Multi-substituted 8-aminoimidazo[1,2-a]pyrazines by Groebke-Blackburn-Bienaym reaction and their Hsp90 inhibitory activity

Article abstract of DOI:10.1039/c4ob01865f

Using a 2,3-diamino pyrazine substrate and yttrium triflate catalyst, various 2-alkyl and aryl substituted 3,8-diaminoimidazo[1,2-a]pyrazines were efficiently prepared through Groebke-Blackburn-Bienaym MCR. In particular, a novel 2-piperonyl 3,8-diaminoimidazo[1,2-a]pyrazine structure was prepared exclusively with this new method and was found to have moderate Hsp90 inhibitory activity. A crystalline complex with N-terminus ATP domain of Hsp90 and one of the new Hsp90 inhibitors was also obtained to elucidate the origin of activity of 2-piperonyl 3,8-diaminoimidazo[1,2-a]pyrazines.

Full text of DOI:10.1039/c4ob01865f

Organic &
Biomolecular Chemistry
View Article Online
View Journal
PAPER
Multi-substituted 8-aminoimidazo[1,2-a]pyrazines
by Groebke–Blackburn–Bienaymé reaction and
their Hsp90 inhibitory activity†
Cite this: DOI: 10.1039/c4ob01865f
Jing Ren,‡a Min Yang,‡b Hongchun Liu,c Danyan Cao,a Danqi Chen,a Jian Li,b
Le Tang,a Jianhua He,b Yue-Lei Chen,*a Meiyu Geng,c Bing Xiong*a and
Jingkang Shen*a
Using a 2,3-diamino pyrazine substrate and yttrium triflate catalyst, various 2-alkyl and aryl substituted
3,8-diaminoimidazo[1,2-a]pyrazines were efficiently prepared through Groebke–Blackburn–Bienaymé
MCR. In particular, a novel 2-piperonyl 3,8-diaminoimidazo[1,2-a]pyrazine structure was prepared exclu-
sively with this new method and was found to have moderate Hsp90 inhibitory activity. A crystalline
complex with N-terminus ATP domain of Hsp90 and one of the new Hsp90 inhibitors was also obtained
to elucidate the origin of activity of 2-piperonyl 3,8-diaminoimidazo[1,2-a]pyrazines.
Received 1st September 2014,
Accepted 15th November 2014
DOI: 10.1039/c4ob01865f
www.rsc.org/obc
Introduction
8-Aminoimidazo[1,2-a]pyrazines I are highly useful in medic-
inal chemistry research for their evident similarity with
adenine II, which is ubiquitous in bioactive structures. Conse-
quently, installation of different substituents on the 8-amino-
imidazo[1,2-a]pyrazine ring system has become an intriguing
topic, and can usually be achieved via certain ring formation
reactions from substituted fragments.1 Preparation of a multi-
substituted 8-aminoimidazo[1,2-a]pyrazine ring system is more
demanding and less reported. It is known that multicompo-
nent reactions (MCRs) are advantageous in the syntheses of
heavily substituted heterocycles. However, syntheses of multi-
substituted 8-aminoimidazo[1,2-a]pyrazines through the MCR
pathway are rarely discussed and seem to be less efficient. For
example, David et al.2 attempted the preparation of 2-substi-
tuted 3,8-diaminoimidazo[1,2-a]pyrazines through Groebke–
Blackburn–Bienaymé MCR3 and obtained poor yields. Interest-
ingly, one recent article by Pirali et al.4 described more
efficient syntheses of 2-substituted 3,8-diaminoimidazo[1,2-a]-
pyrazines VI starting from chloropyrazine 1, isocyanides III
Scheme 1 A comparison of imidazo[1,2-a]pyrazines I and adenine II
and one of the known synthetic methods4 to 8-aminoimidazo[1,2-a]pyr-
azines VI. Reaction conditions: (a) compound
(1.2 equiv.), MeCN, reflux, 2 h; (b) TMSCl (1.2 equiv.), MeCN/DCM,
30 min; (c) R1NC (1.2 equiv.), reflux, overnight; (d) aq. NH4OH/dioxane,
100 °C, overnight.
