Synthesis and in vitro evaluation of (R), (S) and (R/S)-2-hexyne-1,4-diol, a natural product produced by fungus Clitocybe catinus, and related analogs as potential anticancer agents

Article abstract of DOI:10.1016/j.bmcl.2016.04.060

The search for natural products and related analogs as potential anticancer agents has seen a significant growth worldwide. Since small sized propargylic diols can be found in nature and chemically synthesized, their evaluation against cancer cells has been of great interest, being a topic of relevance to be investigated. For this purpose, a scalable approach aiming at the synthesis of several propargylic diols and their bioactivity against seven tumor cell lines were evaluated. Interestingly, when the compound 1a, a natural product produced by fungus Clitocybe catinus, was tested in its racemic mixture a more effective activity was observed if compared when enantiopure R-1a or S-1a were tested separately.

Full text of DOI:10.1016/j.bmcl.2016.04.060

Bioorganic & Medicinal Chemistry Letters xxx (2016) xxx–xxx
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and in vitro evaluation of (R), (S) and
R/S)-2-hexyne-1,4-diol, a natural product produced by fungus
Clitocybe catinus, and related analogs as potential anticancer agents
(
a,b
a
b
b
Iza Mirela R. G. Princival , Jeiely G. Ferreira , Teresinha G. Silva , Jaciana S. Aguiar ,
Jefferson L. Princival
a
a,
⇑
Departamento de Química Fundamental, Universidade Federal de Pernambuco, Recife, PE, Brazil
Departamento de Antibióticos, Universidade Federal de Pernambuco, Recife, PE, Brazil
b
a r t i c l e i n f o
a b s t r a c t
Article history:
The search for natural products and related analogs as potential anticancer agents has seen a significant
growth worldwide. Since small sized propargylic diols can be found in nature and chemically synthe-
sized, their evaluation against cancer cells has been of great interest, being a topic of relevance to be
investigated. For this purpose, a scalable approach aiming at the synthesis of several propargylic diols
and their bioactivity against seven tumor cell lines were evaluated. Interestingly, when the compound
Received 17 March 2016
Revised 11 April 2016
Accepted 20 April 2016
Available online xxxx
1
a, a natural product produced by fungus Clitocybe catinus, was tested in its racemic mixture a more
Keywords:
Enantiomers
Bioactive
Propargylic
Tumor
effective activity was observed if compared when enantiopure R-1a or S-1a were tested separately.
Ó 2016 Elsevier Ltd. All rights reserved.
Synthesis
Cancer remains one of the main global diseases, being responsi-
ble for about 15% of death worldwide.1 Due to these expressive
fatalities, several classes of compounds have been investigated as
potential anticancer agents, including natural products. Examples
of successfully employed compounds as anticancer agents are
Taxol and Discodermolide, which possess IC50 in low nanomolar
range. Although several natural products and related analogs have
been exhaustively studied for this purpose, the search for new can-
didates which possess smaller side effects on cancer treatment
remains of great interest.
cytotoxic effect against human leukemia (LC50 = 25 l
M)7 and
Nepheliosyne A (5), a cytotoxic metabolite produced by the marine
8
sponge Niphates sp. Although many studies focusing on macro-
molecules have been done, few examples related to small sized
propargylic diols have been reported to date. Examples of small
sized metabolites containing propargylic diols are the compounds
1–3. These compounds are natural products produced by fungus
Clitocybe catinus, being firstly isolated in their enantiomerically
2
3
9
pure form by Pava and co-workers in 2000. All the afore-men-
tioned substances and their related structures, which contain a
propargylic diol backbone are shown in the Figure 1.
Biologically active polyacetylenic metabolites are natural prod-
ucts containing a linear alkynylic moiety as main carbon backbone,
differing from each other by the chain-length and/or the number of
functional groups. Although these compounds are found in many
organisms such algae, fungi, plants and sponges4 and display a
Therefore, due to our interest in synthesizing functionalized
acetylenic natural products, we reported herein a scalable synthe-
sis of natural and unnatural propargylic diols based on metabolites
1–2, and an analysis of their potential anticancer properties again
seven tumor cell lines, which has not yet been done.
5
wide range of biochemical and ecological functions, they are usu-
ally isolated in very small quantities.
