Microwave-assisted synthesis of biologically relevant steroidal 17-exo-pyrazol-5'-ones from a norpregnene precursor by a side-chain elongation/heterocyclization sequence

Article abstract of DOI:10.3762/bjoc.14.236

Multistep syntheses of novel 17β-pyrazol-5'-ones in the Δ⁵-androstane series were efficiently carried out from pregnenolone acetate. A steroidal 17-carboxylic acid was first synthesized as a norpregnene precursor by the bromoform reaction and subsequent acetylation. Its CDI-activated acylimidazole derivative was then converted to a β-ketoester containing a two carbon atom-elongated side chain than that of the starting material. A Knorr cyclization of the bifunctional 1,3-dicarbonyl compound with hydrazine and its monosubstituted derivatives in AcOH under microwave heating conditions led to the regioselective formation of 17-exo-hetero-cycles in good to excellent yields. The suppression of an acid-catalyzed thermal decarboxylation of the β-ketoester and thus a significant improvement in the yield of the desired heterocyclic products could be achieved by the preliminary liberation of the aryl-hydrazines from their hydrochloride salts in EtOH in the presence of NaOAc. The reaction rates were found to depend on the electronic character of the substituent present in the phenylhydrazine applied. The antiproliferative activities of the structurally related steroidal pyrazol-5'-ones and their deacetylated analogs were screened on three human adherent breast cancer cell lines (MCF7, T47D and MDA-MB-231): the microculture tetrazolium assay revealed that some of the presented derivatives exerted cell growth inhibitory effects on some of these cell lines comparable to those of the reference compound, cisplatin.

Full text of DOI:10.3762/bjoc.14.236

Microwave-assisted synthesis of biologically
relevant steroidal 17-exo-pyrazol-5'-ones from
a norpregnene precursor by a side-chain
elongation/heterocyclization sequence
Gergő Mótyán1, László Mérai1, Márton Attila Kiss1, Zsuzsanna Schelz2, Izabella Sinka2,
István Zupkó2 and Éva Frank*1
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2018, 14, 2589–2596.
1Department of Organic Chemistry, University of Szeged, Dóm tér 8,
H-6720 Szeged, Hungary and 2Department of Pharmacodynamics
and Biopharmacy, University of Szeged, Eötvös u. 6, H-6720 Szeged,
Hungary
doi:10.3762/bjoc.14.236
Received: 13 July 2018
Accepted: 25 September 2018
Published: 08 October 2018
Email:
Éva Frank* - frank@chem.u-szeged.hu
Associate Editor: I. R. Baxendale
* Corresponding author
© 2018 Mótyán et al.; licensee Beilstein-Institut.
License and terms: see end of document.
Keywords:
antiproliferative activity; Knorr reaction; microwave; pyrazol-5-ones;
steroids
Abstract
Multistep syntheses of novel 17β-pyrazol-5'-ones in the Δ5-androstane series were efficiently carried out from pregnenolone
acetate. A steroidal 17-carboxylic acid was first synthesized as a norpregnene precursor by the bromoform reaction and subsequent
acetylation. Its CDI-activated acylimidazole derivative was then converted to a β-ketoester containing a two carbon atom-elongated
side chain than that of the starting material. A Knorr cyclization of the bifunctional 1,3-dicarbonyl compound with hydrazine and its
monosubstituted derivatives in AcOH under microwave heating conditions led to the regioselective formation of 17-exo-hetero-
cycles in good to excellent yields. The suppression of an acid-catalyzed thermal decarboxylation of the β-ketoester and thus a sig-
nificant improvement in the yield of the desired heterocyclic products could be achieved by the preliminary liberation of the aryl-
hydrazines from their hydrochloride salts in EtOH in the presence of NaOAc. The reaction rates were found to depend on the elec-
tronic character of the substituent present in the phenylhydrazine applied. The antiproliferative activities of the structurally related
steroidal pyrazol-5'-ones and their deacetylated analogs were screened on three human adherent breast cancer cell lines (MCF7,
T47D and MDA-MB-231): the microculture tetrazolium assay revealed that some of the presented derivatives exerted cell growth
inhibitory effects on some of these cell lines comparable to those of the reference compound, cisplatin.
