oncology field. Approximately 60% of clinically approved anticancer
drugs are based on secondary metabolites found in nature [1]. Terrestrial NPs are rich and a relatively
untapped source of molecular scaffolds for the development of tool compounds and/or therapeutic
agents [2]. Our research is focused on identifying new lead compounds from NPs against leukemia.
Using NP fractions, phenotypic screens were conducted on stable B and T human leukemic cell lines. In
a preliminary screen, we identified bakuchiol and curcumin as active compounds against B cells in the
30-40 µM range. This account describes the synthesis and evaluation of bakuchiol derivatives against
acute lymphoblastic leukemia (ALL).
(S)-Bakuchiol (BA, Fig. 1) is a prenylated phenolic monoterpene isolated from Psoralea corylifolia
Leguminoesae, widely use in Chinese and Indian traditional medicine [3]. Monoterpenes are naturally
occurring hydrocarbons composed of the condensation of two isoprenes. They are widely distributed in the
plant kingdom and are mostly recognized as plant essential oils. BA has been reported to exert anticancer,
anti-bacterial, and anti-inflammatory biological activity [3-7]. Cytotoxicity properties on hematological
cancer cell lines have been reported for curcumin [8], but to our knowledge, not for BA. We
hypothesized that hybrid molecular scaffolds of BA and curcumin would provide compounds with
improve biological potency and selectivity towards ALL cellular models. The optically active BA
features a quaternary carbon center, bearing a vinyl group, and an isoprene unit that can be
chemoselectively differentiated. Representative members (2-7, Fig.1) of this natural product family
share a phenolic core and different levels of complexity/biological activity [9]. Our central objective was
to develop NP 1 derivatives at C3-C4, C12-C13 and C18 to evaluate their biological properties against
ALL cellular models.

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Figure 1. Constituents of Psoralea corylifolia and related natural products.
ALL is the most common cancer among children and the most frequent cause of death for those
under 20 years of age in industrialized nations [10]. Although, five-year cure rates are high for most
ALL cases, two of its subgroups remain challenging and would benefit from the discovery of new
therapeutic agents, infant ALL and glucocorticoid resistant ALL [10]. The human AF4 (ALL-1 fused
gene on chromosome 4) gene (4q11) is recurrently involved in reciprocal translocations to the mixed
lineage leukemia (MLL) gene (11q23), and correlates with high-risk ALL in infants and early childhood
[11]. Outcome of infants with MLL-rearranged (MLL-r) B-ALL with a pro-B/mixed phenotype remains
dismal, displaying a particularly poor prognosis. To identified potential lead compounds, a high
throughput screen including the B cells (Nalm06, Nalm16, 697, Reh, SEM) and the T cells (Jurkat,
CEM, Molt-3, Loucy) was conducted. The disclosed study focuses on the SEM (a model for MLL-r B-
ALL) and the pre-B cell Nalm06 (a standard model for B cell ALL).
Results and Discussion
The synthetic strategy focused on chemical modification of BA, which was isolated from seeds of
Psoralea corylifolia as pure oil in 3% yield by mass, as the starting material. Derivatization at three
regions of the molecule (Fig. 2) was feasible as orthogonal reactions were available for structure activity
relationship studies (SAR). The phenolic C4-center can be o-alkylated or displaced by an aryl group or
heteroatom. The C3, ortho-position of the phenol group can be activated, allowing for the introduction
of alkyl groups. The appended olefin at C9 can be exploited through Palladium-mediated reactions and
the isoprene unit can be readily oxidized to be extended through homologation reactions [12]. With
sufficient compound 1 at hand, several chemical transformations at C3-C4, C12-C13 and C18 were
amenable for biological evaluation (Fig. 2).
Our synthetic studies began with a global evaluation of the natural product 1 to better understand
potential sites of relevant SAR. Etherification of the phenol provided compounds 10-13 under
nucleophilic conditions in almost quantitative yields, while overall double bond hydrogenation of 1
yielded compound 14. Chemoselective epoxidation using mCPBA and osmium mediated
dihydroxylation of 1 afforded compound 15 and 16 respectively [13]. Oxidative cleavage of diol 16
resulted in aldehyde 17, which was reduced to afford the corresponding alcohol 18. Further
derivatization of aldehyde 17 through treatment with stabilized or in situ prepared ylide reagents [14]
provided the corresponding compounds 19-22, and the corresponding hydrazine 23. Allylic oxidation of
C14 (or C15) with SeO2 in AcOH [15] resulted in aldehyde product 24, and the corresponding reduced

