Design and synthesis of 3,5-disubstituted 1,2,4-oxadiazole containing retinoids from a retinoic acid receptor agonist

Article abstract of DOI:10.1016/j.tetlet.2011.03.011

We previously synthesized novel retinoid libraries, and after screening for bioactivity found one compound BT10 that functions as a specific agonist for retinoic acid receptors. This lead compound was further derivatized using SAR and LRD to obtain 3,5-di

Full text of DOI:10.1016/j.tetlet.2011.03.011

Tetrahedron Letters 52 (2011) 2433–2435
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Design and synthesis of 3,5-disubstituted 1,2,4-oxadiazole containing retinoids
from a retinoic acid receptor agonist
Bhaskar C. Das a,b, , Xiang-Ying Tang b, Swarnava Sanyal b, Seetaram Mohapatra b, Patrick Rogler b,
⇑
Sabita Nayak b,d, Todd Evans c,
⇑
a Department of Nuclear Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA
b Department of Developmental & Molecular Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA
c Department of Surgery, Weill Cornell Medical College, Cornell University, New York, NY 10065, USA
d Ravenshaw University, Cuttack, Orissa 753003, India
a r t i c l e i n f o
a b s t r a c t
Article history:
We previously synthesized novel retinoid libraries, and after screening for bioactivity found one com-
pound BT10 that functions as a specific agonist for retinoic acid receptors. This lead compound was fur-
ther derivatized using SAR and LRD to obtain 3,5-disubstituted-1,2,4-oxadiazole-containing retinoids.
The new oxadiazole (amide bioisosters)-containing retinoids (compounds 1, 2, 3, 4, 5, and 6) were syn-
thesized in 42–65% yield by reacting with (E)-4-((3-ethyl,2-4,4,4-trimethylcyclohex-2-enylid-
ene)methyl)benzoic acid and phenyl substituted amidoxime in DMF using CDI as the coupling reagent.
The biological activities of the synthesized compounds are currently being evaluated.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 31 December 2010
Revised 25 February 2011
Accepted 1 March 2011
Available online 6 March 2011
Retinoids (retinol [vitamin A] and its biologically active metabo-
lites) are essential signaling molecules that control various develop-
mental pathways and influence the proliferation and differentiation
of a variety of cell types in the adult.1,2 A number of synthetic reti-
noids have been synthesized that interact selectively with their
receptors.3 Considering the importance of the retinoids, we were
interested in synthesizing a small library of new retinoids.
In the context of our ongoing chemical biology project, studying
the role of retinoic acid signaling pathways during zebrafish
embryogenesis, we synthesized novel retinoid libraries.4a–f
This small library of compounds was screened for bioactivity in
living zebrafish embryos. We found that several structurally re-
lated compounds significantly affect development. Distinct pheno-
types are generated depending on time of exposure, and we
characterized one compound BT10 (Fig. 1) that produces specific
cardiovascular defects when added 1 day post fertilization. When
compared to all-trans retinoic acid (atRA), BT10 shows similar
but not identical changes in the expression pattern of embryonic
genes that are known targets of the retinoid pathway. Reporter as-
says determined that BT10 interacts with all three RAR receptor
sub-types, but has no activity for RXR receptors, at all concentra-
tions tested.4g
O
B
N
O
O
N
2
O
OH
N
H
BT10
OMe
N
O
N
1
Figure 1.
undertook this project to synthesize oxadiazole-containing novel
retinoids as BT10 analogues.
Our lead molecule BT10 is an amide derivative of retinoic acid
(containing polyene alkene spacers and amide linkage). Attempt-
ing to increase efficacy and receptor subtype specificity, we tried
to synthesize new retinoic acid analogues by (a) introducing a con-
strained phenyl ring system in place of the conjugated alkene back-
bone (spacers in atRA) to avoid the metabolism of atRA into its
isomers, 9-cis-RA and 13-cis-RA, (b) bio-isosterically replacing
the amide linkage with oxadiazoles5 to prevent the in vivo protease
cleavage of the amide groups, and (c) introducing the methoxy
group by replacing the methyl alcohol group of BT10 to increase
This lead compound may be useful for manipulating compo-
nents of retinoid signaling networks, and may be further deriva-
tized to enhance activity and selectivity. For that purpose we
⇑
Corresponding authors. Tel.: +1 718 430 2422; fax: +1 718 430 8853. (B.C.D.)
E-mail addresses: bdas@aecom.yu.edu (B.C. Das), tre2003@med.cornell.edu (T.
Evans).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.03.011

2434
B. C. Das et al. / Tetrahedron Letters 52 (2011) 2433–2435
the efficacy. Here, we report success at synthesizing novel oxadiaz-
ole-containing retinoids, which may provide new tools for probing
retinoic acid signaling pathways.