Introduction
17-exo-Heterocyclic androstanes with five or six-membered analogs in consequence of their dual pharmacological impor-
heterocyclic rings connected directly to C-17 of the sterane core tance. A number of these derivatives display an inhibitory effect
represent a remarkable subclass of semisynthetic sex hormone on 17α-hydroxylase-C17,20-lyase (P45017α) enzyme, which,
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Beilstein J. Org. Chem. 2018, 14, 2589–2596.
acting as an important regulator, plays an essential role in the In view of the above-mentioned reasons, the main objective of
endogenous production of androgen hormones, and therefore, in the present study was to design and carry out the preparation of
the development of prostate cancer [1]. According to extensive novel steroidal heterocycles containing pyrazol-5-one moieties
structure–activity relationship and docking studies, a potent attached to C-17 of the sterane core, using both conventional
steroidal inhibitor should possess certain structural characteris- heating and MW irradiation. The reaction conditions were opti-
tics for efficient P45017α inhibition [1-3], such as (i) a five or mized in order to improve the yields of the desired products and
six-membered non-bulky heterocycle containing O, N or the influences of substituents of the hydrazine reagents investi-
S atoms attached to position C-17 of the sterane skeleton with gated. The in vitro antiproliferative activities of the synthesized
the lone electron pairs capable of coordinating with the heme compounds were also determined on three human breast malig-
iron at the active site; (ii) a N atom at either position 3′ or 4′ nant cell lines (MCF7, T47D, and MDA-MB-231) by means of
relative to the atom through which the heterocyclic ring is 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide
connected to the sterane framework; (iii) a hydroxy or keto (MTT) assay [20]. Furthermore, the most promising molecules
group at C-3 and (iv) the presence of a C16–C17 double bond, were additionally tested on mouse fibroblasts (NIH-3T3) in
which facilitates the inhibitory effect but is not an essential order to obtain preliminary results concerning the cancer selec-
requirement. Some 17-heterocycle-substituted androstanes, tivity of the selected agents.
even those that lack the structural features described above, are
Results and Discussion
also known to display cytotoxic effects on diverse cancer cells
by inducing a disturbance in the cell cycle and promoting apo- Synthetic studies
ptosis without affecting normal cellular proliferation [4,5]. In The steroidal β-ketoester precursor 4, suitable for the attempted
these latter cases, detailed structural criteria are still not avail- heterocyclization reaction with hydrazines was synthesized
able owing to little information about the mode of action of from commercially available pregnenolone acetate (1) via a
these derivatives.
multistep sequence (Scheme 1). First compound 1 was con-
verted to the 17β-carboxylic acid 2b by the bromoform reaction
Amongst steroidal 17-exo-heterocycles, those containing a and subsequent acetylation according to well-known literature
pyrazole heteroaromatic ring are of special relevance with procedures [21-23]. After the activation of 2b with 1,1′-
respect to the above-mentioned bioactivities [6-9]. Interestingly, carbonyldiimidazole (CDI) as coupling reagent in THF, the
so far only a few examples of compounds in which a pyra- magnesium enolate of malonic acid half ester, prepared in situ
zolone moiety is attached to the sterane skeleton have been from potassium methyl malonate, MgCl2 and triethylamine in
published, but not to C-17 [10]. Nevertheless, this heterocyclic acetonitrile, was added [24,25]. The acylation of magnesium
scaffold is also an important building block in many clinically methyl malonate by the preformed imidazole 3 led to the
relevant drugs, agrochemicals, dyes, pigments and chelating desired bifunctional starting material 4 in good yield (79%).
agents [11-13], and therefore its introduction to C-17 of
androstanes may be of interest from a pharmacological point of Analogously, β-ketoester 4' could be obtained from pregna-
view.