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allylic alcohol 25. Homologation reactions of aldehyde 24 yielded compounds 26-28. The isolated yields
of these compounds were in modest to good (67-98%, see SI for detail information).
Figure 2. BA derivatives at C4 and C11-C12.
Next synthetic modifications of C3 and C18 were carried out to introduce aliphatic and
aromatic functional groups at these centers for a thorough evaluation of the chemical space and
electronic properties of this scaffold [16]. First regioselective ortho-formylation of the substituted
phenol using the MgCl2–Et3N base system and paraformaldehyde under refluxing conditions [17]
afforded the ortho-aldehyde 30, which was reduced with NaBH4 to generate alcohol 29 in excellent
yields. Compound 30 was treated with stabilized ylide reagents [12] in benzene under refluxing
conditions to produce a library of compounds, including electron-withdrawing groups 31-41, and
electron-donating groups (42) at C3 (75-80% yield, Fig. 3).

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Figure 3. BA analogs evaluating C3 and C18.
Furthermore, compound 1 was evaluated under the Heck-Matsuda reaction (Fig. 3, and 4).
Successful Heck-Matsuda arylation reactions of non-activated olefins applying microwave irradiation
and heat can generate compounds bearing electron-donating or electron-withdrawing groups in good to
excellent yields with reduced reaction time [18]. One of the disadvantages of the original reaction
without microwave irradiation requires long reaction times that result in several side products, reducing
the reaction efficiency of metal catalyzed coupling reaction.
Compound 1 was treated with 1-iodo-4-methoxybenzene, Pd(OAc)2 and base (K2CO3, which offers
excellent functional group tolerance and high efficiency) to introduce the p-OMe Aryl group at C18 to
evaluate the effects of substitution at this center. The resulting intermediate was o-formylated to
generate compound 43, which was reacted with stabilized ylide to produce compounds (44-50 in 70-
80% yield, Fig. 3).
Next, we evaluated other functional groups on C18 by the introduction of other substituted aryl
groups through the Heck-Matsuda reaction conditions previously described. BA was treated with either
Pd (0) or Pd (II) along with the halogenated aryl, K2CO3 and base in DMF. The reaction was carried out
under microwave conditions to afford compound 51-57 (Fig. 4) in modest to good yields (70-80%).
Figure 4. BA analogs evaluating C18.
Finally, we investigated coupling reactions at the C4 of BA to introduce either amines or alkyl
groups. Despite the abundant number of reaction conditions to mediate C–N coupling reactions, only a
relatively limited number has practical applications in terms of catalyst system, ligand availability and
scope of substrate. The Buchwald-Hartwig reaction is one of the most reliable reactions [19]. The
palladium catalyzed amination was conducted with the corresponding triflated phenol of BA, which
subsequently treated with aryl amine, Pd(OAc)2, and Cs2CO3 (provided the best tolerance and highest

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reaction rate over other bases) in DMF. The catalytic presence of the ligand (2, 2'-
bis(diphenylphosphino)-1,1'-binaphthyl, (±)-binap) facilitated the reaction in good yield to provide
compounds 58-76 (75-80%, Fig. 5). Oxidative addition of benzyl, and aryl halides was performed under
Suzuki-Miyaura reaction conditions [19]. The cross-coupling reaction of the aryl organoboronic acid
compounds with triflated phenol of BA proceeds smoothly in DMF to effectively afford compounds 77-
83 (60-80% yield, Fig. 5).
Figure 5. BA analogs evaluating C4.
A representative of the tested compounds is shown in table 1. The SAR indicate that i) the
substitution pattern in the phenyl part of BA showed sensitivity towards modification with promising
results at C3 (30-36) ii) modification at the isopropylidene group showed some activity (14-16 against
Nalm06, while no significant difference was observed between SEM and BJ cells), iii) modification at
terminal olefin resulted in greater potency when an electrophile was present against Nalm06 or SEM
(24, 43, table 1). Some of the compounds were globally cytotoxic such as compound 44 with no
therapeutic window. Furthermore, the study showed that addition of a hydroxyphenyl or mono
methoxyphenyl moiety at C4 plays an important role in the biological activity. The most potent

