Synthesis, conformational analysis, and biological evaluation of 19-nor-vitamin D3 analogues with A-ring modifications

Article abstract of DOI:10.1021/jm900711d

We have synthesized several isomers of 19-nor-vitamin D analogues possessing a hydroxy group at C-2 as well as novel derivatives bearing an epoxy substituent at the A-ring. All vitamins were prepared in convergent syntheses utilizing the modified Julia ol

Full text of DOI:10.1021/jm900711d

6158 J. Med. Chem. 2009, 52, 6158–6162
DOI: 10.1021/jm900711d
Synthesis, Conformational Analysis, and Biological Evaluation of 19-nor-Vitamin D3
Analogues with A-Ring Modifications
†
†
‡
‡
,†
Laura Sanchez-Abella, Susana Fernandez, Annemieke Verstuyf, Lieve Verlinden, Vicente Gotor,* and Miguel Ferrero*
,†
ꢀ
ꢀ
†
´
ꢀ
ꢀ
´
Departamento de Quımica Organica e Inorganica and Instituto Universitario de Biotecnologıa de Asturias, Universidad de Oviedo,
33006-Oviedo (Asturias), Spain, and ‡Laboratorium voor Experimentele Geneeskunde en Endocrinologie, Katholieke Universiteit Leuven,
Gasthuisberg, B-3000 Leuven, Belgium
Received May 26, 2009
We have synthesized several isomers of 19-nor-vitamin D analogues possessing a hydroxy group at C-2
as well as novel derivatives bearing an epoxy substituent at the A-ring. All vitamins were prepared in
convergent syntheses utilizing the modified Julia olefination. 1R,2R,25-Trihydroxy-19-nor-vitamin D3
(3) and 2β,3β-epoxy-1R,25-dihydroxy-3-deoxy-19-nor-vitamin D3 (10), which showed the highest
affinity to the vitamin D receptor, displayed the highest potency among the tested compounds to
inhibit the proliferation of MCF-7 breast cancer cells.
Introduction
synthesized novel analogues containing an epoxy function at
the A-ring (9 and 10).
First discovered as a treatment for the rickets disease in late
18th century, the efficacy of 1R,25-(OH)2-D3 (1R,25-(OH)2-
D3 (1), Figure 1) as therapeutic agent in a variety of human
diseases such as cancer, psoriasis, immunodeficiency, and
osteoporosis is extremely promising.1
Results and Discussion
Chemistry. The synthesis of compounds 5-10 was envi-
saged using the modified Julia olefination to construct a
diene unit between the A-ring and the CD side chain frag-
ment as previously reported by Kittaka.5c
A-Ring synthons were obtained starting from methyl
quinate and its 3-epi and 5-epi-isomers7 (Scheme 1). The next
step was selective protection of the hydroxyl groups at C-3,
C-4, and C-5 as tert-butyldimethylsilyl ethers. Reaction of the
esters 12a-c with NaBH4 generated the alcohols 13a-c, which
were directly oxidized to cyclohexanone derivatives 14a-c
using NaIO4.
The synthesis of the CD-ring/side chain fragment was
accomplished starting from Grundmann0s ketone, which
was oxidized at the 25-position (steroid numbering) and then
protected as an ethoxymethyl ether to afford 16 (Scheme 2).
The ketone was transformed to vinyl ester 17, which was
treated with DIBALH in toluene to provide the allylic
alcohol 18. The latter was converted to sulfone 19 through
sulfonation with 2-mercaptobenzothiazole under Mitsuno-
bu conditions and subsequent oxidation catalyzed by
(NH4)6MoO24.
A-Ring modified 19-nor-vitamin D3 analogues were
synthesized as illustrated in Scheme 3. Reaction of ketone
14a with the lithium enolate of sulfone 19 and deprotection
of the protecting groups with (-)-CSA gave 1R,2R,25-
(OH)3-19-nor-D3 (3) and 1R,2β,25-(OH)3-19-nor-D3 (4) as
a mixture of diastereoisomers in a 4:1 ratio.
