Stereoelectronic effects dictate molecular conformation and biological function of heterocyclic amides

Article abstract of DOI:10.1021/ja506518t

Heterocycles adjacent to amides can have important influences on molecular conformation due to stereoelectronic effects exerted by the heteroatom. This was shown for imidazole- and thiazole-amides by comparing low energy conformations (ab initio MP2 and DFT calculations), charge distribution, dipole moments, and known crystal structures which support a general principle. Switching a heteroatom from nitrogen to sulfur altered the amide conformation, producing different three-dimensional electrostatic surfaces. Differences were attributed to different dipole and orbital alignments and spectacularly translated into opposing agonist vs antagonist functions in modulating a G-protein coupled receptor for inflammatory protein complement C3a on human macrophages. Influences of the heteroatom were confirmed by locking the amide conformation using fused bicyclic rings. These findings show that stereoelectronic effects of heterocycles modulate molecular conformation and can impart strikingly different biological properties.

Full text of DOI:10.1021/ja506518t

Subscriber access provided by UniSA Library
Communication
Stereoelectronic effects dictate molecular conformation
and biological function of heterocyclic amides
Robert C Reid, Mei-Kwan Yau, Ranee Singh, Junxian Lim, and David P. Fairlie
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/ja506518t • Publication Date (Web): 07 Aug 2014
Downloaded from http://pubs.acs.org on August 11, 2014
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a free service to the research community to expedite the
dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts
appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been
fully peer reviewed, but should not be considered the official version of record. They are accessible to all
readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered
to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published
in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just
Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor
changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers
and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors
or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
Journal of the American Chemical Society is published by the American Chemical
Society. 1155 Sixteenth Street N.W., Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 5
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
Stereoelectronic Effects Dictate Molecular Conformation and
Biological Function of Heterocyclic Amides
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Robert C. Reid*, Mei-Kwan Yau, Ranee Singh†, Junxian Lim, and David P. Fairlie*
Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, The University of Queensland,
Brisbane, QLD 4072, Australia
Supporting Information Placeholder
ABSTRACT: Heterocycles adjacent to amides can have im-
portant influences on molecular conformation due to stereo-
electronic effects exerted by the heteroatom. This was shown
for imidazole- and thiazole- amides by comparing low ener-
gy conformations (ab initio MP2 and DFT calculations),
charge distribution, dipole moments, and known crys-
tal structures which support a general principle. Switching a
heteroatom from nitrogen to sulfur altered the amide con-
formation, producing different three-dimensional electro-
static surfaces. Differences were attributed to different dipole
and orbital alignments and spectacularly translated into op-
posing agonist vs antagonist activity in activating a G-protein
coupled receptor for inflammatory protein complement C3a
on human macrophages. Influences of the heteroatom were
confirmed by locking the amide conformation using fused
bicyclic rings. These findings show that stereoelectronic ef-
fects of heterocycles modulate molecular conformation and
can impart strikingly different biological properties.
Heterocyclic rings are important components of many or-
ganic compounds, including natural products, pharmaceuti-
Figure 1. a) Partial charges on heteroatoms determined by
cals and peptidomimetics, and can influence molecular con-
formation, solubility, chemical and biological activity.1 Het-
natural population analysis on geometries optimized at
MP2/6-311++(2d,2p) level using Gaussian 09.4 Dihedral angle
eroatoms are hydrogen bond donors or acceptors, general
(χ). S-O distance (Å). b) Variation in energy with dihedral
acids or bases, and confer different electrostatic properties
that fine-tune chemical reactivity or biological interactions.2
angle X-C-C-O reveals barriers to rotation from low energy
conformations. 1H-imidazole-4-carboxamide 1 (blue) shows
preferred dihedral angle 180° with high barrier to rotation.
