Synthesis of vinca alkaloid–triphenylphosphine derivatives having potential antitumor effect

Article abstract of DOI:10.1080/10426507.2018.1550780

The successful therapy of cancer is still unresolved. For that reason enormous efforts are being made to increase the effectiveness of anticancer drugs and reduce their side effects at least. An important approach to the development of selective molecules is the synthesis of drug conjugates, also called as “hybrids”. Taking this into consideration two Vinca alkaloid derivatives conjugated with triphenylphosphine have been synthetized. The incorporation of the mentioned two pharmacophores in the same molecule could amplify the evolving cumulative antineoplastic impact and/or counterbalance the side effects. Thus a development of hybrid anticancer molecules has been started by synthesis of Vinca alkaloid–triphenylphosphine conjugates, which could have higher efficacies and safety profiles than the present drugs available in market.

Full text of DOI:10.1080/10426507.2018.1550780

Phosphorus, Sulfur, and Silicon and the Related Elements
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Synthesis of vinca alkaloid–triphenylphosphine
derivatives having potential antitumor effect
András Keglevich, Áron Szigetvári, Miklós Dékány, Csaba Szántay Jr., Péter
Keglevich & László Hazai
To cite this article: András Keglevich, Áron Szigetvári, Miklós Dékány, Csaba Szántay Jr., Péter
Keglevich & László Hazai (2019): Synthesis of vinca alkaloid–triphenylphosphine derivatives
having potential antitumor effect, Phosphorus, Sulfur, and Silicon and the Related Elements, DOI:
10.1080/10426507.2018.1550780
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PHOSPHORUS, SULFUR, AND SILICON AND THE RELATED ELEMENTS
https://doi.org/10.1080/10426507.2018.1550780
Synthesis of vinca alkaloid–triphenylphosphine derivatives having potential
antitumor effect
a
b
b
b
a
a
ꢀ
Andr ꢀa s Keglevich , Aron Szigetv ꢀa ri , Mikl oꢀ s D ꢀe k ꢀa ny , Csaba Sz ꢀa ntay Jr. , P eꢀ ter Keglevich , and L ꢀa szl oꢀ Hazai
a
b
Department of Organic Chemistry and Technology, Budapest University of Technology and Economics, Budapest, Hungary; Spectroscopic
Research Department, Gedeon Richter Plc, Budapest, Hungary
ABSTRACT
ARTICLE HISTORY
The successful therapy of cancer is still unresolved. For that reason enormous efforts are being
made to increase the effectiveness of anticancer drugs and reduce their side effects at least. An
important approach to the development of selective molecules is the synthesis of drug conju-
gates, also called as “hybrids”. Taking this into consideration two Vinca alkaloid derivatives conju-
gated with triphenylphosphine have been synthetized. The incorporation of the mentioned two
pharmacophores in the same molecule could amplify the evolving cumulative antineoplastic
impact and/or counterbalance the side effects. Thus a development of hybrid anticancer molecules
has been started by synthesis of Vinca alkaloid–triphenylphosphine conjugates, which could have
higher efficacies and safety profiles than the present drugs available in market.
Received 25 September 2018
Accepted 18 November 2018
KEYWORDS
Anticancer drugs;
triphenylphosphine;
1
7-desacetylvindoline; dimer
alkaloids; hybrid molecules
GRAPHICAL ABSTRACT
Introduction
designed to react with multiple targets or to increase the
effectiveness and/or decrease the coexisting side effects
through the united molecule built by two or more beneficial
pharmacophore parts. Building hybrid molecules is a
well-known and widespread method in modern drug investi-
gation, especially in the field of oncology. Natural or ori-
ginally natural molecules conjugated with (semi)synthetic
compounds possessing at least two pharmacophores in one
single derivative should be meant by “hybrids”.
The main purpose of the project in question was to make
and analyze some of these hybrids which may have reason-
able safety profile and significant efficacy at the same time.
Attempts have been made to get Vinca alkaloid conjugates
The dimer alkaloids vinblastine (vincaleukoblastine, VLB, 1)
and vincristine (VCR, 2) (Figure 1), isolated from the
Madagascar periwinkle Catharanthus roseus are remarkable
representatives of the family called as “bisindole” alkaloids.
Their structure consists of two monomers with an indole skel-
eton: derivatives catharanthine (3) and vindoline (4). VLB (1),
VCR (2) and some of their semi-synthetic analogs have been
playing a considerable part in cancer chemotherapy for deca-
[
6]
[1,2]
des
especially in the field of lymphomas and leukemia.
In order to improve the activity, the structures of the
mentioned alkaloids have been modified using differ-
[
3–5]
ent methods.
Another important approach in the development of coupled with synthetic pharmacophore compounds, first of
selective anticancer drugs is the synthesis of special mole- all with triphenylphosphine (TPP), a generally known
cules called “hybrids”. These derivatives are basically pharmacophore unit.
CONTACT Andr ꢀa s Keglevich
keglevich.andras@mail.bme.hu; L ꢀa szl ꢀo Hazai
hazai@mail.bme.hu
Department of Organic Chemistry and Technology,
Budapest University of Technology and Economics, Gell ꢀe rt t ꢀe r 4, Budapest H-1111, Hungary.
Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/gpss.
ß 2018 Taylor & Francis Group, LLC