Among several natural products containing an alkynylic moiety,
propargylic diols are of great interest. These substances are com-
monly isolated as polyacetylenes compounds which possess high
cytotoxic behavior. Examples are the polyols such Osirisyne E (4),
isolated from the sponge Haliclonaosiri (Chalinidae), that exhibit
For the synthesis of bis-substituted propargylic diols 1a–o a lit-
1
0
erature modified method was employed. Thereby, commercially
available propargylic and homo propargylic alcohols were reacted
with two equivalents of n-butyl lithium, in order to generate reac-
tive bis-lithium salts in situ. Thereafter their reactivity was tested
by reacting them with aldehydes, ketones and propylene oxide as
appropriated electrophiles (Scheme 1).
6
After reacting the prepared bis-lithium salts using the condi-
tions depicted in Scheme 1, the prepared diols 1a–o were produced
⇑
Corresponding author.
http://dx.doi.org/10.1016/j.bmcl.2016.04.060
960-894X/Ó 2016 Elsevier Ltd. All rights reserved.
0
Please cite this article in press as: Princival, I. M. R. G.; et al. Bioorg. Med. Chem. Lett. (2016), http://dx.doi.org/10.1016/j.bmcl.2016.04.060

2
I. M. R. G. Princival et al. / Bioorg. Med. Chem. Lett. xxx (2016) xxx–xxx
OH
OH
OH
HO2C
OH
OH
OH
OH
OH
OH
13
(
S)-1a
OH
OH OH
OH
Osirisyne E (4)
OH
OH
(S,S)-2 OH
OH OH
OH
OH
11
HO2C
O
Nepheliosyne A (5)
OH
(
S,S)-3 OH
OH
Figure 1. Naturally occurring propargylic diols.
OH
R1
n
OH
2
eq. [ n-BuLi ]
OH
OH
THF/ -78ºC
OH
OH
1a
OH
1b
OH
1c
1d
OH
OLi
6
Li
1
)
R1
OH
n
O
O
OH
a-c
or R2
R3
OH
OH
OH
2
) NH Cl
4 (aq)
OH
OH
HO
OH
1e
1f
1g
1h
OH
1j
OH
OH
OH
OH
1
i
1k
OH
1l
OH
OH
OH
OH
OH
1m
OH
1n
OH
1o
Scheme 1. Preparation of propargylic diols 1.
in considerable amounts and good overall yields, through large-
scale reactions.
Conversion
ee
1
00
8
0
As is well known, isomers of specific molecules can exhibit dif-
ferent biological activities. Consequently, in order to identify lead
compounds for development, it is crucial to establish the cytotoxic
profiles of both racemates and optical pure enantiomers. As we
were particularly interested in synthesizing the compound 1a in
their enantiopure form from (R/S)-1a, it was subjected to a
lipase-catalyzed resolution, in order to achieve R and S enan-
tiomers in high ee. For this, a lipase-screened test was performed
using two equivalents of vinyl acetate as acyl donor and dry
n-hexane as organic solvent. For this, a literature-modified method
60
4
0
0
0
2
Figure 2. Screening based on conversion of (R/S)-1a. Conditions: (R/S)-1a
0.1 mmol), Enzyme (10 mg)/[5 mg/mL], vinyl-acetate (0.1 mL), n-hexane (2.0 mL),
50 rpm, 35 °C.
(
1
1
1
was employed, where the follow isolated lipases were tested for
the initial study: immobilized Candida antarctica lipase B, supported
on acrylic resin (CAL-B) and the powder free enzymes: Amano
Lipase G from Penicillium camemberti (PCL-G); Lipase A amano12
enantioselective biotransformation, due to this it was chosen as
the lipase of choice. Thus, after an enzymatic kinetic resolution
of racemic 1a, the enantiomer (S)-7a and (R)-8a could be obtained
in 95% and 99% ee, respectively, after a quantitative conversion of
(R/S)-1a. Although other lipases such AE07 and A2AE011
have shown similar degree of conversion, (S)-7a was obtained in
moderate selectivity (78–87% ee).
(A12L-A); lipase from Pseudomonas stutzeri (AE07) and lipase from
Alcaligenes spp. (A2AE011). The results from the enzymatic kinetic
resolution studies upon (R/S)-1a are depicted in the Figure 2.
Analyzing the result from the lipase screening tests, the immo-
bilized CAL-B has proved to be the more efficient catalyst on the
Please cite this article in press as: Princival, I. M. R. G.; et al. Bioorg. Med. Chem. Lett. (2016), http://dx.doi.org/10.1016/j.bmcl.2016.04.060

I. M. R. G. Princival et al. / Bioorg. Med. Chem. Lett. xxx (2016) xxx–xxx
3
(
S)-7a
Although compounds 1 possess similar structure, very different
results were obtained after their evaluation against the seven
tumor cell lines.