Heterocycles can constrain molecular conformation by ori-
enting substituents or through intramolecular interactions.3
Thiazole-5-carboxamide 2 (red) has access to low energy
For example, heterocycles such as the imidazole in 1 and the
conformers with dihedral angles close to 0° and 180°
thiazole in 2 (Fig. 1) might influence the conformation of the
adjacent amide due to 1,4-N(heteroatom)…O(amide) or 1,4-
S(heteroatom)…O(amide) orbital interactions.
deficient sulfur have been described previously5 and associ-
ated with drug like molecules.6 Ab initio calculations for 2
suggest that the S-O distance (2.93Å) is less than the sum of
the sulfur and oxygen van der Waals radii (3.4 Å)7,
supporting a non-covalent interaction. Conversely, com-
pound 1 should adopt a trans orientation due to electron
lone pair repulsion separating the negatively charged atoms.8
A significant barrier to rotation was predicted to stabilize
these different conformations. To assess this, we performed
ab initio DFT calculations at the B3LYP/6-311++g(2d,2p) level
of theory on 1 and 2 to identify conformational preferences
Ab initio calculations (Fig. 1a) suggest that the trigonal ni-
trogen of the imidazole adjacent to the carbonyl of 1 may
have a large partial negative charge, whereas the sulfur atom
in the aromatic thiazole ring may carry a partial positive elec-
trostatic potential. The electronegative carbonyl oxygen ad-
jacent to the thiazole in 2 should preferentially adopt a cis
orientation due to a significant electrostatic attraction. Non-
covalent n0ꢀσ* interactions between lone pairs and electron
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 2 of 5
(Fig. 1b). The dihedral angle X-C-C-O was varied in 10° in-
(v5.34, 2012) for crystal structures containing imidazole-,
thiazole- and thiophene- carboxamides (Fig. 3,
Supplementary Tables 1-3). All thirty four diverse structures
for 1H-imidazole-4-carboxamides (3) showed a conformation
with a N-C-C-O dihedral angle 153-180° (ave 173°). Of six
thiazole-5-carboxamide analogues (4), four showed a S-C-C-
1
2
3
4
crements with subsequent energy minimisation and total
energy of each conformer was plotted relative to minimum
energy structure. All calculations were performed using
Gaussian 09 through the graphical interface GaussView 5.4.
5
6
7
8
The imidazole carboxamide 1 had a strong preference for a
dihedral angle N-C-C-O ~180° with a high barrier to rotation
(10.5 kcal.mol-1) to a conformer with dihedral angle 40° and
9.7 kcal.mol-1 higher in energy than the lowest energy con-
former. By contrast, the thiazole carboxamide 2 had no pref-
erence for either conformation (ꢀE ∼0.8 kcal.mol-1), and only
a small barrier to rotation (∼3.5 kcal.mol-1). The fractional
population of conformers of different energy followed a Bolt-
zmann distribution, with ∼100% of 1H-imidazole-4-carbox-
amides having a dihedral angle N-C-C-O of 180°, and rotation
to alternate conformations being energetically unfavourable.
O
dihedral angle 11-37°, while two had the opposite
conformation (165° and 173°). Of fifty four thiophene-2-
carboxamide compounds (5), all but two (163° and 166°) had
a S-C-C-O dihedral angle 0-49° (ave 13°). In all structures
where S-C-C-O was ≤40°, the S-O distance (2.8-3.0 Å) was
less than the sum of the individual sulfur and oxygen van der
Waals radii (3.4 Å)7 and comparable with our calculated
value of 2.93 Å (Figure 1a).
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
These conformational preferences are consistent with the
expected alignment of the electric dipole moments of the
heterocyclic ring and carbonyl group connected by a rotata-
ble bond. Fig. 2a shows that the dipole moment of imidazole
(3.88 D) is oriented away from the trigonal nitrogen atom at
the 3-position, thus an appended carbonyl group (4.28 D for
acetamide) must adopt a dihedral angle N-C-C-O of 180° for
these dipoles to align in preferred anti-parallel directions.
Conversely, the weaker dipole moment of thiazole (1.65 D)
points in the opposite direction, away from the trigonal ni-
trogen at the 3-position. When an amide carbonyl group is
attached, it preferentially adopts an S-C-C-O dihedral angle
~0° to place these dipoles in anti-parallel directions, although
the effect is weaker (Fig. 2b). These differences result in dif-
ferent electrostatic surfaces (Fig. 2c, 2d) that are predicted to
result in different chemical and biological properties.
Figure 3. Query structures 3-5 searched in the CSD.9
This suggests that an attractive non-bonded sulfur-oxygen
interaction,9c,9d,10 exists for thiazole amides (e.g. 2), whereas
electron pair repulsion theory8 predicts that the amide car-
bonyl oxygen would favour the conformer with dihedral an-
gle N-C-C-O 180° for 1H-imidazole-4-carboxamide (e.g. 1), as
observed. Thus, structurally very similar heterocycles do
indeed adopt quite different conformations that might
translate into very different chemical and biological
properties.