However, its clinical utility is limited because the therapeu-
tically effective doses induce hypercalcemia and hypercalciu-
ria. A continuing challenge in vitamin D research is to achieve
an optimal balance between high antiproliferative and differ-
entiation activities and low calcemic potency. During the last
years, much attention has been focused on the synthesis of
19-nor-vitamin D derivatives. The effects of 1R,25-dihydroxy-
19-nor-vitamin D3 (2)2 on HL-60 leukemia cell differentiation
and osteocalcin secretion by MG63 cells were nearly identical
to the natural hormone.3b Interestingly, its calcemic effects
were clearly reduced (e10%) compared to 1R,25-(OH)2-D3.3
Recently, DeLuca and co-workers synthesized several 19-nor
C-2 substituted derivatives, some of which have interesting
biological activities.4
Synthesis of 1R,2R,25-trihydroxy-19-nor-vitamin D3 (3,
Figure 2) and 1R,2β,25-trihydroxy-19-nor-vitamin D3 (4) have
been reported.5 The 2β-hydroxy analogue 4 had potent intest-
inal calcium transport equal to that of the native hormone,
while the 2R-isomer 3 possessed less activity. The latter showed
high potency in inducing differentiation of HL-60 cells with
weak ability to mobilize calcium from bone.5a
Because of the importance of A-ring stereochemistry in the
biological response, this paper aims to describe the synthesis of
various 2-hydroxy derivatives (5-8) of the natural hormone
with different stereochemistry at C-1, C-2, and C-3. In addition,
the biological properties of these compounds were evaluated in
order to compare with the corresponding 6-s-cis locked analo-
gues previously described by us.6 In this context, we also
Both analogues were separated by reverse phase HPLC.
Since these derivatives have been previously described,5
comparison of 1H NMR data revealed that the major isomer
was the 2R-hydroxy compound 3, which was isolated in
52% yield (coupling and deprotection steps). Conforma-
tional equilibrium of 3 is strongly shifted to the R-chair
conformer. On the other hand, compound 4 prefers a β-chair
*To whom correspondence should be addressed. For V.G.: phone,
þ34 98 510 3448; fax, þ34 98 510 3448; E-mail, VGS@uniovi.es. For
M.F.: E-mail, MFerrero@uniovi.es.
r
pubs.acs.org/jmc
Published on Web 09/09/2009
2009 American Chemical Society

Brief Article
Journal of Medicinal Chemistry, 2009, Vol. 52, No. 19 6159
Scheme 2. Synthesis of CD-Ring/Side Chain Fragment 19
Figure 1. Chemical
1R,25-(OH)2-19-nor-D3.
structures
of
1R,25-(OH)2-D3
and
Scheme 3. Syntheses of 19-nor-Derivatives 3 and 4
them A and B according to the rate of elution in the HPLC
chromatogram (p S89, panel A, SI). The identification of the
synthesized analogues was determined as follows.
The protons at C1, C2, and C3 of derivative A appear close
1
by in the H NMR spectrum, and it was not possible to
identify these signals. From their coupling constants, it is
possible to determine the preferred chair conformation
(Figure 3). In addition to the geminal constant, a coupling
of 12 Hz in the axial H4 proton was attributed to an
axial-axial coupling to H3, establishing the axial orientation
of the latter. With these data, any of the chairs shown in
Figure 3 could be from compound A.
Figure 2. 2R- and 2β-1R,25-trihydroxy-19-nor-vitamin D3 and new
derivatives.
In the case of compound B, signals for H1 and H3 overlap.
The magnitude of the vicinal constants of H2 (3JHH 8.4, 8.4
Hz) indicates the axial disposition of H1, H2, and H3. This is
supported also by the coupling constants of H1 and H3 with
the corresponding methylene adjacent protons. Thus, a
coupling of 12 Hz between axial H4 and H3 establish their
trans relationship.
Scheme 1. Syntheses of A-Ring Precursors 14a-c
These data indicate that both analogues exist in a chair
conformation with the hydroxyl groups in equatorial dis-
position (chairs shown in Figure 3), but at this point we can
not assign which chair corresponds to compound A or B. To
identify the correct isomer, selected ROE experiments on H6
and H7 of both diastereoisomers were performed. In addi-
tion, optimized structures of compounds A and B calculated
by hybrid DFT with GAUSSIAN-03 based on NMR data
were obtained. From the data (p S2-S4, SI), it is possible to
intuit that compound A corresponds to analogue 6 and
therefore compound B is analogue 5.