2
A. KEGLEVICH ET AL.
OH
H
N
N
N
H
H
COOCH3
N
N
H
3
H COOC
3
N
H CO
N
R
OCOCH3
3
H
OH
COOCH3
1
2
R = CH3
R = CHO
H3CO
N
OCOCH3
H
OH
CH3
COOCH3
4
Figure 1. The alkaloids vinblastine (1), vincristine (2), catharanthine (3) and vindoline (4).
1
5
Table 1. Growth percent rates of the investigated molecules at NIH (9 and
1
6
1
1 ) against variety of cell lines of different tumors.
[15]
[16]
9
11
Leukemia
HL-60(TB)
90.48
253.10
Non-small cell lung cancer
HOP-92
NCI-H522
77.57
79.00
240.05
235.39
Colon cancer
COLO 205
101.01
287.91
Melanoma
SK-MEL-2
SK-MEL-5
UACC-62
103.22
84.26
83.77
265.31
291.47
259.27
Figure 2. The structure of the triterpenoid betulin (5).
Breast cancer
MDA-MB-468
95.74
275.59
9
1
: 17-desacetylvindoline linked with 4-bromobutiric acid.
1: 17-desacetylvindoline–4-bromobutiric acid–triphenylphosphine hybrid.
N
1
0
derivatives of betulin (5) against variety of tumors in vitro
and in vivo.
We were interested in not only the TPP moiety which
might be built into the Vinca alkaloids but in acyl linkers
with different length of the chain. The length of the linker
compound may affect the cytotoxic activity of the conju-
[
9]
1
7
1
6
H CO
N
OH
3
H
OH
COOCH3
CH3
6
Figure 3. The structure of the 17-desacetylvindoline (6) with possible cou- gated product. Noble et al. reported that minor modifica-
pling positions.
tions in the bisindole structure can result in major changes
[
10]
in the biological activity of the whole molecule.
It is important to mention that vindoline (4) could be
lin (5) (Figure 2) were synthesized and evaluated for cyto- connected indirectly with linkers in several positions such as
A series of new TPP derivatives of the triterpenoid betu-
[
7]
toxic effects by Tsepaeva et al.
10, 16, and 17. In this project the starting point was 17-
In their experiments the TPP moiety was applied as a desacetylvindoline (17-DV, 6) (Figure 3). This material can
carrier group through an acyl linker to betulin (5) promot- be obtained by a simple hydrolysis of vindoline (4) in pos-
[
11]
ing cellular and mitochondrial accumulation of the com- ition 17.
pound. An enhanced antiproliferative activity toward
vinblastine-resistant MCF-7 cells was demonstrated. Betulin
1
Results and discussion
(
5) is a naturally occurring triterpenoid which can be iso-
[
8]
lated from the bark of birch trees. This molecule has a 17-DV (6) is a monomer which does not possess any bio-
pentacyclic ring structure and two hydroxyl groups in posi- logical activity but it is stable and relatively easy to work
tions C3 and C28. It is famous for its biological activity and with. In contrast, VLB (1) or VCR (2) have antitumor activ-
several examinations have shown the effectiveness of the ity, but also suffer from degradability. Therefore a hypoth-
esis has been made predicting that not just dimeric Vinca
1
alkaloids, but also an ineffective monomer—in our case 17-
DV (6)—could be cytotoxic as part of a hybrid molecule.
MCF-7: breast cancer cell line. It is the acronym of Michigan Cancer
Foundation-7.