OH
NH
H
To synthesize our lead compound 1 (Fig. 1), we first synthesized
N
CDI, DMF, rt, 30 min
then reflux
O
the
acid;
(E)-4-((3-ethyl,2-4,4,4-trimethylcyclohex-2-enylid-
2
N
+
ene)methyl)benzoic acid 8. The acid 84d,e was synthesized starting
from b-cyclocitral in a manner reported by us previously.4d Next
we synthesized different substituted amidoximes by refluxing an
ethanolic solution of substituted phenyl nitriles and hydroxylamine
hydrochloride using NaOH as base.6 The oxadiazole-containing
retinoid 1 was synthesized by an amide coupling strategy7 using
methoxy amidoxime 7 and acid 8, which were readily available
though simple transformations, as the substrates. The correspond-
ing acid 8 was treated with 1.2 equiv of CDI in DMF for 30 min at
room temperature, then the methoxy amidoxime 7 was added
and the resulting reaction mixture was heated under reflux for
about 12 h (or until the acid was consumed completely as moni-
tored by TLC) (Scheme 1).8a After purification by silica-gel chroma-
tography (Hexanes/EtOAc: 3:1) compound 1 was obtained as a
white solid, melting point 133–135 °C with 48% yield.
N
R
HO
3: R = F
7b: R = F
O
4: R = Br
5: R = CH
6: R = Me
8
7c: R = Br
7d: R = CH
7e: R = Me
C
C
R
Scheme 2. Reagents and conditions: compound 3: R@F, (42% yield, white solid, mp
135–137 °C); compound 4: R@Br, (65% yield, white solid, mp 130–132 °C);
compound 5: R@C@CH, (52% yield, brown solid; mp 124–126 °C); compound 6:
R@CH3, (46% yield, yellow solid, mp120–122 °C).
O
O
N OH
Bases, EtOH
rt
O
O
B
B
+ H NOH.HCl
2
CN
NH2
9
11
10
Scheme 3.
To validate the generality of the coupling reaction, we synthe-
sized compounds 3, 4, 5, and 6 using acid 8 and various substituted
amidoximes (7b–7e) using CDI as coupling reagent in DMF
(Scheme 2). Compounds 3,48b,5, and 6 were also successfully syn-
thesized in 42–65% yield. Derivatives may have useful additional
features. For example, compound 5 contains free acetylene, which
could be further converted in vivo into a triazole derivative for tar-
get identification purposes. Compounds 3 and 6 could be further
derivatized to 18F and 11C PET (Positron Emission Tomography)
agents for noninvasive diagnostic agents, for diseases with over ex-
pressed RAR-alpha receptors.
We further envisioned developing a boron-based oxadiazole-
containing small molecule retinoid library (Fig. 1), based on the
hypothesis that introducing a boron atom in a biologically active
framework might allow interaction with a target protein, not only
through hydrogen bonds but also through covalent bonds. Such
interactions could produce potent biological activity.9 With this
in mind, we synthesized compound 2.
H
H
B2Pin2, Pd(PPh3)2Cl2
O
O
AcOK, DMSO, 80o
12 h
C
N
N
N
N
2
4
Br
B
O
O
Scheme 4.
In conclusion, we report for the first time the synthesis of 3,5-
disubstituted-1,2,4-oxadiazole-containing retinoids. The detailed
biological evaluation of these compounds as possible RA pathway
modulators is currently ongoing in our laboratory.
To synthesize compound 2 we first tried to synthesize 10 ((Z)-
N0-hydroxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzi-
midamide) and planned to attach it with acid 8 using CDI as a cou-
pling reagent in DMF. To synthesize 10 we started with nitrile 9 (4-
(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile)
and
Acknowledgments
hydroxylamine hydrochloride 11. But unfortunately, we failed to
synthesize 10 in spite of using different bases [like NaOH/EtOH,
K2CO3/DMSO, Et3N/EtOH, and (iPr)2NH/EtOH)] and reaction condi-
tions (Scheme 3).10
As we failed to synthesize 10, a separate reaction scheme was
devised. A Suzuki coupling reaction was introduced using bromide
compound 48b and B2Pin2 (Bis-pinocolatodiboron) as the sub-
strates to give the boronic ester containing compound 2 in 45%
yield as a white solid (Scheme 4).11
The author B.C.D. is thankful to AECOM for start up funding. The
instrumentation in the AECOM Structural NMR Resource is sup-
ported by the Albert Einstein College of Medicine and in part by
Grants from the NSF (DBI9601607 and DBI0331934), the NIH
(RR017998) and the HHMI Research Resources for Biomedical Sci-
ences. Authors X-Y.T. and S.S. are thankful to Dr.IlHwan An for syn-
thesizing acid 8.