1
(1 equiv.), R2CHO
and aldehydes IV via two step sequences, including Groebke–
Blackburn–Bienaymé MCR and the following aminolysis of
intermediate V. Nevertheless, it was found that only aryl car-
boxaldehydes were produced under the reported conditions,
and this meant that the R2 on the 2-substituted 3,8-diamino-
imidazo[1,2-a]pyrazine products VI could only be aryl groups
(Scheme 1).
aMedicinal Chemistry Department, Shanghai Institute of Materia Medica,
Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, P. R. China.
E-mail: bxiong@simm.ac.cn
During our study of Groebke–Blackburn–Bienaymé MCR,5 a
typical experiment indicated that 2,3-diaminopyrazine was a
superior substrate for this MCR, leading to 2-aryl, 2-benzyl,
and 2-alkyl 3,8-diaminoimidazo[1,2-a]pyrazines. Using this
efficient methodology, a panel of 2-piperonyl substituted 3,8-
diaminoimidazo[1,2-a]pyrazines were prepared for the first
time. Some of the 2-piperonyl substituted 3,8-diaminoimidazo-
[1,2-a]pyrazines were found to have moderate heat shock
bShanghai Institute of Applied Physics, Chinese Academy of Sciences, 239 Zhang
Heng Road, Shanghai 201203, P. R. China
cDivision of Antitumor Pharmacology, Shanghai Institute of Materia Medica,
Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, P. R. China
†Electronic supplementary information (ESI) available: Experimental details,
crystallographic data, and copies of NMR spectra. See DOI: 10.1039/c4ob01865f
‡These authors contributed equally to this work.
This journal is © The Royal Society of Chemistry 2014
Org. Biomol. Chem.

View Article Online
Paper
Organic & Biomolecular Chemistry
protein 90 (Hsp90) inhibitory activity and could serve as leads
for further optimization. These results are described herein.
Results and discussion
Initially, using yttrium triflate catalyst, it was found that the
N-2,4-dimethoxybenzyl (N-DMB) protected diamino pyrazine 2
reacted with isocyanide 3 and phenyl acetaldehyde 4 to give
the desired product 5 with good yield, after removing the
N-protection with acid (Table 1, entry 1). This was unique
because in comparison experiments, TMSCl4 failed to give the
conversion and TfOH only gave low yield (Table 1, entries 2
and 3). Changing from diamino pyrazine 2 back to chloropyr-
azine 1 again failed to give the reaction with TMSCl, and this
was consistent with the findings by Pirali et al.4 (Table 1, entry 4).
With TfOH or rare earth-metal triflate catalysts, the product 5
was observed after aminolysis, however, the yield was low
(Table 1, entries 5–7). As phenyl acetaldehyde 4 is a special
type of alkyl aldehyde, the abovementioned discovery served as
a successful example of a Groebke–Blackburn–Bienaymé MCR
leading to 2-alkyl 3,8-diaminoimidazo[1,2-a]pyrazines.
To further explore the scope of the yttrium triflate catalyzed
synthesis of 2-substituted 3,8-diaminoimidazo[1,2-a]pyrazines,
different substrates, including pyrazines 6–8, isocyanides 9–11,
as well as aldehydes 4 and 12–16, were subjected to the new
reaction conditions described in Table 1, entry 1 (Scheme 2).
For common electron rich substituted phenyl acetaldehydes,
the yields were moderate to good with different isocyanides.
Because the yields were still lower than that with phenyl
Table 1 MCR of pyrazines 1 or 2, isocyanide 3, and aldehyde 4a
No.
Pyrazine
Catalyst
Yield (for 2 steps)b
1
2
3
4
5
6
7
2
2
2
1
1
1
1
Yb(OTf)3
TMSCl
TfOH
TMSCl
TfOH
Sc(OTf)3
Yb(OTf)3
75%
n.d.
28%
n.d.
4%
8%
11%
a Reaction conditions: for entries 1 and 3: (a) compound 2 (1.0 equiv.),
compound 3 (1.2 equiv.), compound 4 (1.2 equiv.), catalyst (10 mol%),
MeOH, 70 °C, 5 h; (b) TFA, DCM, 50 °C, 1 h. For entries 2 and 4:
(a) compound 4 (1.2 equiv.), MeCN, 100 °C, 2 h; (b) TMSCl (1.2 equiv.),
MeCN/DCM, rt, 30 min; (c) compound 3 (1.2 equiv.), 100 °C, 12 h. For
entries 5–7: (a) compound 1 (1.0 equiv.), compound 3 (1.2 equiv.),
compound 4 (1.2 equiv.), catalyst (10 mol%), MeOH, 100 °C, 12 h;
(b) aq. NH4OH/dioxane, sealed tube, 120 °C, 24 h. b Yield was
determined after flash chromatography.