dienolone acetate 1' through a Δ5,16-carboxylic acid intermedi-
ate [23,26] under identical conditions albeit in disappointing
The first and probably most frequently used method for the syn- low yield (33%) which is presumably caused by the decreased
thesis of pyrazolones is based on the Knorr condensation of propensity of the conjugated carbonyl compound to react with
β-ketoesters with substituted or unsubstituted hydrazines. How- the magnesium enolate. Although the presence of a C16–C17
ever, these reactions often suffer from certain disadvantages, double bond as in 4' is assumed to be beneficial for a P45017α-
such as the necessity of high temperature or prolonged reaction inhibitory effect, further transformations of this compound were
time and low yields of the desired products [14]. A rate acceler- abandoned because of the insufficient yield and its potential
ation and yield improvement could be achieved in some cases tendency to react with monosubstituted hydrazines – not only
by performing the reactions under microwave (MW) conditions with its β-ketoester moiety to give 17-exo-heterocycles, but
[15-17]. Especially with respect to pyrazol-5-ones, keto–enol also with its enone part to provide ring D-condensed pyrazo-
tautomerism can be challenging and is of special importance in lines [27].
biological systems, chemical reactivity, and molecular recogni-
tion [18]. The tautomeric equilibrium in solution is strongly Therefore, the ring-closure reactions of 4 with unsubstituted and
influenced by the substitution pattern of the heterocyclic monosubstituted hydrazines as binucleophilic reagents were in-
ring, the polarity and protic nature of the solvent and, vestigated next. First, compound 4 was reacted with hydrazine
although to a lesser extent, by the temperature and concentra- hydrate (5a) in refluxing ethanol containing a catalytic amount
tion [19].
of AcOH (Scheme 2).
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Beilstein J. Org. Chem. 2018, 14, 2589–2596.
Scheme 1: Multistep synthesis of steroidal β-ketoesters 4 and 4' from pregnenolone acetate (1) and pregnadienolone acetate (1').
Scheme 2: Cyclization of compound 4 with hydrazine hydrate (5a), phenylhydrazine (5b) and methylhydrazine (5c).
TLC monitoring of the reaction indicated full conversion of 4 tion indirectly. This derivatization did not only improve the
within 4 h reaction time to afford a fairly polar product insol- solubility of the compound, but also eliminated the possibility
uble or only slightly soluble in all commonly used NMR sol- of prototropic tautomerism through acetylation of both the
vents. However, a subsequent derivatization with acetic an- amino and hydroxy groups present in the heterocyclic ring in
hydride in pyridine to afford 8, allowed its structure verifica- 6a. The 1H and 13C NMR spectroscopical analysis confirmed
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the structure of 8, which at the same time supported the forma- amount of EtOH under mild heating for 10 min. To this solu-
tion of 6a in a yield of 84% during the previous reaction step. tion, containing NaCl as the only solid substance, the steroidal
While N-unsubstituted pyrazolones such as 6a theoretically dicarbonyl compound 4 dissolved in AcOH was added. The so
may have eight tautomeric forms [28], their N(1')-substituted obtained mixture was then irradiated in a MW reactor at 120 °C
derivatives, lacking a functionality on pyrazole C-4, can only for 20 min. Under these conditions, the corresponding product
exist in three equilibrating tautomers (OH, CH and NH) [18,29]. 6b was obtained in 85% yield after chromatographic purifica-
Therefore, further heterocyclizations of 4 were performed with tion without notable formation of 1.
monosubstituted hydrazine derivatives. The reaction with
phenylhydrazine (5b) was completed within 7 h in refluxing After optimizing the conditions for the MW-assisted synthesis
EtOH in the presence of an acid catalyst. A reduction of the of 6b from 4 with 5b·HCl, analogous heterocyclization reac-
reaction time to 3 h could be achieved by changing the solvent tions were carried out with different substituted phenylhydra-
to AcOH affording the desired product 6b in high yield (86%, zine hydrochlorides 5d–j. All reactions furnished the corre-
Scheme 2). On the other hand, the reaction of 4 with methylhy- sponding 17-exo-heterocycles 6d–j in good to excellent yields
drazine (5c) required a longer reaction time (5 h) in refluxing (83–92%, Table 1).