However, to deduce unequivocally the correct stereo-
chemistry, an alternative synthesis of 5 and 6 were carried
out. For that, quinate derivative 207a was transformed to
ketone 22 (Scheme 4).
conformation (p S2, Supporting Information (SI)). This
procedure constitutes an improvement on other reported
methods.5
The coupling of ketone 14b with sulfone 19 in similar
conditions as above-described gave a 1:1 mixture of diastereo-
isomers 5 and 6 with moderate yield. At this stage, we called
Coupling of ketone 22 with the anion generated from 19
followed by deprotection with aqueous trifluoroacetic acid
give 5 and 6 as a mixture of diastereoisomers (approximately
3:7) in 65% yield (Scheme 5). In the HPLC chromatogram
(p S89, panel B, SI), the major compound has higher rate
of elution, previously assigned as B. Deprotection with

6160 Journal of Medicinal Chemistry, 2009, Vol. 52, No. 19
Saꢀnchez-Abella et al.
Scheme 6. Synthesis of A-Ring Precursor 27
Figure 3. Preferred A-ring conformations for 5 and 6.
Scheme 4. Synthesis of A-Ring Precursor 22
Table 1. In Vitro Effects of 19-nor-Vitamin D3 Analogues on VDR and
hDBP Binding and MCF-7 Cell Proliferationa
VDR
(%)
hDBP
(%)
MCF-7
(%)
compd
1R,25-(OH)2-D3
3
100
20
10
0.4
5
100
4
100
20
5
4
3
5
3
5
6
14
17
45
38
5
7 þ 8
9
10
1
7
0.4
25
1
16
a The in vitro effect is expressed as percentage activity at EC50 in
comparison with 1R,25-(OH)2-D3 (= 100% activity). The concentration
of 1R,25-(OH)2-D3 necessary for half-maximal response in a [3H-
thymidine] incorporation assay on MCF-7 cells was 5.2 ( 1.4 ꢀ 10-8
M. 1R,25-(OH)2-D3 Kd for VDR: 0.7 ( 0.02 ꢀ 10-10 M. 1R,25-(OH)2-D3
Kd for DBP: 2.4 ( 0.4 ꢀ 10-8 M (in all cases, mean ( SD, n = 3).
Scheme 5. Syntheses and Selected ROEs of 19-nor-Derivatives
23 and 24
their calcemic effects more than 100-fold.8 Because these
derivatives of vitamin D show remarkable biological activ-
ities, epoxy A-ring analogues 9 and 10 were envisioned from
the 1,2,3-triol moiety (C1, C2, C3) of preceding compounds
3-8 (Figure 2).
The A-ring epoxy precursor was prepared as depicted in
Scheme 6. Starting from methyl quinate (11a), mesylate 25
was obtained in 64% yield.9 Reduction of the ester to alcohol
26 and subsequent oxidation afforded ketone 27 in 50%
overall yield.
Coupling of 19 and 27 with LHMDS, deprotection of all
the protecting groups with (-)-CSAa, and treatment with
DBU in THF gave the isomeric epoxides 9 and 10 (ca. 3:2
diastereosiomeric mixture) in 53% yield. Both isomers were
carefully separated by HPLC. Analysis of their coupling
constants revealed the axial orientation of the 1R-hydroxyl
group exhibited by the major isomer 10 (p S5, SI).
Biological Evaluation. The synthesized vitamin analogues
were tested for their ability to bind the pig vitamin D receptor
(VDR) and human vitamin D-binding protein (hDBP). A
comparison between the natural hormone 1 and 2-hydroxy
substituted analogues 3-8 indicates that derivatives with the
natural configuration at C-1 and C-3 (3 and 4, Table 1)
exhibited more potent affinity for the receptor than other
isomers. The corresponding 2R-hydroxy analogue 3 dis-
played about 5 times less binding affinity than 1R,25-
(OH)2-D3, while the 2β-hydroxy derivative 4 demonstrated
10-fold less binding affinity. The unnatural configuration at
TBAF instead of trifluoroacetic acid afforded compounds 23
and 24.