Scheme 2 New conditions for Groebke–Blackburn–Bienaymé MCR led
to various multisubstituted 3,8-diaminoimidazo[1,2-a]pyrazines. [a]
Reaction conditions: for products 17–21: (a) pyrazines (1.0 equiv.), iso-
cyanides (1.2 equiv.), aldehydes (1.2 equiv.), Yb(OTf)3 (10 mol%), MeOH,
70 °C, 5 h; (b) TFA, DCM, 50 °C, 1 h. For products 22–26: pyrazines
(1.0 equiv.), isocyanides (1.2 equiv.), aldehydes (1.2 equiv.), Yb(OTf)3
(10 mol%), MeOH, 70 °C, 5 h. [b] Yield was determined after flash
chromatography.
Org. Biomol. Chem.
This journal is © The Royal Society of Chemistry 2014

View Article Online
Organic & Biomolecular Chemistry
Paper
acetaldehyde 4 (Table 1, entry 1), it might be speculated that the
electron donating groups on the phenyl ring of the aldehyde
component reduced the yield. Retaining phenyl acetaldehyde
4, chloro-substituted pyrazine 6 gave product 20 again with
good yield. The above examples (for products 17–21) were all
based on N-DMB protected pyrazines 6, and several points
are noteworthy: (1) compared to chloropyrazine 1 starting
material, vic-diamino substitution on diamino pyrazine 2
could significantly improve the MCR yield with various iso-
cyanide and aldehyde components; (2) as illustrated in the
general reaction schemes in Scheme 2 and Table 1, deprotec-
tion of N8-DMB on 3,8-diaminoimidazo[1,2-a]pyrazine inter-
mediate (formed from pyrazine 2) gave better yield than
aminolysis of 8-Cl on 3,8-diaminoimidazo[1,2-a]pyrazine inter-
mediate (formed from chloropyrazine 1), rendering the synth-
eses of 2-substituted 3,8-diaminoimidazo[1,2-a]pyrazines more
efficient.
Scheme 3 The structure similarity between compound 19 and a known
Hsp90 inhibitor PU-H71.
Subsequently, morpholine substituted pyrazine 7 reacted
with acetaldehyde 15 and different isocyanides to give pro-
ducts 22 and 23 with good yields (Scheme 2). This is not
trivial, because simple aldehydes, such as 15, were poor part-
ners for this type of reaction. Moreover, pyrazines 7 and 8
could react with aryl carboxaldehydes 14 and 16 as well to give
the desired 2-substituted 3,8-diaminoimidazo[1,2-a]pyrazines
24–26 (Scheme 2). The reactions with morpholine substituted
pyrazine 7 and N-cyclohexyl pyrazine 8 were highly practical
for the following reasons: (1) the diamino substituted pyrazine
substrates improved the MCR yield substantially, with both
alkyl aldehyde and aryl carboxaldehyde; (2) they eliminated
the necessity of N-deprotection and yielded more interesting
N-alkylated 2-substituted 3,8-diaminoimidazo[1,2-a]pyrazines;
(3) morpholine or alkylated amino groups are widely used in
medicinal chemistry.
For the Groebke–Blackburn–Bienaymé MCR, there might
be several reasons accounting for the yield improvement
using diamino substituted pyrazine substrates and yttrium
triflate catalyst: (1) vic-diamino substitution could enhance
the nucleophilicity of pyrazine substrates and result in an
improved condensation reaction; (2) vic-diamino substitution
could provide a better chelation environment for yttrium
metal,6 which is an essential catalyst for Groebke–Blackburn–
Bienaymé MCR. This might also explain why TMSCl failed to
work with diamino substituted pyrazine substrates.