Based on these findings, we modified a simple flexible lig-
and (N2-[(2,2-diphenylethoxy)acetyl]-
to compete with human inflammatory protein
L-arginine), reported
a
(complement C3a) for a G protein-coupled receptor found on
human immune cells.11 We synthesized compounds 6 and 7
containing a heterocyclic carboxamide, where the only dif-
ference was the heterocycle, imidazole 6 versus thiazole 7.
We found that these compounds had completely opposite
biological functions in modulating the human complement
C3a protein receptor (Figure 4). While 6 potently activated
the receptor (i.e. an agonist), 7 inhibited its activation (i.e. an
Figure 2. Electric dipole moment of heterocycles and amide
carbonyl depicted by vectors (blue arrows) with magnitude
proportional to length (3 D.cm-1) and direction towards δ+
(arrowhead). Favored antiparallel dipoles require different
dihedral angles: a) 1H-imidazole-4-carboxamide N-C-C-O
dihedral angle 180°; b) thiazole-5-carboxamide S-C-C-O di-
hedral angle 0°. Electrostatic surface potential: c) 1H-
imidazole-4-carboxamide 1 , d) thiazole-5-carboxamide 2
Calculations used Gaussian 09, images in GaussView 5.4
To test these conformational predictions, we used
ConQuest to search the Cambridge Structural Database9
ACS Paragon Plus Environment

Page 3 of 5
Journal of the American Chemical Society
antagonist).
an agonist (Fig. 6a) just like its more flexible congener 6 (Fig.
4).
Support for the hypothesis, that physiological function is
driven by ligand conformation, was also sought for the thiaz-
ole-5-carboxamide with an S-C-C-O dihedral angle ~0°, as in
compound 2. The conformationally locked lactam 11 was
1
2
3
4
5
6
7
Figure 4. Structures for compounds 6 and 7. a) intracellullar
Ca2+ release in human macrophages induced by different
concentrations of agonist 6 (EC50 24 nM) and b) compound 7
has no agonist activity (ꢀ) but increasing concentrations of
antagonist 7 (ꢁ) (IC50 1 ꢁM) block iCa2+ release induced by
100 nM hC3a all data n ≥ 3 error bars are ± SEM.
8
9
These opposing functions are due to the imidazole and
thiazole rings in compounds 6 and 7 promoting two distinct-
ly different conformations controlled by stereoelectronic
effects intrinsic to the specific heterocycle present (Figure 1).
Although the thiazole can also adopt a conformation with an
S-C-C-O dihedral angle ~180°, the receptor preferentially
binds its conformer with a dihedral angle ~0° which the im-
idazole cannot access due to the high barrier to rotation.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
This surprizing switch in function between compounds 6
and 7 (Figure 4) was not related to the NH present at the 1-
position of the imidazole (perhaps through a hydrogen bond
to the receptor). We synthesised the isomeric thiazole com-
pound 8 and the 1-methyl-1H-imidazole analogue 9 which are
incapable of making such interactions. Both had similar bio-
logical activity (agonists) to the imidazole 6 (Fig. 5). Com-
pound 8 was less effective than 9, suggesting that fine tuning
of activity was influenced by subtle changes to other regions.
Compound 9 also removes any ambiguity about the tauto-
meric form of the biologically active imidazole 6. Thus, sub-
tle changes to electrostatic surface potentials (mapped in
Figure 2c, d) dramatically alter complementarity between
ligand and receptor, conferring a switch in biological func-
tion.
Figure 6. Structures of the constrained 1H-imidazo[4,5-
c]pyridine 10 and lactam 11. a) intracellular Ca2+ release in
macrophages induced by different concentrations of agonist
10 (EC50 15 nM) and b) increasing concentration of antagonist
11 blocks iCa2+ release induced by hC3a (100 nM) (IC50 0.32
ꢁM). all data n ≥ 3 error bars are ± SEM.
consequently designed and synthesised via Scheme 2. The
methylene group that completes the lactam ring fuses the 4-
methyl group and amide nitrogen, thereby restricting the
lactam carbonyl to one conformation where the S-C-C-O
dihedral angle was close to 0°. The arginine αNH proton is
removed as a consequence of lactam formation, but this is
unlikely to be important for receptor binding because the
amide NH in 7 is shielded from receptor interactions by the
5-methyl group. Compound 11 was found to be an antagonist
(Fig. 6b) just like its more flexible analogue 7 .