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compound that was identified was compound 31, with an EC50 of 4.5 µM against Nalm06 and 8.0 µM
against SEM while it displayed some toxicity in BJ (>20 µM), but no toxicity was observed in the
HEPG2 cells at the tested concentrations (<90 µM). Interesting, compound 50 (which differs from
compound 31 by the p-OMePh at C18) showed some activity against SEM (30 µM), no effect on
NALM06, and EC50 higher than 36 µM in BJ and no toxicity against HEPG2. Despite the fact that
compound 31 carries a Michael acceptor, it shows promise and further derivatization will provide a lead
compound suitable for in vivo work. In the meantime, this compound will serve as a tool compound to
identify the biological target and understand the involved biochemical pathways.
Nalm06
EC50<9µM
EC50<29µM
SEM
BJ
EC50<35µM
HEPG2
EC50>52µM
#
1
14 15 16 24 25 26 28 29 43 30 31 32 33 36 38 44 49 50 67
Table 1. Representative heat map of selected compounds.
From a mechanistic perspective, here we focused our attention on the effects of compound 31 and
used compound 51 as a negative control on (a) cell growth and cell cycle progression. Flow cytometric
analysis was performed for cell cycle progression and apoptosis studies. Western immunoblotting was
utilized to investigate if JNK was involved and end point markers of apoptosis. The MAPK, c-Jun NH2-
terminal protein kinase (JNK) has been proposed to play an important role in the regulation of apoptosis.
Fluorochrome-labeled Annexin V and DNA content with PI [21] were studied treatment with compound
31 for a 24 hr period in SEM and Nalm06 to confirm apoptosis, or programmed cell death (for complete
data set see SI). Representative images of 3 independent experiments are shown for negative control
(DMSO), positive control (1 µM staurosporine) and 8.0 µM compound 31 for 24 hr treatment (Fig. 6).
Data presented on SEM cells (A. DMSO, B. 1 µM of Staurosporine, C. 8.0 µM 31) and Nalm06 (D.
DMSO, E. 1 µM of Staurosporine, F. 8.0 µM 31) shows that after 24 hr treatment under this conditions,
the cultured cells were captured in the late apoptotic state (Fig. 6). Both panels C and F depict over 80%
of the cells were in late apoptotic state (Q2), with the remaining cells entering early apoptosis with only
less than 3% cells remaining viable. Next, DNA content of the cells was measured to monitor cell
proliferation and cell cycle. Proliferating cells progress through various phases of the cell cycle (G0, G1,
S, G2, and M phase) and serum starvation is a widely used method to synchronize cells in a culture into
the G0/G1 phase. This experiment was design to capture the exact changes in the cells upon treatment

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with compound 31 for 24 hours under culture conditions. Graphical quantitation of the respective cell
cycle phases for compound 31 versus DMSO control (Fig. 6, G) showed that 36.25% of cells were in the
G0/G1 phase, 55.75% in the S phase, and 8.00% in the G2/M phase. While the DMSO control showed
45.75% increase in the G0/G1 phase, 46.62% in the S phase, and 7.63% in the G2/M phase. These
results indicate that, as expected, the SEM cells used in this study were responsive to compound 31,
appeared to have arrested in S phase (ModFit LT™ plots are included in the SI for detailed account).
Figure 6. Representative Annexin V and cell cycle for SEM (A negative control, B. positive control, C.
31) and Nalm06 (D. negative, E. positive, F. 31) and cell cycle for SEM.
The activation of caspase proteases is a critical event in the induction of apoptosis [22] so this
process was investigated for compound 31 in a time-dependent by immunoblot analysis as shown in
Figure 7. Compound 31 induced caspase-3, caspase-7-dependent apoptosis in vitro as well as PARP
cleavage in both Nalm06 and SEM cell lines. The cells were treated with compound 31 for 3, 6, 12 and
24 hr at concentrations of 8.0 µM for SEM and 4.5 µM for Nalm06. As negative controls, DMSO
(vehicle) and compound 51 were utilized at 20 µM. Significant caspase-3- activity was induced within
12 hr after exposure to 4.5 and 8.0 ꢀM of compound 31 for Nalm06 and SEM respectively (Fig. 7). The
data suggests that compound 31-induced apoptosis in ALL cell models via the caspase-3-dependent
pathway.
For Nalm06, caspase 3 activation was captured at the 12 hr time point (cleaved caspase 3, 17 kDa)
while the positive control, staurosporine (0.5 µM) shows caspase-3 activation by the 3 hr time point.