ROESY spectrum of the mixture 23 and 24 shows in the
major isomer a ROE between H3 and one of the methoxy
groups, which are oriented in the axial orientation to obtain
the maximum anomeric stabilization. Therefore, the struc-
ture of this isomer is that depicted as compound 23 in
Scheme 5. This proved that the major compound is 5, as
previously predicted by NMR experiments and calculations.
Thus, A-ring chair conformation of 5 and 6 was unambigu-
ously determined.
The vitamin D analogues 7 and 8 were obtained as a ca. 7:3
diastereoisomer mixture by coupling of 14c with 19 as
described above. Separation of these isomeric compounds
was not possible.
There are scarcely examples of vitamin D analogues with
an oxirane in its structure. Bouillon and co-workers reported
some interesting vitamin D derivatives with epoxy functions
in the side chain whose cell differentiating activity exceeded
a Abbreviations (-)-CSA, camphorsulfonic acid; VDR, vitamin D
receptor; hDBP, human vitamin D binding protein; MCF-7, breast
cancer cells; TBDMSCl, tert-butyldimethylsilyl chloride.

Brief Article
Journal of Medicinal Chemistry, 2009, Vol. 52, No. 19 6161
C-3 resulted in a decreased affinity for the VDR (4 vs 6,
Table 1). In the case of the epoxy analogues, derivative 10
retained a significant binding affinity (25% with respect to
the natural hormone), but the 1R,2R-epoxy analogue 9 was
devoid of any affinity for VDR. These results indicated that
vitamins with the axial orientation of the 1R-hydroxyl group
exhibited the most potent affinity to VDR.
2β-isomer 4. In vivo calcemic effects of synthesized analogues
were evaluated showing very low calcemic effect.
Experimental Section
Chemistry. Synthesis of 11b,7a 11c,7b 20,7a and 259 were pre-
viously reported. The purity of compounds was determined in all
cases as >99% by HPLC analysis.
When hDBP binding of the 2-hydroxy analogues were
compared, the 1R,2β,3R isomer 6 and the mixture 7 þ 8
proved to possess more affinity. Interestingly, introduction
of an epoxy function in the A-ring increased the binding
potency. Both oxirane derivatives, 9 and 10, showed 45%
and 38% binding afffinity for hDBP, respectively, relative to
the parent hormone. The lack of the C-1 hydroxyl group in 9
was not essential for binding. These epoxy analogues ex-
hibited large differences in hDBP binding compared with the
2-hydroxy derivatives with the same stereochemistry in the
A-ring (9 vs 3 and 10 vs 4, Table 1).
Next, the ability of these compounds to inhibit proliferation
was examined in MCF-7 breast cancer cells. The 2R-hydroxy
analogue 3 and the 2β,3β-epoxy derivative 10, which showed
the highest affinity to the VDR, displayed the highest potency
among the tested compounds. Thus, at a concentration of 10-6
M, compound 3 can inhibit cell proliferation by 60%, which is
comparable with 1R,25-(OH)2-D3 (p S7, Figure S7, SI). How-
ever, this derivative was 5 times less potent than 1R,25-(OH)2-
D3 at the EC50 concentration. Similar results were observed
with the epoxy analogue 10. In contrast, epoxy 9 was almost
unable to inhibit cell proliferation. In comparing antiproli-
ferative activity of the 2R- and 2β-hydroxy derivatives (3
and 4), the 2R-analogue 3 exhibited a 4-fold increase in
potency.
Comparison of the biological activity of these derivatives
with our previous results of the corresponding 6-s-cis
counterparts6,10 possessing the same functionalities and
stereochemistries showed that the 6-s-trans conformers
displayed markedly increased binding affinity to VDR
and hDBP and increased potency to inhibit MCF-7 cell
proliferation.
Besides the in vitro screening, the in vivo calcemic effects
of the compounds 3, 9, and 10 were evaluated. All tested
analogues were less calcemic than 1R,25-(OH)2-D3 (p S7,
Figure S8, SI). The tetraol analogue 3 demonstrated the
weakest calcemic activity in mice because a daily injection of
a dose exceeding 1000-fold the maximal tolerable dose of
1R,25-(OH)2-D3 (0.1 μg/kg/day) resulted in a smaller in-
crease (13%) in serum calcium levels than 1R,25-(OH)2-D3
(27%).