On the basis of the abovementioned discovery, we looked
for applications in medicinal chemistry. It is known that
Hsp90 belongs to a large family of heat shock proteins, which
are evolutionarily conserved and required for essential house-
keeping functions such as protein folding, assembly, and
transportation.7 Discovering new Hsp90 inhibitors is an
important approach in combating cancer.8 We noticed that
some ATP-competitive Hsp90 inhibitors contain the 8,9-disub-
stituted adenine motif,9 which might be replaced with the 2,3-
disubstituted 8-aminoimidazo[1,2-a]pyrazine scaffold, accord-
ing to the structural similarity between adenine and 8-aminoi-
midazo[1,2-a]pyrazine. Furthermore, computational study
using the scaffold hopping concept also suggested that our
Scheme 4 Synthesis and activity study of a Hsp90 targeted, focused
library. [a] Reaction conditions: (a) pyrazines (1.0 equiv.), isocyanides
(1.2 equiv.), aldehydes (1.2 equiv.), Yb(OTf)3 (10 mol%), MeOH, 70 °C, 5 h;
(b) TFA, DCM, 50 °C, 1 h. [b] Yield was determined after flash chromato-
graphy. [c] See ESI† for details.
new product 19 or similarly substituted 8-aminoimidazo[1,2-a]-
pyrazines might possess Hsp90 inhibitory activity due to the
remarkable resemblance to PU-H71,10 an Hsp90 inhibitor in
Phase I clinical trial (Scheme 3).
To test the hypothesis, a focused library of 8-aminoimidazo-
[1,2-a]pyrazines bearing 2-piperonyl and 3-alkyl amino substi-
tutions was prepared using the new methodology (Scheme 4).
This journal is © The Royal Society of Chemistry 2014
Org. Biomol. Chem.

View Article Online
Paper
Organic & Biomolecular Chemistry
Hsp90 affinity, as demonstrated by the activities of compounds
29, 31, 32, and 33. The 2-tert-butyl amine group on compound
31 or the 2-cyclohexyl amino group on compound 32 may
not be long enough to reach the van der Waals surface
of the Hsp90 protein, and resulted in decreased activities.
(3) The 6-chloro substitution on 8-aminoimidazo[1,2-a]pyra-
zine was found to be destructive to Hsp90 inhibitory
activity, and this was demonstrated by the data of compounds
34 and 35. Generally, the moderate inhibitory activity of
2-piperonyl and 3-alkyl amino 8-aminoimidazo[1,2-a]-
pyrazines suggests that this new scaffold could serve as a
promising starting point for further structural optimi-
zation.
For a better understanding of the interactions between
2,3-disubstituted 8-aminoimidazo[1,2-a]pyrazine and Hsp90
binding site, compound 29 was cocrystallized with the
N-terminus ATP domain of Hsp90 and the co-crystal structure
was successfully determined (pdb entry: 4R3M).11 As shown
in Fig. 1, in the Hsp90 N-terminus ATP domain, the 8-amino-
imidazo[1,2-a]pyrazine ring was situated at the same position
as the adenine ring of PU-H71 (Fig. 1B). The 8-aminoimidazo
[1,2-a]pyrazine ring system formed several indirect
hydrogen bonds with the binding site of Hsp90 through
four conserved water molecules (red spheres in Fig. 1) and
two direct hydrogen bonds with ASP93 and THR184 residues.
The 2-piperonyl substitution showed typical π–π stacking
interaction with the PHE138 residue, and the bromine on
2-piperonyl substitution was close to GLY135 residue on the
Hsp90 backbone. A halogen bond with the oxygen atom of
the GLY135 residue was thus speculated for the short Br–O
distance of 3.4 Å. In addition, compared to the PU-H71
structure, a discrepancy between the orientations of the
3-benzyl amino group on compound 29 and the 9-alkyl
amino group on PU-H71 was observed. This might account
partially for the activity difference between these two
compounds.
Fig. 1 (A) Co-crystal structure of Hsp90 with compound 29 (pdb entry:
4R3M). (B) Superimposition of crystal structures 29-Hsp9011 and
PU-H71-Hsp90 (pdb entry: 2FWZ). The protein is shown in cartoon
style, and the crystal water molecules are shown as red spheres. The
carbon atoms of compound 29 are in green, and those of PU-H71 in
blue.
