Supporting information
Crystallographic Information File (CIF) https://doi.org/10.1107/S0108270110005871/sq3232sup1.cif | |
Structure factor file (CIF format) https://doi.org/10.1107/S0108270110005871/sq3232Isup2.hkl |
CCDC reference: 774902
Compound (I) was obtained from the Drug Synthesis and Chemistry Branch, Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis of the National Cancer Institute.
All H atoms were refined as riding on their parent atoms, with C—H = 0.93–0.98 Å and Uiso(H) = 1.2Ueq(C) or 1.5Ueq(C). The absolute structure cannot be determined reliably from the X-ray data, so the Friedel pairs were merged before refinement.
Data collection: SMART (Bruker, 2003); cell refinement: SAINT (Bruker, 2003); data reduction: SAINT (Bruker, 2003); program(s) used to solve structure: SHELXS97 (Sheldrick, 2008); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008); molecular graphics: ORTEPII (Johnson, 1976); software used to prepare material for publication: SHELXL97 (Sheldrick, 2008).
Fig. 1. ORTEPII (Johnson, 1976) plot of the title compound. Displacement ellipsoids are drawn at the 50% level. | |
Fig. 2. View of the unit cell parallel to the ac plane. |
C19H26O2 | F(000) = 312 |
Mr = 286.40 | Dx = 1.143 Mg m−3 |
Monoclinic, P21 | Mo Kα radiation, λ = 0.71073 Å |
a = 6.2000 (12) Å | Cell parameters from 1004 reflections |
b = 10.890 (2) Å | θ = 2.5–18.8° |
c = 12.530 (3) Å | µ = 0.07 mm−1 |
β = 100.49 (3)° | T = 293 K |
V = 831.9 (3) Å3 | Prism, colourless |
Z = 2 | 0.28 × 0.24 × 0.21 mm |
Bruker APEX CCD area-detector diffractometer | 2063 independent reflections |
Radiation source: fine-focus sealed tube | 1681 reflections with I > 2σ(I) |
Graphite monochromator | Rint = 0.020 |
ϕ and ω scans | θmax = 27.9°, θmin = 1.7° |
Absorption correction: multi-scan (SADABS; Sheldrick, 2000) | h = −8→7 |
Tmin = 0.980, Tmax = 0.985 | k = −13→14 |
18767 measured reflections | l = −16→14 |
Refinement on F2 | Secondary atom site location: difference Fourier map |
Least-squares matrix: full | Hydrogen site location: inferred from neighbouring sites |
R[F2 > 2σ(F2)] = 0.036 | H-atom parameters constrained |
wR(F2) = 0.100 | w = 1/[σ2(Fo2) + (0.0571P)2 + 0.0324P] where P = (Fo2 + 2Fc2)/3 |
S = 1.06 | (Δ/σ)max < 0.001 |
2063 reflections | Δρmax = 0.11 e Å−3 |
193 parameters | Δρmin = −0.14 e Å−3 |
0 restraints | Absolute structure: unk |
Primary atom site location: structure-invariant direct methods |
C19H26O2 | V = 831.9 (3) Å3 |
Mr = 286.40 | Z = 2 |
Monoclinic, P21 | Mo Kα radiation |
a = 6.2000 (12) Å | µ = 0.07 mm−1 |
b = 10.890 (2) Å | T = 293 K |
c = 12.530 (3) Å | 0.28 × 0.24 × 0.21 mm |
β = 100.49 (3)° |
Bruker APEX CCD area-detector diffractometer | 2063 independent reflections |