AcOH to furnish the purified product (6c) in a diminished yield
(61%). This may be attributed to the weaker nucleophilic char- The electronic features of the substituents on the aromatic ring
acter of the external N compared to the internal one in 5c [27], of 5 had a notable influence on the reaction rates. The ring-
in contrast to phenylhydrazine (5b), making the first condensa- closure of 4 with 5d–g containing electron-donating groups
tion step more difficult. The regioselectivity of the reactions (Table 1, entries 1–4) took place within shorter reaction times
with monosubstituted hydrazines is controlled by the higher re- (5–10 min) compared to phenylhydrazine (5b). On the other
activity of the ketone moiety over the ester towards nucleo- hand the presence of electron-withdrawing halogens on the aro-
philes, and the least hindered terminal nitrogen atom of the matic ring of 5 (Table 1, entries 5–7) lengthened the reaction
binucleophiles. Both reactions were repeated in AcOH under time to 30 min. This observation can be explained by the en-
microwave conditions at 120 °C furnishing products 6b and 6c hanced or diminished nucleophilic character of the nitrogen
within shorter time (20 min and 40 min), however, without a atoms caused by the different groups on the aromatic ring in 5,
substantial improvement in the yields.
favoring or hampering their nucleophilic attack during the
intermolecular heterocyclization. In order to enlarge the
Since commercially available arylhydrazine hydrochlorides compound library available for pharmacological studies, the
were intended to be applied for further transformations, the 3β-OH analogs 7a–j of the primary products 6a–j were also
reactions of 4 with 5b·HCl using an equivalent amount of synthesized through simple alkaline deacetylation (Scheme 2,
NaOAc in AcOH, both under conventional heating and MW ir- Table 1).
radiation, were also carried out. Although similar reaction
conditions have been described in the literature for the reac- The structures of all synthesized compounds were character-
tions of methyl acetoacetate with arylhydrazine hydrochlorides ized by 1H and 13C NMR spectroscopy supplemented by IR and
to afford the corresponding pyrazol-5-ones in 50–70% yields MS measurements. The dependence of the tautomeric equilib-
within 5–10 h [30], no full conversion of 4 could be achieved. rium on the polarity of the applied solvent was observed during
Even after refluxing the mixture for 24 h the desired product 6b the NMR experiments. For example, in the 1H NMR spectrum
was obtained only in low yield (≈30%). At the same time, the of compound 7f recorded immediately after dissolution in
use of the MW-assisted method at 120 °C shortened the conver- CDCl3, the pyrazolone heterocyclic ring mainly exists as the
sion time significantly (80 min). However, in addition to 6b CH-tautomeric form (Figure 1). The characteristic signals of the
(≈50%), the conventional, and even more the MW-promoted 4'-methylene hydrogens appear at 3.36 and 3.46 ppm in the
transformations led to a considerable amount (20–25%) of preg- 1H NMR spectrum. However, in the more polar solvent DMSO-
nenolone acetate (1) as a byproduct. The latter is thought to be d6, the equilibrium mixture of the NH- and OH-tautomers of 7f
produced by an acid-catalyzed thermal decarboxylation of 4 predominates. As the activation barrier between these latter
during the relatively long heating period. Further the unwanted isomers is low and their interconversion is rapid on the NMR
side reaction was attributed to the poor solubility of 5b·HCl in timescale, only average signals can be observed for the 4'-H and
AcOH resulting in a heterogeneous reaction mixture even at NH/OH protons [31].
high temperature and therefore a slow liberation of 5b from its
salt upon the addition of NaOAc. In order to circumvent this Pharmacological studies
issue, the reaction was repeated with in situ-liberated phenylhy- The pharmacological activities of the synthesized 17-exo-
drazine (5b) by dissolving 5b·HCl and NaOAc in a small heterocycles 6a–j and 7a–j were studied in vitro. Their antipro-
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Table 1: Synthesis of steroidal N(1')-aryl-substituted pyrazol-5'-onesa.
entry
arylhydrazine hydrochloride
R
pyrazol-5-one
irradiation time (min)
yieldb (%)
1
2
3
4
5
6
7
5d
5e
5f
Me
iPr
6d
6e
6f
10
10
10
5
86
90
87
92
85
83
85
t-Bu
OMe
F
5g
5h
5i
6g
6h
6i
30
30
30
Cl
5j
Br
6j
aReagents and conditions: arylhydrazine hydrochloride 5d–j·HCl (1.2 equiv), NaOAc (1.2 equiv), EtOH (10 mL), 40 °C, 10 min, then compound 4
(1.0 mmol) in AcOH (20 mL), MW, 120 °C, 5–30 min. bAfter purification by column chromatography.