By checking the structure of the more active compounds, as
potential cytotoxic agents, it becomes clear that the cytotoxic
behavior could be due to the presence of both a terminal hydroxyl
group and a non-ramified alkylic side-extended chain, as end
groups. It can be seeing comparing the structures of 1a–d with
compounds 1e–o.
OAc
OH
9
9% ee
CALB, 35ºC
n-hexane
O
CALB, 35ºC
n-hexane
O
(
R/S)-1a
(
S)-7a
95% ee OAc
(
9
R)-8a
9% ee OAc
(R)-8a
99% ee
O
O
Scheme 2. CALB-catalyzed resolution of (R/S)-1a.
OH
OH
From a broader analysis, the highest active compounds in the
screening assays such diols 1a–d must be highlighted due to their
good in vitro antitumor activity, exhibiting a total growth inhibi-
tion against all of the tested cells lines. Thus, the fixed concentra-
tion (100 lg/mL) was property converted and the total growth
inhibition values were found as follows; 1a 0.84 mM, 1b
2
K CO3,
MeOH
(
S)-7a
(R)-8a
99% ee
or
or
9
9% ee
r.t. 2 h
OH
OH
(
S)-1a
9% ee
(R)-1a
99% ee
9
Scheme 3. Synthesis of enantiopure (R)- and (S)-1a.
0.76 mM, 1c 1.00 mM and 1d 0.64 mM.
Surprisingly, when enantiopure (R)-1a and (S)-1a were sepa-
rately subjected to the in vitro assays, both of them showed to
be far less effective than racemic 1a. Therefore, comparing the
results it is possible to see that for the HL-60 (R/S)-1a has shown
to be 70 times more effective than (S)-1a (entry 3), while if com-
pared with the (R)-1a for the cell such J774.A1 the racemate was
500 times more toxic.
We also observed compounds 1e and 1i–o exhibited low, or no,
cytotoxicity. Analyzing the results from compounds such 1f–g,
despite they have shown moderate activity upon HEp-2 cells they
provided no encouraging results for other cell lines. However, ana-
lyzing the results upon diol 1h (entry 10), which has a tertiary
dibenzylic alkynol as feature, was possible to observe a wider
range of cytotoxicity, being liable for the following growth inhibi-
tions HEp-2 (84%), NCI-H292 (91%), HL-60 (96%), J774.A1 (93%),
K562 (80%) and RAW 264.7 (95%).
Although (S)-1a has been achieved in 95% ee, for an accurate
in vitro evaluation we decided to re-subject it to an additional
asymmetric acetylation upon CALB. Thereby, both (S)-7a and (R)-
a were achieved in their enantiopure form (Scheme 2).
8
The achievement of the absolute configuration for the unre-
acted enantiomer in the enzymatic kinetic resolution was done,
comparing the experimental optical rotation value obtained for
2
2
(
S)-7a [
a]
D
= À4.1 (c 1.0, CHCl
3
), 99% ee with the literature, where
). Then, after (S)-7a and (R)-8a have been
2
0
10
[
a
]
D
= À3.4 (c 1.0, CHCl
3
obtained in their enantiopure form, they were treated with CaCO
3
in MeOH, in order to hydrolyze de acetyl group, which furnished
the diols (R)-1a and (S)-1a (Scheme 3). Regarding to antiprolifera-
tive activity tests all the in vitro assays contained herein were
accomplished submitting the compounds (R)-1a, (S)-1a and (R/S)-
a–o against HEp-2, NCI-H292, MCF-7, K562, HL-60, J774.A1
e RAW 264.7 cell lines, that were obtained from the Cell Bank of
Rio de Janeiro, Brazil.
1
Although these results being less significant if compared with
the more complex structural natural product Osirisyne E (4), that
exhibit cytotoxicity against human leukemia cell line (LC50 = 25
Thus, a cytotoxic activity was evaluated using a colorimetric
lM), this communication shows the possibility of these com-
1
2
method (MTT), where the bioassay screening was conducted to
pounds be structurally modified into more cytotoxic derivatives.
Therefore, new opportunities aiming at the synthesis of small to
medium sized compounds containing a 1,4-alkynylic portion as
target can be evaluated.
determine the cytotoxic potential of the compounds 1a–o, at
1
00
lg/ml as the final concentration.
As shown in Table 1, the compounds R/S-1a, 1b, 1c and 1d
demonstrated cytotoxic activity with 100% inhibiting against the
cancer and normal cells lines.