Absorption correction: multi-scan (SADABS; Sheldrick, 2000) | 1681 reflections with I > 2σ(I) |
Tmin = 0.980, Tmax = 0.985 | Rint = 0.020 |
18767 measured reflections |
R[F2 > 2σ(F2)] = 0.036 | 0 restraints |
wR(F2) = 0.100 | H-atom parameters constrained |
S = 1.06 | Δρmax = 0.11 e Å−3 |
2063 reflections | Δρmin = −0.14 e Å−3 |
193 parameters | Absolute structure: unk |
Geometry. All esds (except the esd in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell esds are taken into account individually in the estimation of esds in distances, angles and torsion angles; correlations between esds in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell esds is used for estimating esds involving l.s. planes. |
Refinement. Refinement of F2 against ALL reflections. The weighted R-factor wR and goodness of fit S are based on F2, conventional R-factors R are based on F, with F set to zero for negative F2. The threshold expression of F2 > σ(F2) is used only for calculating R-factors(gt) etc. and is not relevant to the choice of reflections for refinement. R-factors based on F2 are statistically about twice as large as those based on F, and R- factors based on ALL data will be even larger. |
x | y | z | Uiso*/Ueq | ||
O3 | 0.5631 (3) | −0.0052 (2) | 0.64262 (12) | 0.0859 (6) | |
O17 | 0.7520 (4) | 0.3925 (2) | −0.09009 (15) | 0.0989 (7) | |
C1 | 0.7719 (4) | 0.2483 (2) | 0.50049 (16) | 0.0603 (5) | |
H1A | 0.6257 | 0.2776 | 0.4705 | 0.072* | |
H1B | 0.8647 | 0.3192 | 0.5212 | 0.072* | |
C2 | 0.7627 (4) | 0.1705 (3) | 0.60146 (17) | 0.0688 (6) | |
H2A | 0.9111 | 0.1557 | 0.6396 | 0.083* | |
H2B | 0.6864 | 0.2163 | 0.6496 | 0.083* | |
C3 | 0.6488 (3) | 0.0486 (2) | 0.57534 (16) | 0.0597 (5) | |
C4 | 0.6400 (3) | −0.0006 (2) | 0.46559 (16) | 0.0547 (5) | |
H4 | 0.5665 | −0.0742 | 0.4470 | 0.066* | |
C5 | 0.7337 (3) | 0.05629 (17) | 0.39162 (14) | 0.0429 (4) | |
C6 | 0.7088 (3) | 0.02076 (17) | 0.27229 (15) | 0.0461 (4) | |
H6 | 0.5525 | 0.0238 | 0.2402 | 0.055* | |
C8 | 0.8247 (3) | 0.12602 (17) | 0.22295 (14) | 0.0431 (4) | |
H8 | 0.9799 | 0.1045 | 0.2284 | 0.052* | |
C9 | 0.8077 (3) | 0.23460 (17) | 0.29987 (14) | 0.0429 (4) | |
H9 | 0.6520 | 0.2570 | 0.2884 | 0.051* | |
C10 | 0.8610 (3) | 0.17559 (17) | 0.41394 (14) | 0.0447 (4) | |
C11 | 0.9296 (4) | 0.3497 (2) | 0.27459 (18) | 0.0612 (5) | |
H11A | 1.0862 | 0.3341 | 0.2885 | 0.073* | |
H11B | 0.9006 | 0.4164 | 0.3213 | 0.073* | |
C12 | 0.8542 (4) | 0.3865 (2) | 0.15472 (18) | 0.0646 (6) | |
H12A | 0.7036 | 0.4150 | 0.1440 | 0.078* | |
H12B | 0.9445 | 0.4536 | 0.1372 | 0.078* | |
C13 | 0.8705 (3) | 0.2791 (2) | 0.07891 (17) | 0.0566 (5) | |
C14 | 0.7365 (3) | 0.16807 (19) | 0.10807 (14) | 0.0480 (4) | |
