J. Porter et al. / Bioorg. Med. Chem. Lett. 19 (2009) 1767–1772
1771
Table 2
Bcl-2 activity and 600 MHz NMR data for the atropisomeric forms of analogues of compound 7
O
X
N(nBu)2
NH2
N
N
O
N
R
Compound
R
X
HPLC
Pyrazole 4-H d
H1, H2
–
4.44, 4.29
4.27, 4.15
4.84, 4.19
5.21, 3.85
–
d
H1, H2 J (Hz)
H3
–
4.61
4.54
3.76
3.69
–
d
Bcl-2 IC50 (nM)
10a
Me
H
Mixture
–
–
175
55
358
nd
nd
42
Fraction 1
Fraction 2
Fraction 3
Fraction 4
Mixture
Fraction 1
Fraction 2
Mixture
6.33
6.46
6.36
6.43
n/a
6.35
6.43
–
16.6
16.6
18.0
18.0
–
16.2
16.7
–
10b
16a
Me
CF3
Cl
H
4.35, 4.18
4.24, 4.07
–
4.50
4.46
–
16% at 30
14,400
1070
lM
16b
NH2
H
Compound 10a fractions 3 and 4 were not physically separated, their NMR data was determined from the spectrum of the mixture, nd = not done.
Figure 6. The X-ray conformation of 1 (white) and the nOe-derived solution-phase conformation model of the cis, a-R bioactive atropisomer of 7 (cyan). Comparison of the
structures shows that they share a common rotameric conformation about the THIQ amide. The absence of nOe information relating to the diphenyl amide prevents
assignment of a preferred orientation of this group, however it is likely that this part of the molecule rotates freely in solution.
C.; Wang, X.; Wendt, M. D.; Yang, X.; Zhang, H.; Fesik, S. W.; Rosenberg, S. H.;
Elmore, S. W. J. Med. Chem. 2008, 51, 6902.
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lm
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C18 110 Å 150 Â 21 mm HPLC column (Phenomenex, Macclesfield, Cheshire,
UK). Mobile phase composition of 0.1% formic acid in water + 10% acetonitrile
(phase A) and 0.1% formic acid in acetonitrile + 10% water (phase B). 0–0.5 min,
95% A 5% B; 0.5–9.5 min, 50% A 50% B; 9.5–10 min, 40% A 60% B; 10–11.5 min,
5% A 95% B; 11.5–12 min, 95% A 5% B, at a constant flow rate of 20 mL/min. The
7. (a) Tse, C.; Shoemaker, A. R.; Adickes, J.; Anderson, M. G.; Chen, J.; Jin, S.;
Johnson, E. F.; Marsh, K. C.; Mitten, M. J.; Nimmer, P.; Roberts, L.; Tahir, S. K.;
Xiao, Y.; Yang, X.; Zhang, H.; Fesik, S.; Rosenberg, S. H.; Elmore, S. W. Cancer Res.
2008, 68, 3421; (b) Park, C.-M.; Bruncko, M.; Adickes, J.; Bauch, J.; Ding, H.;
Kunzer, A.; Marsh, K. C.; Nimmer, P.; Shoemaker, A. R.; Song, X.; Tahir, S. K.; Tse,
compound was dissolved in DMSO (10 mg/mL, 250 lL) and loaded onto the