Supplementary data
Supplementary data ((copies of 1H, 13C NMR and Mass spectra)
are available online with this paper in Science Direct)associated
with this article can be found, in the online version, at
doi:10.1016/j.tetlet.2011.03.011.
OH
N
CDI, DMF, rt, 30 min
then reflux
O
NH
+
2
N
References and notes
N
MeO
HO
1
7a
1. Moon, R. C.; Mehta, R. G.; Rao, K. V. N.; Spron, M. B., 2nd In The Retinoids:
Biology, Chemistry and Medicine; Robert, A. B., Goodman, D. S., Eds.; Raven Press:
New York, 1994; pp 573–630.
O
8
MeO
2. (a) Loeliger, P.; Bollag, W.; Mayer, H. Eur. J. Med. Chem. 1980, 15, 9–15; (b)
Dawson, M. I.; Hobbs, P. D.; Derdzinski, K.; Chan, L-S.; Gruber, J.; Chao, W.;
Smith, S.; Thies, R. W.; Schiff, L. J. J. Med. Chem. 1984, 27, 1516–1531.
Scheme 1. Reagents and conditions: Compound 1 (42% yield, white solid, mp 133–
135 °C).

B. C. Das et al. / Tetrahedron Letters 52 (2011) 2433–2435
2435
3. (a) Nadzan, A. M. Annu. Rep. Med. Chem. 1995, 30, 119–128; (b) Altucci, L. A.;
Leibowitz, M. D.; Ogilvie, K. M.; deLera, A. R.; Gromemeyer, H. Nat. Rev. Drug
Discov. 2007, 6, 793; (c) Kuendgen, A.; Schmid, M.; Schlenk, R.; Kinpp, S.;
Hilderbrandt, B.; Steidi, C. Cancer 2006, 19, 1161.
132 °C. 1H NMR (300 MHz, CDCl3, TMS) d 1.10 (t, J = 7.5 Hz, 3H, CH3), 1.12 (s,
6H, 2CH3), 1.52–1.58 (m, 2H, CH2), 1.96 (s, 3H, CH3), 2.26 (q, J = 7.5 Hz, 2H,
CH2), 2.62–2.68 (m, 2H, CH2), 6.50 (s, 1H, CH), 7.46 (d, J = 8.1 Hz, 2H, Ar), 7.67
(d, J = 8.1 Hz, 2H, Ar), 8.08 (d, J = 8.1 Hz, 2H, Ar), 8.17 (d, J = 8.1 Hz, 2H, Ar); 13
C
4. (a) Das, B. C.; Smith, M. E.; Kalpana, G. V. Bioorg. Med. Chem. Lett. 2008, 18,
4177; (b) Das, B. C.; Smith, M. E.; Kalpana, G. V. Bioorg. Med. Chem. Lett. 2008,
18, 3805; (c) Das, B. C.; Evans, T. Mol. Biosystem (communicated) .; (d) Das, B. C.;
Kabalka, G. W. Tetrahedron Lett. 2008, 49, 4695–4696; (e) Das, B. C.;
Mahalingam, S. M.; Evans, T.; Kabalka, G. W.; Anguiano, J.; Hema, K. Chem.
Commun 2009, 2133; (f) Das, B. C.; Anguiano, J.; Mahalingam, S. M. Tetrahedron
Lett. 2009, 50, 5670–5672; (g) Das, B. C.; McCartin, K.; Liu, T.-C.; Peterson, R. T.;
Evans, T. PloS ONE 2010, 5.
NMR (75 MHz, CDCl3, TMS) d 14.7, 15.2, 23.0, 24.4, 27.6, 35.9, 38.8, 120.3,
121.0, 125.6, 126.1, 127.0, 127.8, 129.0, 129.9, 132.1, 142.8, 144.0, 149.3, 168.2,
176.0. Anal. Calcd for C26H27BrN2O: C, 67.39%; H, 5.87%; N, 6.05%. Found: C,
67.13%; H, 6.08%; N, 5.68%.
9. (a) Groziak, M. P. In Progress in Heterocyclic Chemistry; Gribble, G. C., Gilchrist, T.
L., Eds.; Pergamon: Oxford, 2000; 12, pp 1–21; (b) Morin, C. Tetrahedron 1994,
50, 12521–12569; (c) Yang, W.; Gao, X.; Wang, B. Med. Res. Rev. 2003, 23, 346;
(d) Matterson, D. S. Tetrahedron 1989, 45, 1859; (e) Tian, Z.-Q.; Brown, B. B.;
Mack, D. P.; Hutton, C. A.; Bartlett, P. A. J. Org. Chem. 1997, 62, 514; (f) Leung, D.;
Abbenante, G.; Fairlie, D. P. J. Med. Chem. 2003, 63, 1144; (g) Kabalka, G. W.;
Das, B. C.; Das, S. Tetrahedron Lett. 2001, 42, 7145–7146.