H14 | 0.5878 | 0.1986 | 0.1080 | 0.058* | |
C15 | 0.7195 (5) | 0.0820 (2) | 0.01026 (16) | 0.0708 (7) | |
H15A | 0.5981 | 0.0251 | 0.0070 | 0.085* | |
H15B | 0.8541 | 0.0361 | 0.0119 | 0.085* | |
C16 | 0.6795 (6) | 0.1729 (3) | −0.08528 (19) | 0.0939 (9) | |
H16A | 0.7572 | 0.1467 | −0.1419 | 0.113* | |
H16B | 0.5243 | 0.1779 | −0.1156 | 0.113* | |
C17 | 0.7652 (4) | 0.2971 (3) | −0.03964 (19) | 0.0718 (7) | |
C18 | 1.1134 (4) | 0.2463 (3) | 0.0779 (2) | 0.0771 (7) | |
H18A | 1.1851 | 0.3153 | 0.0517 | 0.116* | |
H18B | 1.1197 | 0.1771 | 0.0311 | 0.116* | |
H18C | 1.1860 | 0.2264 | 0.1501 | 0.116* | |
C19 | 1.1077 (3) | 0.1490 (2) | 0.44974 (18) | 0.0640 (6) | |
H19A | 1.1309 | 0.1038 | 0.5166 | 0.096* | |
H19B | 1.1869 | 0.2251 | 0.4601 | 0.096* | |
H19C | 1.1590 | 0.1015 | 0.3948 | 0.096* | |
C66 | 0.7940 (5) | −0.1080 (2) | 0.25294 (19) | 0.0711 (6) | |
H66A | 0.9481 | −0.1125 | 0.2821 | 0.107* | |
H66B | 0.7700 | −0.1245 | 0.1764 | 0.107* | |
H66C | 0.7172 | −0.1678 | 0.2882 | 0.107* |
U11 | U22 | U33 | U12 | U13 | U23 | |
O3 | 0.0890 (11) | 0.1116 (15) | 0.0628 (9) | −0.0086 (11) | 0.0292 (8) | 0.0188 (10) |
O17 | 0.1106 (15) | 0.1049 (16) | 0.0816 (12) | 0.0152 (12) | 0.0186 (10) | 0.0488 (12) |
C1 | 0.0836 (13) | 0.0494 (12) | 0.0475 (10) | 0.0074 (11) | 0.0105 (10) | −0.0053 (9) |
C2 | 0.0907 (15) | 0.0712 (14) | 0.0457 (11) | 0.0079 (14) | 0.0159 (10) | −0.0024 (11) |
C3 | 0.0579 (10) | 0.0728 (14) | 0.0503 (11) | 0.0085 (10) | 0.0150 (9) | 0.0146 (11) |
C4 | 0.0567 (10) | 0.0524 (11) | 0.0565 (11) | −0.0049 (9) | 0.0142 (8) | 0.0058 (9) |
C5 | 0.0402 (8) | 0.0404 (9) | 0.0483 (9) | 0.0035 (8) | 0.0084 (7) | 0.0027 (8) |
C6 | 0.0497 (9) | 0.0419 (10) | 0.0461 (9) | −0.0029 (8) | 0.0074 (7) | 0.0005 (8) |
C8 | 0.0407 (8) | 0.0432 (9) | 0.0461 (9) | 0.0033 (7) | 0.0099 (7) | 0.0027 (8) |
C9 | 0.0411 (8) | 0.0398 (9) | 0.0479 (9) | 0.0003 (8) | 0.0086 (7) | 0.0030 (8) |
C10 | 0.0458 (8) | 0.0428 (9) | 0.0445 (9) | −0.0005 (8) | 0.0052 (7) | −0.0001 (8) |
C11 | 0.0769 (13) | 0.0440 (11) | 0.0626 (13) | −0.0101 (10) | 0.0121 (10) | 0.0008 (10) |
C12 | 0.0777 (14) | 0.0482 (12) | 0.0712 (13) | −0.0014 (11) | 0.0220 (11) | 0.0170 (11) |
C13 | 0.0554 (10) | 0.0606 (12) | 0.0570 (11) | 0.0088 (9) | 0.0183 (8) | 0.0162 (10) |
C14 | 0.0484 (8) | 0.0508 (10) | 0.0461 (9) | 0.0061 (9) | 0.0122 (7) | 0.0041 (9) |
C15 | 0.0964 (17) | 0.0722 (17) | 0.0452 (11) | 0.0077 (13) | 0.0165 (11) | −0.0041 (11) |
C16 | 0.135 (2) | 0.101 (2) | 0.0459 (13) | 0.021 (2) | 0.0160 (14) | 0.0050 (14) |
C17 | 0.0767 (15) | 0.0866 (18) | 0.0572 (13) | 0.0192 (13) | 0.0258 (11) | 0.0210 (13) |
C18 | 0.0627 (12) | 0.0866 (17) | 0.0899 (17) | 0.0086 (13) | 0.0346 (11) | 0.0285 (15) |