Figure 5. Thiazole 8 and 1-methyl-1H-imidazole analogue 9
have agonist activity similar to 6.
The 1H-imidazo[4,5-c]pyridine 10 was prepared as shown
in Scheme 1. The known 4-amino-3-nitro-2-chloropyridine12
12 was acylated with diphenylacetyl chloride after deprotona-
tion with NaOtBu at -10 °C to give anilide 13. Nucleophilic
aromatic substitution of 13 with Nδ-Cbz-L-ornithine tert-
butyl ester gave 14. Hydrogenation reduced the nitro group
to amine and simultaneously cleaved the Cbz protecting
group. Cyclisation of the aminoanilide intermediate to the
1H-imidazo[4,5-c]pyridine 15 occurred rapidly and cleanly in
glacial acetic acid solution with only mild heating. The ami-
no group was converted to the guanidine using N,N'-di-Boc-
1H-pyrazole-1-carboxamidine, and removal of the tert-butyl
ester and Boc groups with TFA gave 10. Lactam 11 was syn-
thesized (Scheme 2) by nucleophilic substitution of chloro-
methylthiazole 16 with Nδ-Cbz-L-ornithine tert-butyl ester to
give 17, accompanied by hydroxylation of the benzhydryl
group despite effort to exclude moisture and air. This was
removed during subsequent deprotections. Hydrolysis of
To confirm the importance of stereoelectronic effects in
dictating conformation in these heterocycle-carboxamide
compounds, we designed conformationally rigid compounds
10 and 11. Since stereoelectronic effects enforce 1H-
imidazole-4-carboxamides to adopt an N-C-C-O dihedral
angle ~180° as in 1 and hence 6, we designed and synthesised
the constrained 1H-imidazo[4,5-c]pyridine analogue 10. This
presents
a
strong hydrogen bond-accepting trigonal
nitrogen, and a heterocycle locked into this arrangement.
Creating the pyridine ring was not expected to impinge on
interactions that 10 may make with the receptor, because the
5-methyl group of 6 shields one of the electron lone pairs on
the amide oxygen leaving only one hydrogen bond acceptor,
the pyridine trigonal nitrogen of 10. The arginine αNH
proton remains available as a hydrogen bond donor and thus
the hydrogen bonding properties of 10 are expected to
resemble those observed in, for example, adenine-thymine
DNA base pairing. Compound 10, prepared via Scheme 1, was
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 4 of 5
ethyl ester 17 followed by cyclisation to lactam and deprotec-
calculations reveal that both trans conformers are respective-
1
2
3
4
tion including ionic hydrogenation gave 18. The amino group
was converted to the guanidine using N,N'-di-Boc-1H-
pyrazole-1-carboxamidine and deprotected with TFA to give
11 (Scheme 2, details in supporting information).
ly 9.1 and 8.7 kcal/mol more stable. Understanding orbital
and dipole alignments can enable more rational selection of
heterocyclic templates for elaboration in drug design and
discovery.
5
6
7
8
ASSOCIATED CONTENT
Supporting Information
Experimental procedures, analytical data (1H, 13C NMR) for
all new compounds, CSD searches and cell assays. This mate-
rial is available free of charge via the Internet at
http://pubs.acs.org.
Scheme 1. Synthesis of the constrained agonist 10
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
AUTHOR INFORMATION
Corresponding Authors
e-mail: r.reid@imb.uq.edu.au, d.fairlie@imb.uq.edu.au
Present Addresses
† Dr. Ranee Singh, Dept. Pharmacol. & Toxicol., Faculty of
Veterinary Medicine, Khon Kaen University, Thailand
Notes
The authors are inventors on C3a patent applications owned
by University of Queensland. No other competing interests.
a) NaOtBu, Ph2CHCOCl, THF -10 °C; b) H-Orn(Cbz)-OtBu,
NMM, EtOH, ꢀ; c) H2, 10% Pd-C, EtOH, room temp, 30 min;
d) glacial AcOH, 40 °C, 30 min; e) N,N'-Di-Boc-1H-pyrazole-
1-carboxamidine, DMF; f) TFA.
