Synthetic Diazabicyclo Analogs of the HIV-1 Inhibitor BMS-378806
4, 339–355; c) F. Shaheen, R. G. Collman, Curr. Opin. Infect.
Dis. 2004, 17, 7–16; d) I. Markovic, Curr. Pharm. Des. 2006,
12, 1105–1119.
T. Wang, Z. Zhang, O. B. Wallace, M. Deshpande, H. Fang, Z.
Yang, L. M. Zadjura, D. L. Tweedie, S. Huang, F. Zhao, S.
Ranadive, B. S. Robinson, Y. F. Gong, K. Ricarrdi, T. P. Spicer,
C. Deminie, R. Rose, H. G. H. Wang, W. S. Blair, P. Y. Shi, P. F.
Lin, R. J. Colonno, N. A. Meanwell, J. Med. Chem. 2003, 46,
4236–4239.
a) P. F. Lin, W. Blair, T. Wang, T. Spicer, Q. Guo, N. Zhou,
Y. F. Gong, H. G. H. Wang, R. Rose, G. Yamanaka, B. Robin-
son, C. B. Li, R. Fridell, C. Deminie, G. Demers, Z. Yang, L.
Zadjura, N. Meanwell, R. A. Colonno, Proc. Natl. Acad. Sci.
USA 2003, 100, 11013–11018; b) Q. Guo, H.-T. Ho, I. Dicker,
L. Fan, N. Zhou, J. Friborg, T. Wang, B. V. McAuliffe, H. H.
Wang, R. E. Rose, H. Fang, H. T. Scarnati, D. R. Langley,
N. A. Meanwell, R. Abraham, R. J. Colonno, P. F. Lin, J. Virol.
2003, 77, 10528–10536.
was similarly repeated for the B arrangement. Vibrational fre-
quencies were computed at the same level of theory to verify that
the optimized structures were minima. The population percentages
were calculated through the Boltzmann equation at 248 K. GIAO
NMR calculations[14] were carried out at the B3LYP/6-31G(d)
level.
[4]
[5]
NMR Spectroscopy: NMR spectra of compounds 2–4 were re-
corded with a Bruker AVANCE-500 spectrometer operating at
500.13 MHz for 1H or at 125.76 MHz for 13C NMR spectra by
using a 5-mm z-PFG (pulsed field gradient) broadband reverse
probe at different temperatures obtained through a Bruker BVT
3000 digital temperature control unit connected to a liquid nitrogen
evaporator system. Chemical shifts (δ) are reported in ppm and are
relative to residual methanol signals (δ =3.30 ppm) or 47.0 ppm
(central line) for CD3OD 13C NMR spectra, and scalar coupling
constants are reported in Hz. The data were collected and pro-
cessed by XWIN-NMR software (Bruker) running on a PC with
Microsoft Windows XP. Compounds 2–4 (4–8 mg) were dissolved
in CD3OD (0.6 mL) and put in 5-mm NMR tubes. The signal as-
signment was given by a combination of 1D and 2D (COSY and
HSQC) experiments, by using standard Bruker pulse programs. The
1H-1H and 13C-1H bond correlations were confirmed by COSY and
HSQC experiment by using Z-PFGs. The pulse widths were 8.00 μs
[6]
R. S. Veazey, P. J. Klasse, S. M. Schader, Q. Hu, T. J. Ketas, M.
Lu, P. A. Marx, J. Dufour, R. J. Colonno, R. J. Shattock, M. S.
Springer, J. P. Moore, Nature 2005, 438, 99–102.
[7]
[8]
D. Colombo, S. Villa, L. Solano, L. Legnani, F. Marinone Al-
bini, L. Toma, Eur. J. Org. Chem. 2009, 3178–3183.
a) R.-J. Lu, J. A. Tucker, T. Zinevitch, O. Kirichenko, V. Kono-
plev, S. Kuznetsova, S. Sviridov, J. Pickens, S. Tandel, E. Brah-
machary, Y. Yang, J. Wang, S. Freel, S. Fisher, A. Sullivan, J.
Zhou, S. Stanfield-Oakley, M. Greenberg, D. Bolognesi, B.
Bray, B. Koszalka, P. Jeffs, A. Khasanov, Y.-A. Ma, C. Jeffries,
C. Liu, T. Proskurina, T. Zhu, A. Chucholowski, R. Li, C.
Sexton, J. Med. Chem. 2007, 50, 6535–6544; b) T. Wang, Z.
Yin, Z. Zhang, J. A. Bender, Z. Yang, G. Johnson, Z. Yang,
L. M. Zadjura, C. J. DЈArienzo, D. DiGiugno Parker, C. Ge-
senberg, G. A. Yamanaka, Y.-F. Gong, H.-T. Ho, H. Fang, N.