C19 | 0.0488 (10) | 0.0732 (15) | 0.0649 (12) | −0.0061 (10) | −0.0035 (9) | 0.0078 (12) |
C66 | 0.1097 (19) | 0.0432 (11) | 0.0621 (13) | 0.0017 (12) | 0.0196 (12) | −0.0020 (10) |
O3—C3 | 1.224 (3) | C11—H11A | 0.9700 |
O17—C17 | 1.211 (3) | C11—H11B | 0.9700 |
C1—C10 | 1.525 (3) | C12—C13 | 1.521 (3) |
C1—C2 | 1.532 (3) | C12—H12A | 0.9700 |
C1—H1A | 0.9700 | C12—H12B | 0.9700 |
C1—H1B | 0.9700 | C13—C17 | 1.522 (3) |
C2—C3 | 1.511 (4) | C13—C14 | 1.548 (3) |
C2—H2A | 0.9700 | C13—C18 | 1.550 (3) |
C2—H2B | 0.9700 | C14—C15 | 1.531 (3) |
C3—C4 | 1.468 (3) | C14—H14 | 0.9800 |
C4—C5 | 1.333 (3) | C15—C16 | 1.538 (4) |
C4—H4 | 0.9300 | C15—H15A | 0.9700 |
C5—C10 | 1.519 (3) | C15—H15B | 0.9700 |
C5—C6 | 1.525 (3) | C16—C17 | 1.526 (5) |
C6—C66 | 1.533 (3) | C16—H16A | 0.9700 |
C6—C8 | 1.541 (3) | C16—H16B | 0.9700 |
C6—H6 | 0.9800 | C18—H18A | 0.9600 |
C8—C14 | 1.515 (2) | C18—H18B | 0.9600 |
C8—C9 | 1.541 (3) | C18—H18C | 0.9600 |
C8—H8 | 0.9800 | C19—H19A | 0.9600 |
C9—C11 | 1.526 (3) | C19—H19B | 0.9600 |
C9—C10 | 1.547 (2) | C19—H19C | 0.9600 |
C9—H9 | 0.9800 | C66—H66A | 0.9600 |
C10—C19 | 1.541 (3) | C66—H66B | 0.9600 |
C11—C12 | 1.543 (3) | C66—H66C | 0.9600 |
C10—C1—C2 | 111.91 (19) | C13—C12—C11 | 111.43 (18) |
C10—C1—H1A | 109.2 | C13—C12—H12A | 109.3 |
C2—C1—H1A | 109.2 | C11—C12—H12A | 109.3 |
C10—C1—H1B | 109.2 | C13—C12—H12B | 109.3 |
C2—C1—H1B | 109.2 | C11—C12—H12B | 109.3 |
H1A—C1—H1B | 107.9 | H12A—C12—H12B | 108.0 |
C3—C2—C1 | 113.13 (18) | C12—C13—C17 | 116.44 (19) |
C3—C2—H2A | 109.0 | C12—C13—C14 | 110.70 (16) |
C1—C2—H2A | 109.0 | C17—C13—C14 | 100.20 (18) |
C3—C2—H2B | 109.0 | C12—C13—C18 | 110.9 (2) |
C1—C2—H2B | 109.0 | C17—C13—C18 | 105.42 (18) |
H2A—C2—H2B | 107.8 | C14—C13—C18 | 112.70 (18) |
O3—C3—C4 | 121.6 (2) | C8—C14—C15 | 122.40 (17) |
O3—C3—C2 | 121.0 (2) | C8—C14—C13 | 110.11 (15) |
C4—C3—C2 | 117.38 (18) | C15—C14—C13 | 104.54 (16) |
C5—C4—C3 | 122.3 (2) | C8—C14—H14 | 106.3 |
C5—C4—H4 | 118.8 | C15—C14—H14 | 106.3 |
C3—C4—H4 | 118.8 | C13—C14—H14 | 106.3 |
C4—C5—C10 | 123.17 (18) | C14—C15—C16 | 101.9 (2) |
C4—C5—C6 | 125.79 (18) | C14—C15—H15A | 111.4 |
C10—C5—C6 | 110.72 (15) | C16—C15—H15A | 111.4 |
C5—C6—C66 | 114.25 (17) | C14—C15—H15B | 111.4 |
C5—C6—C8 | 103.49 (15) | C16—C15—H15B | 111.4 |
C66—C6—C8 | 114.69 (17) | H15A—C15—H15B | 109.2 |
C5—C6—H6 | 108.0 | C17—C16—C15 | 106.4 (2) |
C66—C6—H6 | 108.0 | C17—C16—H16A | 110.4 |
C8—C6—H6 | 108.0 | C15—C16—H16A | 110.4 |
C14—C8—C6 | 119.47 (16) | C17—C16—H16B | 110.4 |
C14—C8—C9 | 107.95 (15) | C15—C16—H16B | 110.4 |
C6—C8—C9 | 103.27 (14) | H16A—C16—H16B | 108.6 |
C14—C8—H8 | 108.6 | O17—C17—C13 | 126.5 (3) |
C6—C8—H8 | 108.6 | O17—C17—C16 | 125.4 (2) |