Conclusions
In conclusion, with 2,3-diamino pyrazine substrate and
yttrium triflate catalyst, various 2-alkyl and aryl substituted
3,8-diaminoimidazo[1,2-a]pyrazines could be efficiently pre-
pared through Groebke–Blackburn–Bienaymé MCR. Elimin-
ation of the chloride aminolysis step made this method more
favorable compared to previous synthetic approaches. We
further demonstrated that 2-piperonyl 3,8-diaminoimidazo
[1,2-a]pyrazine structures, prepared exclusively with our new
synthetic method, were potential Hsp90 inhibitors. A crystal-
line complex with N-terminus ATP domain of Hsp90 and one
of the new Hsp90 inhibitors were also obtained to elucidate
the origin of activity of the 2-piperonyl 3,8-diaminoimidazo
[1,2-a]pyrazines. The new scaffold, moderate preliminary bio-
logical activity, and crystal structure details together suggested
that 2-piperonyl 3,8-diaminoimidazo[1,2-a]pyrazines were
promising leads for Hsp90 inhibitor discovery.
With diamino pyrazine 2 and piperonals 27 and 28, moderate
to good yields were documented for products 29–32. When
chloro-substituted diamino pyrazine 6 was used, the yields
were again good for products 34 and 35, and this was consist-
ent with the observations in Scheme 2, conversions from 6, 3,
and 4 to 22.
The inhibitory activity of the library against Hsp90 was
measured and analyzed (Scheme 4): (1) the halogenated
2-piperonyl substitution was found to be essential for Hsp90
binding, as suggested by the activity comparison of com-
pounds 19, 29, and 30. Compared to compound 19, the
bromine atom on compound 29 significantly increased the
activity to 5.34 μM, whereas the iodine on compound 30
further improved the value to 2.95 μM. (2) The substitution on
C3 of the 8-aminoimidazo[1,2-a]pyrazine scaffold affected the
Org. Biomol. Chem.
This journal is © The Royal Society of Chemistry 2014

View Article Online
Organic & Biomolecular Chemistry
Paper
(b) N. M. Shukla, D. B. Salunke, E. Yoo, C. A. Mutz,
R. Balakrishna and S. A. David, Bioorg. Med. Chem., 2012,
20, 5850–5863.
3 (a) H. Bienaymé and K. Bouzid, Angew. Chem., Int. Ed.,
1998, 110, 2349–2352; (b) C. Blackburn, B. Guan,
P. Fleming, K. Shiosaki and S. Tsai, Tetrahedron Lett., 1998,
39, 3635–3638; (c) K. Groebke, L. Weber and F. Mehlin,
Synlett, 1998, 661–663.
Acknowledgements
This work was supported by the National Natural Science
Foundation of China (81102306, 81273368, 81402850) and
the National Science
& Technology Major Project “Key
New Drug Creation and Manufacturing Program”, China
(2012ZX09301001, 2014ZX09507-002).
4 M. Guasconi, X. Lu, A. Massarotti, A. Caldarelli, E. Ciraolo,
G. C. Tron, E. Hirsch, G. Sorba and T. Pirali, Org. Biomol.
Chem., 2011, 9, 4144–4149.
5 (a) T. Meng, Z. Zhang, D. Hu, L. Lin, J. Ding, X. Wang and
J. Shen, J. Comb. Chem., 2007, 9, 739–741; (b) H. Sun,
H. Zhou, O. Khorev, R. Jiang, T. Yu, X. Wang, Y. Du, Y. Ma,
T. Meng and J. Shen, J. Org. Chem., 2012, 77, 10745–10751;
(c) H. Zhou, W. Wang, O. Khorev, Y. Zhang, Z. Miao,
T. Meng and J. Shen, Eur. J. Org. Chem., 2012, 5585–
5594.
6 S. Kobayashi, in Lanthanides: Chemistry and Use in Organic
Synthesis, ed. S. Kobayashi, Springer, Berlin, Heidelberg,
1999, pp. 63–118.
7 (a) M. Feder and G. Hofmann, Annu. Rev. Physiol., 1999, 61,
243–282; (b) D. Picard, Cell. Mol. Life Sci., 2002, 59, 1640–
1648; (c) C. Garrido, S. Gurbuxani, L. Ravagnan and
G. Kroemer, Biochem. Biophys. Res. Commun., 2001, 286,
433–442.
8 (a) M. Hwang, L. Moretti and B. Lu, Curr. Med. Chem.,
2009, 16, 3081–3092; (b) W. Xu and L. Neckers, Clin. Cancer
Res., 2007, 13, 1625–1629; (c) J. Ren, J. Li, Y. Wang,
W. Chen, A. Shen, H. Liu, D. Chen, D. Cao, Y. Li, N. Zhang,
Y. Xu, M. Geng, J. He, B. Xiong and J. Shen, Bioorg.
Med. Chem. Lett., 2014, 24, 2525–2529; (d) R. Bhat,
S. R. Tummalapalli and D. P. Rotella, J. Med. Chem., 2014,
57, 8718–8728.