Figure 1: 1H NMR spectra of compound 7f in CDCl3 (top; # solvent signal) and in DMSO-d6 (bottom; # solvent signal).
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liferative effects were determined by means of the MTT assay were calculated by using a set of dilutions (Figure S1 in Sup-
[20] on a panel of adherent breast cancer cell lines (MCF7, porting Information File 1). The viability assays were repeated
T47D and MDA-MB-231) after treatment for 72 h (Table 2). with the most potent agents 6h, 7f, 7i and 7j against NIH-3T3
All compounds were initially screened at 10 and 30 μM concen- mouse fibroblasts to generate preliminary data concerning the
trations and for those compounds that elicited growth inhibition cancer selectivity. Since the molecular site of action of the
of at least 50% at 10 μM and around 90% at 30 μM, IC50 values tested compounds is not known, cisplatin (a clinically used
Table 2: Antiproliferative effects of the synthesized compounds on gynecological cell lines and NIH-3T3 fibroblasts.a
compound
conc. (μM)
inhibition of cell proliferation (%) ± SEM
[calculated IC50 (μM)]
MCF7
MDA-MB-231
T47D
NIH-3T3
n.d.
10
30
25.7 ± 1.1
70.0 ± 1.0
–
–
6a
6b
6c
6d
6e
6f
30.9 ± 2.0
58.9 ± 1.0
10
30
–
–
38.2 ± 1.5
90.9 ± 0.6
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
76.8 ± 0.3
72.1 ± 0.4
10
30
–
–
–
52.2 ± 2.8
26.8 ± 1.2
83.8 ± 1,3
10
30
–
–
–
–
35.8 ± 1.1
51.4 ± 1.7
10
30
–
–
–
–
–
41.7 ± 2.6
10
30
–
–
–
73.8 ± 0.6
29.3 ± 3.0
72.2 ± 1.7
10
30
–
–
–
–
6g
47.4 ± 1.5
60.7 ± 2.2
10
30
65.1 ± 0.9
95.1 ± 1.1
[9.0]
–
74.9 ± 2.4
84.2 ± 1.6
[6.5]
–
90.8 ± 0.5
88.3 ± 0.8
[18.1]
6h
10
30
–
–
22.2 ± 1.3
78.0 ± 0.6
6i
6j
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
87.8 ± 0.7
29.2 ± 1.2
10
30
31.0 ± 1.7
86.4 ± 1.4
–
31.1 ± 2.2
77.5 ± 1.1
27.0 ± 1.0
10
30
–
–
–
–
57.0 ± 0.9
65.8 ± 1.3
7a
7b
7c
7d
7e
10
30
–
–
–
85.8 ± 1.0
40.6 ± 1.7
89.6 ± 0.7
10
30
–
–
–
–
23.1 ± 2.6
57.9 ± 2.0
10
30
–
–
–
31.1 ± 1.7
60.3 ± 1.9
27.9 ± 2.7
10
30
–
–
–
–
66.3 ± 1.5
95.8 ± 0.2
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Table 2: Antiproliferative effects of the synthesized compounds on gynecological cell lines and NIH-3T3 fibroblasts.a (continued)
10
30
21.1 ± 2.8
95.8 ± 0.3
31.3 ± 1.3
89.6 ± 0.8
83.1 ± 1.3
87.5 ± 0.5
[4.3]
–
84.6 ± 1.3
[18.2]
7f
10
30
–
–
22.3 ± 1.3
55.7 ± 2.2
7g
7h
n.d.
n.d.