C9—C8—H8 | 108.6 | C13—C17—C16 | 108.1 (2) |
C11—C9—C8 | 114.02 (16) | C13—C18—H18A | 109.5 |
C11—C9—C10 | 120.15 (16) | C13—C18—H18B | 109.5 |
C8—C9—C10 | 103.39 (14) | H18A—C18—H18B | 109.5 |
C11—C9—H9 | 106.1 | C13—C18—H18C | 109.5 |
C8—C9—H9 | 106.1 | H18A—C18—H18C | 109.5 |
C10—C9—H9 | 106.1 | H18B—C18—H18C | 109.5 |
C5—C10—C1 | 109.36 (16) | C10—C19—H19A | 109.5 |
C5—C10—C19 | 110.33 (16) | C10—C19—H19B | 109.5 |
C1—C10—C19 | 111.06 (16) | H19A—C19—H19B | 109.5 |
C5—C10—C9 | 99.71 (14) | C10—C19—H19C | 109.5 |
C1—C10—C9 | 113.41 (15) | H19A—C19—H19C | 109.5 |
C19—C10—C9 | 112.38 (16) | H19B—C19—H19C | 109.5 |
C9—C11—C12 | 110.00 (17) | C6—C66—H66A | 109.5 |
C9—C11—H11A | 109.7 | C6—C66—H66B | 109.5 |
C12—C11—H11A | 109.7 | H66A—C66—H66B | 109.5 |
C9—C11—H11B | 109.7 | C6—C66—H66C | 109.5 |
C12—C11—H11B | 109.7 | H66A—C66—H66C | 109.5 |
H11A—C11—H11B | 108.2 | H66B—C66—H66C | 109.5 |
C10—C1—C2—C3 | −50.7 (3) | C8—C9—C10—C1 | −157.69 (15) |
C1—C2—C3—O3 | −155.4 (2) | C11—C9—C10—C19 | −53.2 (2) |
C1—C2—C3—C4 | 23.0 (3) | C8—C9—C10—C19 | 75.31 (19) |
O3—C3—C4—C5 | −179.5 (2) | C8—C9—C11—C12 | 53.9 (2) |
C2—C3—C4—C5 | 2.1 (3) | C10—C9—C11—C12 | 177.44 (17) |
C3—C4—C5—C10 | 1.1 (3) | C9—C11—C12—C13 | −52.3 (2) |
C3—C4—C5—C6 | −171.83 (17) | C11—C12—C13—C17 | 169.96 (19) |
C4—C5—C6—C66 | −61.8 (3) | C11—C12—C13—C14 | 56.4 (2) |
C10—C5—C6—C66 | 124.54 (18) | C11—C12—C13—C18 | −69.5 (2) |
C4—C5—C6—C8 | 172.79 (18) | C6—C8—C14—C15 | −60.0 (3) |
C10—C5—C6—C8 | −0.86 (18) | C9—C8—C14—C15 | −177.45 (18) |
C5—C6—C8—C14 | −145.17 (16) | C6—C8—C14—C13 | 176.65 (15) |
C66—C6—C8—C14 | 89.7 (2) | C9—C8—C14—C13 | 59.24 (18) |
C5—C6—C8—C9 | −25.36 (17) | C12—C13—C14—C8 | −60.8 (2) |
C66—C6—C8—C9 | −150.48 (17) | C17—C13—C14—C8 | 175.75 (17) |
C14—C8—C9—C11 | −57.7 (2) | C18—C13—C14—C8 | 64.1 (2) |
C6—C8—C9—C11 | 174.86 (15) | C12—C13—C14—C15 | 166.04 (17) |
C14—C8—C9—C10 | 170.11 (14) | C17—C13—C14—C15 | 42.6 (2) |
C6—C8—C9—C10 | 42.68 (16) | C18—C13—C14—C15 | −69.0 (2) |
C4—C5—C10—C1 | −28.4 (2) | C8—C14—C15—C16 | −166.3 (2) |
C6—C5—C10—C1 | 145.43 (16) | C13—C14—C15—C16 | −40.4 (2) |
C4—C5—C10—C19 | 94.0 (2) | C14—C15—C16—C17 | 22.1 (3) |
C6—C5—C10—C19 | −92.12 (18) | C12—C13—C17—O17 | 32.8 (4) |
C4—C5—C10—C9 | −147.59 (18) | C14—C13—C17—O17 | 152.2 (3) |
C6—C5—C10—C9 | 26.26 (17) | C18—C13—C17—O17 | −90.6 (3) |
C2—C1—C10—C5 | 51.9 (2) | C12—C13—C17—C16 | −147.6 (2) |
C2—C1—C10—C19 | −70.1 (2) | C14—C13—C17—C16 | −28.3 (2) |
C2—C1—C10—C9 | 162.17 (17) | C18—C13—C17—C16 | 88.9 (3) |
C11—C9—C10—C5 | −170.02 (17) | C15—C16—C17—O17 | −176.2 (3) |
C8—C9—C10—C5 | −41.55 (15) | C15—C16—C17—C13 | 4.2 (3) |
C11—C9—C10—C1 | 73.8 (2) | C19—C10—C13—C18 | 6.9 (2) |