9 (a) L. Llauger, H. He, J. Kim, J. Aguirre, N. Rosen, U. Peters,
P. Davies and G. Chiosis, J. Med. Chem., 2005, 48, 2892–
2905; (b) S.-H. Kim, A. Bajji, R. Tangallapally, B. Markovitz,
R. Trovato, M. Shenderovich, V. Baichwal, P. Bartel,
D. Cimbora, R. McKinnon, R. Robinson, D. Papac,
D. Wettstein, R. Carlson and K. M. Yager, J. Med. Chem.,
2012, 55, 7480–7501.
Notes and references
1 (a) T. L. Gilchrist, Heterocyclic Chemistry, Prentice Hall,
3rd edn, 1997; (b) J. A. Joule and K. Mills, Heterocyclic
Chemistry, Blackwell Science Ltd., 4th edn, 2000 For some
recent examples, see: (c) H. Zeng, D. B. Belanger,
P. J. Curran, G. W. Shipps Jr., H. Miao, J. B. Bracken,
M. A. Siddiqui, M. Malkowski and Y. Wang, Bioorg. Med.
Chem. Lett., 2011, 21, 5870–5875; (d) S. Martinez Gonzalez,
A. I. Hernandez, C. Varela, M. Lorenzo, F. Ramos-Lima,
E. Cendon, D. Cebrian, E. Aguirre, E. Gomez-Casero,
M. I. Albarran, P. Alfonso, B. Garcia-Serelde, G. Mateos,
J. Oyarzabal, O. Rabal, F. Mulero, T. Gonzalez-Granda,
W. Link, J. Fominaya, M. Barbacid, J. R. Bischoff,
P. Pizcueta, C. Blanco-Aparicio and J. Pastor, Bioorg. Med.
Chem. Lett., 2012, 22, 5208–5214; (e) S. Martinez Gonzalez,
A. I. Hernandez, C. Varela, S. Rodriguez-Aristegui,
R. M. Alvarez, A. B. Garcia, M. Lorenzo, V. Rivero,
J. Oyarzabal, O. Rabal, J. R. Bischoff, M. Albarran,
A. Cebria, P. Alfonso, W. Link, J. Fominaya and J. Pastor,
Bioorg. Med. Chem. Lett., 2012, 22, 1874–1878;
(f) S. Martinez Gonzalez, A. I. Hernandez, C. Varela,
S. Rodriguez-Aristegui, M. Lorenzo, A. Rodriguez, V. Rivero,
J. I. Martin, C. G. Saluste, F. Ramos-Lima, E. Cendon,
D. Cebrian, E. Aguirre, E. Gomez-Casero, M. Albarran,
P. Alfonso, B. Garcia-Serelde, J. Oyarzabal, O. Rabal,
F. Mulero, T. Gonzalez-Granda, W. Link, J. Fominaya,
M. Barbacid, J. R. Bischoff, P. Pizcueta and J. Pastor, Bioorg.
Med. Chem. Lett., 2012, 22, 3460–3466; (g) J. M. Bartolome-
Nebreda, F. Delgado, M. L. Martin-Martin, C. M. Martinez-
Viturro, J. Pastor, H. M. Tong, L. Iturrino, G. J. Macdonald,
W. Sanderson, A. Megens, X. Langlois, M. Somers,
G. Vanhoof and S. Conde-Ceide, J. Med. Chem., 2014, 57,
4196–4212.
10 H. He, D. Zatorska, J. Kim, J. Aguirre, L. Llauger, Y. She,
N. Wu, R. M. Immormino, D. T. Gewirth and G. Chiosis,
J. Med. Chem., 2005, 49, 381–390.
2 (a) D. B. Salunke, E. Yoo, N. M. Shukla, R. Balakrishna,
S. S. Malladi, K. J. Serafin, V. W. Day, X. Wang and
S. A. David, J. Med. Chem., 2012, 55, 8137–8151;
11 See ESI† for additional details.
This journal is © The Royal Society of Chemistry 2014
Org. Biomol. Chem.