PHOSPHORUS, SULFUR, AND SILICON AND THE RELATED ELEMENTS
3
N
1
7
O
H CO
N
O
3
H
OH
COOCH3
N
CH3
n Br
DCC, DMAP, anhydrous DCM
7
(n=1), 55%; 9 (n=3), 67%; 10 (n=4), 60%
O
17
1
6
Br
H CO
N
OH
N
3
H
OH
COOCH
HO
n
CH3
3
n=1: 2-bromoacetic acid (1,80 ekv)
n=2: 3-bromopropionic acid (1,80 ekv)
n=3: 4-bromobutyric acid (1,05 ekv)
n=4: 5-bromovaleric acid (1,70 ekv)
1
7-desacetylvindoline (6)
1
7
O
H CO
N
O
3
H
OH
COOCH3
CH3
8
, 16%
Scheme 1. Esterification of 2-bromoacetic acid, 3-bromopropionic acid, 4-bromobutyric acid and 5-bromovaleric acid.
N
N
anhydrous acetonitrile, argon atm., reflux
O
Br
O
H CO
N
CH
O
3
H
OH
H CO
N
O
3
H
OH
COOCH3
P
3
P
COOCH3
n
CH3
Br
n
triphenylphosphine
9
(n=3)
11 (n=3), 80%
12 (n=4), 44%
(8 ekv)
1
0 (n=4)
16
17
Scheme 2. Synthesis of the Vinca alkaloid–TPP hybrids (11 and 12 ).
Preparation of linker containing 17-desacetylvindoline
6) derivatives
them with TPP. First an acetonitrile solution of product 7
was treated with TPP at room temperature then under
reflux for a few hours. However, a pure product could not
be obtained from the reaction mixture. As a continuation
the remaining experiments were completed with the rest of
(
The first step of our current work has been the investigation
of the reactions of 17-DV (6) and the mentioned acyl linkers.
a-, b-, c- and d bromocarboxylic acids have been used as con-
junctives. First the 2-bromoacetic acid was investigated in cou-
pling reaction with 17-DV (6) in the presence of
[
15]
the conjugates (9
and 10, Scheme 2). The expected
[
16]
hybrid molecules were successfully obtained (11 , 80%
[
17]
0
and 12 , 44%). The order of the addition of the reactants
N,N -dicyclohexylcarbodiimide (DCC) and 4-(dimethylamino)-
was important, the linkers were always coupled first with
pyridine (DMAP). The appropriate product (7) was success-
fully obtained. Then our work has been continued with the
coupling reaction of 3-bromopropionic acid, however, we
could not obtain the expected product, only its analog (8,
1
7-DV (6) and only after with TPP to avoid working
with salts.
1
6%) after elimination of hydrogen bromide. In the case of 4-
Biology
bromobutyric acid and 5-bromovaleric acid the expected prod-
[15]
[15]
The biological activity of two synthesized compounds (9
ucts (9 , 67% and 10, 60%) were obtained. In addition, 10,
delta-valerolactone was also obtained as a byproduct. The
above-mentioned reactions can be seen in Scheme 1.
[
16]
and 11 ) were investigated at the National Institutes of
Health (NIH), US. The cytotoxic effect of the mentioned
The question arises why only the OH group in position 17 derivatives were measured on 60 different tumor cell lines of
was acylated. This regioselectivity is the result of steric hindrance 9 often occurring cancer types in vitro. It was found that
[
15]
proceeded by the tertiary character of OH group in position 16.
compound 9
was ineffective, however, hybrid molecule
[
16]
1
1
showed increased antiproliferative activity. This fact
proved our hypothesis that although Vinca alkaloid mono-
mers do not show any biological activity on their own but
TPP moiety can promote the anticancer efficacy when a
Synthesis of 17-desacetylvindoline
(6)–triphenylphosphine (TPP) hybrids
[
15]
After the corresponding conjugates (7, 9
and 10) were monomer will be converted to
a
hybrid molecule.
[16]
produced with in-built linkers, the next step was to couple Compound 11
has had especially significant inhibiting