General Procedure for 3-8. To a solution of 19 (43 mg, 0.078
mmol) in anhyd THF (260 μL) at -50 °C was added dropwise
LHMDS (78 μL, 1.0 M in THF, 0.078 mmol) and the mixture
was stirred at the same temperature for 2 h. Next, a solution of
the corresponding ketone 14 (23 mg, 0.047 mmol) in anhyd THF
(310 μL) was added dropwise to the mixture. After being stirred
at -50 °C during 5 h, the reaction mixture was poured into a satd
aq solution of NH4Cl and extracted with Et2O. The combined
organic fractions were dried (Na2SO4), filtered, and concen-
trated to give a crude, which was dissolved in anhyd MeOH
(1.2 mL) and cooled down at 0 °C. (-)-CSA (50 mg, 0.220 mmol)
was then added, and the mixture was stirred a room temperature
overnight. The reaction was quenched by adding a satd aq
solution of NaHCO3. The aqueous layer was extracted with
EtOAc. The combined organic fractions were dried (Na2SO4),
filtered, and concentrated to give a crude, which was purified by
˚
column chromatography using silica gel 60 A (32-63 μm) pH 7
and EtOAc as eluent. The diastereoisomers were isolated
by reverse-phase preparative HPLC (ODS-A column, 5 μm,
250 mm ꢀ 10 mm). Conditions: 4.5 mL/min, CH3CN/H2O
(45:55) for 3 and 4; 4 mL/min, CH3CN/H2O (50:50) for 5 and
6. Retention times: tR (3) = 28.6 min; tR (4) = 24.1 min; tR (5) =
20.7 min; tR (6) = 18.9 min.
1r,2r-Epoxy-25-hydroxy-19-nor-vitamin D3 (9) and 2β,3β-
Epoxy-1R,25-dihydroxy-3-deoxy-19-nor-vitamin D3 (10). Cou-
pling of 19 (40 mg, 0.074 mmol) with 27 (20 mg, 0.044 mmol) and
subsequent desilylation was performed through the same pro-
cedure as described above for the synthesis of 3-8. To a solution
of the resulting crude in anhyd THF (500 μL) was added
dropwise DBU (10 μL, 0.066 mmol), and the reaction was
stirred at room temperature for 16 h. Solvent was concentrated,
and the crude was purified by column chromatography using
˚
silica gel 60 A (32-63 μm) pH 7 and 10% hexane/EtOAc as
eluent. The diastereoisomeric mixture was separated by reverse-
phase preparative HPLC (ODS-A column, 5 μm, 250 mm ꢀ 10
mm, 5 mL/min, CH3CN/H2O 65:35). Retention times: tR (9) =
20.4 min. tR (10) = 23.4 min.
Acknowledgment. Financial support by the Spanish Gov-
ernment (MEC-07-CTQ-61126) and the Fonds voor We-
tenschappelijk Onderzoek (FWO grant G.0553.06 and
G.0587.09) are gratefully acknowledged. L.S.-A. thanks MEC
for a predoctoral fellowship.
Supporting Information Available: Experimental procedures,
conformational analyses, energy-minimized conformations, in
vitro and in vivo assays, NMR spectra; HPLC data. This
material is available free of charge via the Internet at http://
pubs.acs.org.
Conclusions
We have described the synthesis and biological evaluation
of 1R,25-dihydroxy-19-nor-vitamin D3 analogues substituted
at C-2 with a hydroxy group or possessing an epoxy function-
ality in the A-ring. To investigate structure-activity relation-
ships, different stereochemistry at C-1, C-2, and C-3 were
investigated. The structures of the analogues were determined
by analysis of their coupling constants in addition to COSY
and ROESY experiments. Results on VDR binding affinity
and MCF-7 cell proliferation revealed that the axial orienta-
tion of the 1R hydroxyl group is necessary for biological
activity. Comparison of the 2R- and 2β-hydroxy derivatives
of 1R,25-dihydroxy-19-nor-vitamin D3 showed that the 2R-
isomer 3 has a higher VDR affinity than the corresponding
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