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Active caspase-7 is observed at the 6 hr time point, albeit at very low expression levels, but by the 12 hr
time point, it can be clearly detected. No cleaved PARP (89 kDa) was detected between 3-6 hr
treatment, but it was observed after 12 hr treatment. In terms of cleaved PARP, the positive control
showed its presence at 3, 6 hr treatment, but at the 12 hr point no more PARP was detected.
For the SEM cell line, caspase 3 activation was observed at the 6 hr time point as well as the positive
control. Active caspase-7 was also observed at the 6 hr and 12 hr time point. Cleaved PARP (89 kDa)
was detected at the 3, 6, and 12 hr time point. No uncleaved PARP was observed at the 12 hr point.
Next, we investigated effects of 31 on MAPKs in Nalm06 and SEM cell lines by immunoblot analysis.
As shown in Fig. 7, compound 31 at concentration of 4.5 ꢀM for Nalm06 and 8.0 ꢀM for SEM
respectively.
Figure 7. Western Blot of Nalm06, SEM for 3, 6, 12 hr respectively.
Compound 31 induced higher levels of phosphorylated JNK in SEM cells, but not in the Nalm06 cell
line, presumably due to different mechanisms regulating apoptosis. JNK activation was increased
through the time points for the positive control in the SEM, but not detected for Nalm06. These results
indicate that JNK is involved in the mode of action of compound 31 in SEM cell lines, but not in
Nalm06. A graphical quantification of JNK expressed as a ratio of Phospho JNK over total JNK
normalized to the DMSO (control set to 1.0) is shown in Fig. 8 (signal intensities in color are included in
SI).

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Figure 8. Phospho-JNK and total JNK (p/t) calculated as a measure of JNK activation.
Conclusions
In conclusion, the present study describes the synthesis and biological evaluation of the derivatives
of the natural product BA against leukemia cellular models. It is well established that apoptosis and its
associated signaling pathways can be targeted as potential therapies against malignancies, including
infant ALL. We have identified lead compound 31 against B cell ALL models with promising potency
(EC50≤8 ꢀM in Nalm06/SEM cells) and minimal cytotoxicity observed in HEPG2/BJ/Hek293
mammalian cell lines. Our results showed apoptosis induction in these ALL cellular models upon
treatment with compound 31. PARP cleavage and active caspase 3 increase levels suggested that the
apoptotic program is caspase dependent. This monoterpene derivative provides a new lead molecular
scaffold for further mechanistic studies to identify potential biological target(s) in ALL. The described
experimental observations, growth inhibition, S phase arrest and caspase mediated apoptotic death in
these leukemia B cell models induced by compound 31 warrant further mechanistic studies, which will
be presented in due time.
Supplementary Data. Full details of the derivative syntheses and biological experimental methods are
provided online at:
Competing interests. The authors declare that they have no competing interests.
Acknowledgments. This study was supported by the American Lebanese Syrian Associated Charities
(ALSAC). The authors thank the High-Throughput Analytical Chemistry Core Facility and the Cell
Cycle Facility for technical support at St. Jude Children’s Research Hospital.

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Highlights
ꢀ A focused-compound library based on the monoterpene, bakuchiol was synthesized.
ꢀ Compound 31 was identified as a potential lead against leukemia
ꢀ Compound 31 induces caspase-3 dependent apoptotic pathway