40.9 ± 1.6
39.6 ± 1.7
10
30
–
–
–
91.3 ± 0.8
96.8 ± 0.2
85.2 ± 1.1
10
30
66.8 ± 1.7
96.3 ± 0.2
[6.9]
31.3 ± 1.5
96.8 ± 0.2
32.8 ± 1.3
87.8 ± 0.5
–
94.0 ± 0.5
[15.3]
7i
7j
10
30
58.6 ± 1.2
89.5 ± 1.1
[8.1]
42.0 ± 0.8
96.1 ± 0.2
48.3 ± 1.9
85.5 ± 1.2
–
91.1 ± 1.0
[17.3]
10
30
66.9 ± 1.8
96.8 ± 0.4
[5.8]
–
51.0 ± 2.0
55.0 ± 1.5
[9.8]
94.2 ± 0.4
96.4 ± 0.2
[3.2]
71.5 ± 1.2
[19.1]
cisplatin
aCompounds eliciting less than 20% inhibition of proliferation were considered ineffective and the exact results are not given, for simplicity. n.d.: not
determined.
DNA-binding anticancer agent) was applied as the reference. decarboxylation of the starting material as an unwanted side
The results indicated that the 3β-acetates 6a–j exhibited weak reaction could be avoided by applying a one-pot two-step
or only modest antiproliferative activities, typically eliciting protocol involving the in situ liberation of the reagent from its
20–30% growth inhibition at 10 μM. However, the p-fluoro de- salt in EtOH followed by the heterocyclization reaction through
rivative 6h, proved to be more effective on MCF7 and T47D the addition of AcOH. Some of the presented compounds 6h,
cells. The deacetylated analogs 7a–j generally inhibited cancer 7f, 7i and 7j exerted considerable antiproliferative activity with
cell growth more efficiently. The character of the substituent on promising cancer selectivity on a panel of human breast cancer
the aromatic ring was crucial for the antiproliferative actions on cell lines. This indicates that the pyrazolone heterocyclic ring at
the different cell lines. A tert-butyl group at the para position the 17β position is a promising scaffold for the design of anti-
(7f) appeared favorable against T47D cells resulting in an IC50 cancer agents of the Δ5 androstene series.
value lower than that of the reference cisplatin. While the
chloro and bromo-substituted derivatives exerted more pro-
Supporting Information
nounced effects on MCF7 cells in their 3-OH form (7i and 7j),
the fluoro compound 7h proved to be less active than its ester
Experimental procedures for compounds 6a–j, 7a–j and 8,
6h. Although the performed viability assay on animal fibro-
their 1H, 13C NMR, MS, IR, elemental analysis data and
blasts cannot be considered as an appropriate toxicological eval-
the copies of their NMR spectra.
uation, the obtained results are promising and point to a less
Supporting Information File 1
Experimental part.
growth inhibiting action of the compounds on fibroblasts than
on cancer cells. All of them displayed less than 20% growth
inhibition at 10 μM and their calculated IC50 values proved to
be higher than those obtained on the malignant cell lines.
[https://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-14-236-S1.pdf]
Conclusion
In summary, a microwave-assisted one-pot method for the Acknowledgements
facile and efficient synthesis of novel steroidal 17-exo-pyrazol- Financial support by National Research, Development and
5'-ones from a β-ketoester precursor with arylhydrazine hydro- Innovation Office – NKFIH through projects GINOP-2.3.2-15-
chlorides has been developed. An acid-catalyzed thermal 2016-00038 and OTKA-109107 is gratefully acknowledged.
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Beilstein J. Org. Chem. 2018, 14, 2589–2596.
23.Kovács, D.; Wölfling, J.; Szabó, N.; Szécsi, M.; Minorics, R.; Zupkó, I.;
Frank, É. Eur. J. Med. Chem. 2015, 98, 13–29.
ORCID® iDs
Gergő Mótyán - https://orcid.org/0000-0002-0741-106X
Márton Attila Kiss - https://orcid.org/0000-0003-3844-3758
Éva Frank - https://orcid.org/0000-0002-1332-0551
doi:10.1016/j.ejmech.2015.05.010
24.Magano, J.; Nanninga, T. N.; Winkle, D. D. Tetrahedron Lett. 2008, 49,
2956–2959. doi:10.1016/j.tetlet.2008.03.004
25.Allan, K. M.; Hong, B. D.; Stoltz, B. M. Org. Biomol. Chem. 2009, 7,
4960–4964. doi:10.1039/B913336D
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