Among all synthesized molecules, (R/S)-1a–d have shown to be
very active compounds against all the cancer cell lines tested.
Table 1
Antiproliferative activity of diols 1a–o against Hep-2; NCI-H292; MCF-7; K562; HL-60; J774.A1; RAW 264.7; cells
Entry
Compound
Percentage of cell death (%)
K562
HEp-2
NCI-H292
MCF-7
HL-60
J774.A1
RAW 264.7
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
(R/S)-1a
(R)-1a
(S)-1a
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k
1l
1m
1n
1o
100 (0.0)
38.8 (0.0)
31.3 (0.0)
100 (0.0)
100 (0.0)
100 (0.0)
28.1 (2.7)
84.1 (0.0)
85.7 (0.0)
84.0 (1.1)
2.2 (0.0)
100 (0.0)
55.7 (8.5)
85.0 (9.0)
100 (0.0)
100 (0.0)
100 (9.1)
86.9 (2.9)
71.5 (10.7)
49.9 (1.6)
91.0 (3.0)
0.3 (1.4)
100 (0.0)
52.5 (2.7)
51.6 (4.6)
100 (0.0)
100 (0.0)
100 (0.0)
68.1 (0.0)
69.5 (0.0)
54.1 (1.2)
27.3 (5.5)
17.8 (0.8)
40.7 (0.0)
34.3 (5.5)
40.8 (3.3)
27.2 (0.6)
28.7 (3.2)
0.0 (6.3)
100 (0.0)
40.9 (3.1)
27.0 (5.0)
100 (0.0)
100 (0.0)
100 (0.0)
3.8 (0.0)
0.0 (0.0)
0.0 (0.0)
80.0 (7.0)
25.1 (3.1)
9.7 (6.7)
0.0 (0.0)
16.7 (4.3)
16.0 (9.8)
20.9 (9.6)
0.0 (1.2)
91.7 (1.4)
100 (0.0)
12.1 (0.0)
1.4 (2.2)
100 (2.7)
100 (0.0)
100 (0.0)
29.5 (2.3)
9.6 (5.0)
0.0 (4.9)
96.1 (1.1)
0.0 (0.0)
7.3 (0.0)
5.1 (9.8)
8.9 (1.6)
13.3 (4.3)
0.0 (0.3)
11.0 (0.0)
92.9 (0.6)
100 (0.0)
0.2 (0.5)
1.7 (1.4)
100 (0.0)
9.6 (3.4)
19.5 (7.3)
100 (0.0)
100 (0.0)
100 (0.0)
16.0 (0.8)
19.3 (2.3)
17.8 (0.8)
95.0 (3.1)
9.4 (3.7)
0.0 (0.0)
6.1 (8.6)
4.2 (3.7)
0.0 (0.0)
17.8 (1.3)
8.5 (8.3)
96.5 (0.8)
100 (0.0)
100 (0.0)
100 (0.0)
17.1 (2.7)
15.7 (5.9)
30.4 (5.5)
93.1 (0.2)
16.5 (3.5)
55.3 (0.2)
42.6 (10.8)
57.5 (3.8)
61.2 (8.2)
2.0 (8.9)
0
1
2
3
4
5
6
7
8
0.0 (0.0)
12.9 (0.0)
9.3 (0.0)
21.5 (1.9)
15.5 (3.6)
6.6 (2.6)
0.0 (0.0)
5.0 (0.2)
42.7 (0.0)
14.8 (0.0)
79,4 (2,6)
69.8 (10)
20.2 (4.8)
94.1 (2.0)
60.8 (5.4)
96.0 (0.1)
DOX
74.8 (2.1)
Results are expressed as means (standard deviations) by MTT assay after 72 h of incubation.
DOX = Doxorubicin was the positive control.
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I. M. R. G. Princival et al. / Bioorg. Med. Chem. Lett. xxx (2016) xxx–xxx
Analyzing the molar concentration, compound (R/S)-1d has proved
to be most active compounds, using a fixed concentration of
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1
00
inhibition.
Thus, the present communication, for which small sized propar-
lg/mL, needing 0.16 mM solution for total cell growth
gylic diols were prepared and had their cytotoxicity evaluated,
should be property expanded and used as a guide for the investiga-
tion of others acetylenic target molecules featuring biochemical
relevance. For this, the current short chemoenzymatic approach
will be combined with others synthetic strategies.
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Please cite this article in press as: Princival, I. M. R. G.; et al. Bioorg. Med. Chem. Lett. (2016), http://dx.doi.org/10.1016/j.bmcl.2016.04.060