ACKNOWLEDGMENT
This study was supported by grants to DPF from the National
Health and Medical Research Council (APP1000745,
APP1028423, SPRF fellowship 1027369), the Australian Re-
search Council (DP130100629, DP1093245, FF0668733), the
ARC Centre of Excellence in Advanced Molecular Imaging
(CE140100011), and the Queensland Government (CIF grant).
Scheme 2. Synthesis of the constrained lactam antagonist 11
REFERENCES
(1) (a) Baumann, M.; Baxendale, I. R.; Ley, S. V.; Nikbin, N.
Beilstein J. Org. Chem. 2011, 7, 442. (b) Reid, R. C.; Yau, M.-K.; Singh,
R.; Hamidon, J. K.; Reed, A. N.; Chu, P.; Suen, J. Y.; Stoermer, M. J.;
Blakeney, J. S.; Lim, J.; Faber, J. M.; Fairlie, D. P. Nat. Commun. 2013,
4, 2802.
(2) Meanwell, N. A. J. Med. Chem. 2011, 54, 2529.
(3) Schaerfer, C.; Schulz-Gasch, T.; Ehrlich, H. C.; Guba, W.;
Rarey, M.; Stahl, M. J. Med. Chem. 2013, 56, 2016.
(4) Frisch, M. J.; Revision A.02 ed.; Gaussian Inc.: Wallingford CT,
2009.
(5) (a) Murray, J. S.; Lane, P.; Politzer, P. Int. J. Quantum Chem.
2008, 108, 2770. (b) Dudkin, V. Y. Chem. Heterocycl. Compd. (N. Y.,
NY, U. S.) 2012, 48, 27.
(6) (a) Franchetti, P.; Cappellacci, L.; Grifantini, M.; Barzi, A.;
Nocentini, G.; Yang, H.; O'Connor, A.; Jayaram, H. N.; Carrell, C.;
Goldstein, B. M. J. Med. Chem. 1995, 38, 3829. (b) Goldstein, B. M.; Li,
H.; Hallows, W. H.; Langs, D. A.; Franchetti, P.; Cappellacci, L.;
Grifantini, M. J. Med. Chem. 1994, 37, 1684. (c) Goldstein, B. M.;
Takusagawa, F.; Berman, H. M.; Srivastava, P. C.; Robins, R. K. J. Am.
Chem. Soc. 1983, 105, 7416. (d) Haginoya, N.; Kobayashi, S.;
Komoriya, S.; Yoshino, T.; Suzuki, M.; Shimada, T.; Watanabe, K.;
Hirokawa, Y.; Furugori, T.; Nagahara, T. J. Med. Chem. 2004, 47, 5167.
(e) Hayashi, K.; Ogawa, S.; Sano, S.; Shiro, M.; Yamaguchi, K.; Sei, Y.;
Nagao, Y. Chem. Pharm. Bull. 2008, 56, 802. (f) Hynes, J., Jr.; Wu, H.;
Pitt, S.; Shen, D. R.; Zhang, R.; Schieven, G. L.; Gillooly, K. M.;
Shuster, D. J.; Taylor, T. L.; Yang, X.; McIntyre, K. W.; McKinnon, M.;
Zhang, H.; Marathe, P. H.; Doweyko, A. M.; Kish, K.; Kiefer, S. E.;
Sack, J. S.; Newitt, J. A.; Barrish, J. C.; Dodd, J.; Leftheris, K. Bioorg.
Med. Chem. Lett. 2008, 18, 1762. (g) Ioannidis, S.; Lamb, M. L.;
a) H-Orn(Cbz)-OtBu, K2CO3, NaI, DMF; b) NaOH, H2O,
MeOH, THF; c) DCC, DCM; d) TFA, Et3SiH, PhSMe; e) N,N'-
Di-Boc-1H-pyrazole-1-carboxamidine, DMF; f) TFA.
In summary, multiple approaches used here show that an
aromatic heterocycle dictates the conformation of an adja-
cent carbonyl group. This finding enables predictions of con-
formational preferences for heterocyclic carboxamides, that
can profoundly influence interactions of small molecules
with proteins. This analysis is expected to extend to other
heterocyclic ring systems, where a single rotatable bond links
the heteroatom to a polar substituent. For example, we found
>200 picolinamides and 12 1,2,3-triazole-4-carboxamides in
the CSD where the N-C-C-O dihedral angle was ~180°. DFT
ACS Paragon Plus Environment

Page 5 of 5
Journal of the American Chemical Society
Almeida, L.; Guan, H.; Peng, B.; Bebernitz, G.; Bell, K.; Alimzhanov,
58, 380. (c) Brameld, K. A.; Kuhn, B.; Reuter, D. C.; Stahl, M. J. Chem.