5. McBriar, M. D.; Clader, J. W.; Chu, I.; Del Vecchio, R. A.; Favreau, L.; Greenlee, W.
J.; Hyde, L. A.; Nomeir, A. A.; Parker, E. M.; Pissarnitski, D. A.; Song, L.; Zhang, L.;
Zhao, Z. Biorg. Med. Chem. Lett. 2008, 18, 215–219.
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A.; Minidis; Alexander, B. E. J. Org. Chem. 2009, 74, 9328–9336.
10. Kianmehr, E.; Yahyaee, M.; Tabatabai, K. Tetrahedron Lett. 2007, 48, 2713–2715.
11. General procedure for synthesis of compound 2: The desired bromide compound
(0.2 mmol) together with B2Pin2 (0.44 mmol, 111.7 mg), AcOK (1.0 mmol,
98.1 mg), Pd(PPh3)2Cl2 (0.02 mmol, 14.0 mg), and DMSO (3 mL) was added into
a 15.0 mL three-necked RBF under N2. The resulting mixture was stirred at rt
for 10 min then heat at 80 °C for about 12 h under N2. After the reaction was
complete (Monitored by TLC), the reaction mixture was poured into 10 mL of
water and extracted by DCM (3 ꢀ 10.0 mL). The combined organic solvent was
dried over Na2SO4, filtered, and concentrated in vacuum. The crude product
was purified by silica-gel chromatography to give the boron-containing
compound 2.
7. Liang, G.-B.; Feng, D. D. Tetrahedron Lett. 1996, 37, 6627–6630.
8. (a) General procedure for synthesis of compound 1: Acid 8 (0.5 mmol) and CDI
(carbonyl diimidazole) (0.6 mmol) were dissolved in 3 mL of DMF and stirred at
room temperature. After 30 min, amidoxime 7a was added and the reaction
mixture was heated under reflux for about 24 h (Monitored by TLC). Then the
mixture was poured into water (20.0 mL), extracted by CHCl3 (3 ꢀ 15.0 mL),
and the combined organic solvent was dried over Na2SO4, filtered, and
concentrated in vacumn. The crude product was purified by silica-gel
chromatography to give a white solid mp 133–135 °C with 48% yield.
1H NMR (300 MHz, Acetone, TMS) d 1.10 (t, J = 7.5 Hz, 3H, CH3), 1.13 (s, 6H,
2CH3), 1.52–1.58 (m, 2H, CH2), 1.96 (s, 3H, CH3), 2.25–2.33 (m, 2H, CH2), 2.65–
2.62 (m, 2H, CH2), 2.83 (s, 3H, CH3), 6.59 (s, 1H, CH), 7.13–7.16 (m, 2H, Ar), 7.59
(d, J = 6.0 Hz, 2H, Ar), 8.10–8.13 (m, 2H, Ar), 8.18 (d, J = 6.0 Hz, 2H, Ar); 13C NMR
(75 MHz, Acetone, TMS) 14.6, 15.0, 23.0, 24.6, 27.4, 36.0, 39.0, 55.3, 114.8,
119.7, 120.8, 121.7, 127.5, 128.0, 129.3, 130.4, 142.8, 144.3, 149.1, 162.7, 168.8,
175.8; HRMS (EI) Calcd for C27H30N2O2 [M+H]+ requires 415.2386. Found
415.2408.
Compound 2 (45%). A white solid. mp 139–141 °C. 1H NMR (300 MHz, CDCl3,
TMS) d 1.11 (t, J = 7.5 Hz, 3H, CH3), 1.12 (s, 6H, 2CH3), 1.53–1.57 (m, 2H, CH2),
1.96 (s, 3H, CH3), 2.25 (q, J = 7.5 Hz, 2H, CH2), 2.67 (t, J = 5.7 Hz, 2H, CH2), 6.50
(s, 1H, CH), 7.46 (d, J = 8.4 Hz, 2H, Ar), 7.97 (d, J = 8.4 Hz, 2H, Ar), 8.19 (dd,
J = 8.4 Hz, 4H, Ar); 13C NMR (75 MHz, CDCl3, TMS) d 14.7, 15.2, 22.9, 24.4, 24.9,
27.6, 35.9, 38.8, 84.1, 120.3, 121.1, 126.6, 127.0, 127.8, 129.4, 129.8, 135.1,
142.7, 143.9, 149.2, 168.9, 175.8. HRMS (EI) Calcd for C32H40BN2O3 [M+H]+
requires 511.3132. Found 511.3131.
(8b) Analytical data’s of compound 4. Compound 4 (65%). A white solid. mp 130–