4
A. KEGLEVICH ET AL.
effect in colon cancer (COLO 205), melanoma (SK-MEL-2
and SK-MEL-5) and breast cancer (MDA-MB-468). There
was no cytotoxicity study regarding compound 10, however,
Vinorelbine Amide Analogues. Bioorg. Med. Chem. Lett. 2012,
2, 7547–7550. DOI: 10.1016/j.bmcl.2012.10.024.
6] Nepali, K.; Sharma, S.; Sharma, M.; Bedi, P. M. S.; Dhar, K. L.
Rational Approaches, Design Strategies, Structure Activity
Relationship and Mechanistic Insights for Anticancer Hybrids.
Eur. J. Med. Chem. 2014, 77, 422–487.
2
[
[17]
the analysis of hybrid molecule 12
is currently
in progress.
The NCI screening procedures have been already
[7] Tsepaeva, O. V.; Nemtarev, A. V.; Abdullin, T. I.; Grigor’eva,
L. R.; Kuznetsova, E. V.; Akhmadishina, R. A.; Ziganshina,
L. E.; Cong, H. H.; Mironov, V. F. Design, Synthesis, and
[
12]
described
lines.
as well as the origins and processing of the cell
In Table 1 the percentages of growth are listed
[
12–14]
Cancer
Cell
Growth
Inhibitory
Activity
of
[15]
[16]
for compounds 9
and 11
at the concentration of
Triphenylphosphonium Derivatives of the Triterpenoid Betulin.
J. Nat. Prod. 2017, 80, 2232–2239. DOI: 10.1021/
acs.jnatprod.7b00105.
ꢀ
5
1
0
M. The larger negative numbers show a more signifi-
cant decrease of cell numbers and the smaller positive num-
bers mean greater growth inhibition. The results are
summarized in Table 1. Only cell lines were represented
where a minimum of one of the two investigated derivatives
[
[
8] Green, B.; Bentley, M. D.; Chung, B. Y.; Lynch, N. G.; Jensen,
B. L. Isolation of Betulin and Rearrangement to Allobetulin. A
Biomimetic Natural Product Synthesis. J. Chem. Educ. 2007, 84,
1985–1987. DOI: 10.1021/ed084p1985.
[
15]
[16]
(9
and 11 ) reached at least -30% growth percent.
€
€
9] Alakurtti, S.; Makela, T.; Koskimies, S.; Yli-Kauhaluoma, J.
Pharmacological Properties of the Ubiquitous Natural Product
Betulin. Eur. J. Pharm. Sci. 2006, 29, 1–13. DOI: 10.1016/
j.ejps.2006.04.006.
Conclusions
[
10] Noble, R. L.; Beer, C. T.; McIntyre, R. W. Biological Effects of
A production of Vinca alkaloid conjugates was proposed in
Dihydrovinblastine. Cancer 1967, 20, 885–890.
conformity with the new trend of building “hybrids” in [11] Passarella, D.; Giardini, A.; Peretto, B.; Fontana, G.; Sacchetti,
[
6]
A.; Silvani, A.; Ronchi, C.; Cappelletti, G.; Cartelli, D.; Borlak,
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Anhydrovinblastine and Vinorelbine with Thiocolchicine,
Podophyllotoxin and Baccatin III. Bioorg. Med. Chem. 2008, 16,
6269–6285. DOI: 10.1016/j.bmc.2008.04.025.
modern drug research. A demonstrable antitumor effect
was presumed by connecting a Vinca alkaloid monomer
with triphenylphosphine (TPP). Coupling reactions of 17-
desacetylvindoline (6) with TPP resulted in the expected
[
16]
[17]
hybrid molecules (11
ously produced conjugates (9
carboxylic acids. The anticancer investigation of hybrid
and 12 ) originated by two previ-
[
15]
[
[
12] Monks, A.; Scudiero, D.; Skehan, P.; Shoemaker, R. H.; Paull,
K.; Vistica, D.; Hose, C.; Langley, J.; Cronise, P.; Vaigro-Wolff,
A.; et al. Feasibility of a High-flux Anticancer Drug Screen
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83.11.757.
13] Alley, M. C.; Scudiero, D. A.; Monks, A.; Hursey, M. L.;
Czerwinski, M. J.; Fine, D. L.; Abbott, B. J.; Mayo, J. G.;
Shoemaker, R. H.; Boyd, M. R. Feasibility of Drug Screening
with Panels of Human Tumor Cell Lines Using a Microculture
Tetrazolium Assay. Cancer Res. 1988, 48, 589–601.
and 10) linked with bromo-
[
16]
molecule 11
showed that it had been effective in different
tumor cell lines. Its promising result confirmed the expected
positive role of TPP group which can facilitate Vinca alkal-
oid monomers to be potent antitumor drugs.
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ꢁ
3] Allemann, O.; Brutsch, M.; Lukesh III, J. C.; Brody, D. M.; [15] Appearance: white, crystalline. Mp 70–74 C. TLC (dichloro-
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ꢀ
1
1616, 1598, 1502, 1435, 1247, 1225, 1168, 1121, 1028 cm
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ꢁ
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f
¼ 0.14. IR (KBr): 3397,
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