Inf. Model. 2008, 48, 1. (d) Burling, F. T.; Goldstein, B. M. Acta
Crystallogr., Sect. B: Struct. Sci. 1993, 49, 738.
(10) (a) Senger, S.; Convery, M. A.; Chan, C. E.; Watson, N. S.
Bioorg. Med. Chem. Lett. 2006, 16, 5731. (b) Iwaoka, M.; Takemoto, S.;
Tomoda, S. J. Am. Chem. Soc. 2002, 124, 10613. (c) Angyan, J. G.;
Poirier, R. A.; Kucsman, A.; Csizmadia, I. G. J. Am. Chem. Soc. 1987,
109, 2237. (d) Burling, F. T.; Goldstein, B. M. J. Am. Chem. Soc. 1992,
114, 2313. (e) Nagao, Y.; Hirata, T.; Goto, S.; Sano, S.; Kakehi, A.;
Iizuka, K.; Shiro, M. J. Am. Chem. Soc. 1998, 120, 3104.
(11) Ames, R. S.; Lee, D.; Foley, J. J.; Jurewicz, A. J.; Tornetta, M. A.;
Bautsch, W.; Settmacher, B.; Klos, A.; Erhard, K. F.; Cousins, R. D.;
Sulpizio, A. C.; Hieble, J. P.; McCafferty, G.; Ward, K. W.; Adams, J.
L.; Bondinell, W. E.; Underwood, D. C.; Osborn, R. R.; Badger, A. M.;
Sarau, H. M. J. Immunol. 2001, 166, 6341.
(12) (a) Chu, D. C. K.; Cho, J. H.; Kim, H.-J.; WO2007047793A2,
University of Georgia Research Foundation, Inc., USA . 2007, p 121pp.
(b) Searls, T.; McLaughlin, L. W. Tetrahedron 1999, 55, 11985.
M.; Zinda, M. Bioorg. Med. Chem. Lett. 2010, 20, 1669. (h) Jung, F. H.;
Pasquet, G.; Van der Brempt, C. L.; Lohmann, J.-J. M.; Warin, N.;
Renaud, F.; Germain, H.; De Savi, C.; Roberts, N.; Johnson, T.;
Dousson, C.; Hill, G. B.; Mortlock, A. A.; Heron, N.; Wilkinson, R.
W.; Wedge, S. R.; Heaton, S. P.; Odedra, R.; Keen, N. J.; Green, S.;
Brown, E.; Thompson, K.; Brightwell, S. J. Med. Chem. 2006, 49, 955.
(i) Li, H.; Hallows, W. A.; Punzi, J. S.; Marquez, V. E.; Carrell, H. L.;
Pankiewicz, K. W.; Watanabe, K. A.; Goldstein, B. M. Biochemistry
1994, 33, 23. (j) Lin, S.; Wrobleski, S. T.; Hynes, J., Jr.; Pitt, S.; Zhang,
R.; Fan, Y.; Doweyko, A. M.; Kish, K. F.; Sack, J. S.; Malley, M. F.;
Kiefer, S. E.; Newitt, J. A.; McKinnon, M.; Trzaskos, J.; Barrish, J. C.;
Dodd, J. H.; Schieven, G. L.; Leftheris, K. Bioorg. Med. Chem. Lett.
2010, 20, 5864. (k) Nagao, Y.; Hirata, T.; Goto, S.; Sano, S.; Kakehi, A.;
Iizuka, K.; Shiro, M. J. Am. Chem. Soc. 1998, 120, 3104. (l) Pierce, A.
C.; ter Haar, E.; Binch, H. M.; Kay, D. P.; Patel, S. R.; Li, P. J. Med.
Chem. 2005, 48, 1278.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(7) Alvarez, S. Dalton Trans. 2013, 42, 8617.
(8) Chein, R. J.; Corey, E. J. Org. Lett. 2010, 12, 132.
(9) (a) Groom, C. R.; Allen, F. H. Angew. Chem. Int. Ed. Engl. 2014,
53, 662. (b) Allen, F. H. Acta Crystallogr., Sect. B: Struct. Sci. 2002,
SYNOPSIS TOC
ACS Paragon Plus Environment