Zhou, B. V. McAuliffe, B. J. Eggers, L. Fan, B. Nowicka-Sans,
I. B. Dicker, Q. Gao, R. J. Colonno, P.-F. Lin, N. A. Meanwell,
J. F. Kadow, J. Med. Chem. 2009, 52, 7778–7787.
M. Li, F. Gao, J. R. Mascola, L. Stamatatos, V. R. Polonis, M.
Koutsoukos, G. Voss, P. Goepfert, P. Gilbert, K. M. Greene,
M. Bilska, D. L. Kothe, J. F. Salazar-Gonzalez, X. Wei, J. M.
Decker, B. H. Hahn, D. C. Montefiori, J. Virol. 2005, 79,
10108–10125.
a) G. Loriga, I. Manca, G. Murineddu, G. Chelucci, S. Villa,
S. Gessi, L. Toma, G. Cignarella, G. A. Pinna, Bioorg. Med.
Chem. 2006, 14, 676–691; b) D. Barlocco, G. Cignarella, D.
Tondi, P. Vianello, S. Villa, A. Bartolini, C. Gheraldini, N. Ga-
leotti, D. J. Anderson, T. A. Kuntzweiler, D. Colombo, L.
Toma, J. Med. Chem. 1998, 41, 674–681; c) G. A. Pinna, G.
Murineddu, M. M. Curzu, S. Villa, P. Vianello, P. A. Borea, S.
Gessi, L. Toma, D. Colombo, G. Cignarella, Farmaco 2000, 55,
553–562.
1
(90°) for H and 13.6 μs (90°) for 13C. Typically, 32 K data points
were collected for one-dimensional spectra. Spectral widths were
1
11.45 ppm (5733 Hz) for H NMR (digital resolution: 0.17 Hz per
point) and 259.84 ppm (32680 Hz) for 13C NMR (digital resolu-
tion: 1.0 Hz per point), 1.5 Hz line broadening. 2D experiment pa-
1
rameters were as follows. For H-1H correlations: relaxation delay
2.0 s, data matrix 1 K ϫ1 K (512 experiments to 1 K zero filling in
F1, 1 K in F2), 2 transients in each experiment for COSY, spectral
width 8.01 ppm (4006.41 Hz). For 13C-1H correlations (HSQC): re-
laxation delay 2.5 s, data matrix 1K ϫ1K (512 experiments to 1 K
zero filling in F1, 1K in F2), 8 transients in each experiment, spec-
tral width 8.0 ppm (4001 Hz) in the proton domain and 200.0 ppm
(25155 Hz) in the carbon domain. A sine-bell weighting was ap-
plied to each dimension. All 2D spectra were processed with the
Bruker software package.
[9]
[10]
Supporting Information (see footnote on the first page of this arti-
cle): Complete 1H and 13C NMR spectroscopic data of compounds
2–4, modeling data of all their located conformations, and com-
parison of the B3LYP/6-31G(d) and 6-311++G(2d,p) GIAO calcu-
1
lated H NMR chemical shifts are presented.
[11]
N. Soundararajan, S. Benoit, S. Gingras (Squibb Bristol Myers
Co.), PCT WO 03082289, 2003 [Chem. Abstr. 2003, 139,
307795].
Acknowledgments
[12]
[13]
a) A. D. Becke, J. Chem. Phys. 1993, 98, 5648–5652; b) C. Lee,
The Authors thank Professor Michael Kay (University of Utah,
U.S.A.) for helpful discussions. They acknowledge the financial
support from the Universities of Pavia and Milano (FAR and PUR
grants, respectively). The study was also supported by Grant no.
201433 from the European Commission/Seventh Framework Pro-
gramme (FP7/2007–2013) and Grant GCE no. 53030 and
PP1008144 from the Bill and Melinda Gates Foundation to L. Lo-
palco.
W. Yang, R. G. Parr, Phys. Rev. B 1988, 37, 785.
a) V. Barone, M. Cossi, J. Tomasi, J. Comput. Chem. 1998, 19,
404–417; b) J. Tomasi, B. Mennucci, R. Cammi, Chem. Rev.
2005, 105, 2999–3093.
a) K. Wolinski, F. James, J. F. Hinton, P. Pulay, J. Am. Chem.
Soc. 1990, 112, 8251–8260; b) R. Ditchfield, Mol. Phys. 1974,
27, 789–807.
GIAO NMR calculations were also performed by using the
larger basis set 6-311++G(2d,p). However, a worsening of the
errors was observed (see Supporting Information).
M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria,
M. A. Robb, J. R. Cheeseman, J. A. Montgomery Jr., T.
Vreven, K. N. Kudin, J. C. Burant, J. M. Millam, S. S. Iyengar,
J. Tomasi, V. Barone, B. Mennucci, M. Cossi, G. Scalmani, N.
Rega, G. A. Petersson, H. Nakatsuji, M. Hada, M. Ehara, K.
Toyota, R. Fukuda, J. Hasegawa, M. Ishida, T. Nakajima, Y.
[14]
[15]
[16]
[1] R. C. Gallo, L. Montagnier, New Engl. J. Med. 2003, 349,
2283–2285.
[2] WHO/UNAIDS, AIDS Epidemic Update 2009.
[3] a) V. Briz, E. Poveda, V. Soriano, J. Antimicrob. Chemother.
2006, 57, 619–627; b) S. Rusconi, A. Scozzafava, A. Mastrolor-
enzo, C. T. Supuran, Curr. Drug Targets Infect. Disord. 2004,
Eur. J. Org. Chem. 2011, 287–294
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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