Experimental details
Crystal data | |
Chemical formula | C19H26O2 |
Mr | 286.40 |
Crystal system, space group | Monoclinic, P21 |
Temperature (K) | 293 |
a, b, c (Å) | 6.2000 (12), 10.890 (2), 12.530 (3) |
β (°) | 100.49 (3) |
V (Å3) | 831.9 (3) |
Z | 2 |
Radiation type | Mo Kα |
µ (mm−1) | 0.07 |
Crystal size (mm) | 0.28 × 0.24 × 0.21 |
Data collection | |
Diffractometer | Bruker APEX CCD area-detector diffractometer |
Absorption correction | Multi-scan (SADABS; Sheldrick, 2000) |
Tmin, Tmax | 0.980, 0.985 |
No. of measured, independent and observed [I > 2σ(I)] reflections | 18767, 2063, 1681 |
Rint | 0.020 |
(sin θ/λ)max (Å−1) | 0.658 |
Refinement | |
R[F2 > 2σ(F2)], wR(F2), S | 0.036, 0.100, 1.06 |
No. of reflections | 2063 |
No. of parameters | 193 |
H-atom treatment | H-atom parameters constrained |
Δρmax, Δρmin (e Å−3) | 0.11, −0.14 |
Absolute structure | Unk |
Computer programs: SMART (Bruker, 2003), SAINT (Bruker, 2003), SHELXS97 (Sheldrick, 2008), SHELXL97 (Sheldrick, 2008), ORTEPII (Johnson, 1976).
6β-Methyl-B-norandrostenedione, (I), is a potent aromatase inhibitor recently identified on the NCI open chemical repository collection following a new steroid-pharmacophore virtual screening strategy developed by our group (Neves et al., 2009). This molecule was tested experimentally on a biochemical assay with aromatase extracted from human term placenta, and was found to be able to block the enzyme with strong potency and a competitive mechanism of inhibition (IC50 = 0.274 µM). Aminoglutethimide, a first-generation aromatase inhibitor, was tested in the same assay conditions (IC50 = 10 µM [should this be defined?]). To the best of our knowledge, this is the first report of B-norandrogens as aromatase inhibitors. Therefore, these compounds represent an important new structural class of anti-aromatase agents and should be further optimized.
Compound (I) shares structural and physicochemical similarities with the natural substrate of the enzyme, androstenedione (Busetta et al., 1972), and with exemestane (Gorlitzer et al., 2006), an important aromatase inhibitor, suggesting a common aromatase recognition mechanism. In particular, the three compounds have very hydrophobic scaffolds and two hydrogen-bond acceptors at equivalent positions, O3 and O17. These are important active sites for either androstenedione or exemestane to bind with aromatase (Ghosh et al., 2009). According to these authors, the 17-keto O atom makes a hydrogen bond with the backbone amide of Met 374 and a weak contact with NH1 of Arg 195. In addition, the 3-keto O atom interacts with the carboxylate moiety of Asp 309, assumed to be protonated. The B-ring of the nor-steroid, a cyclopentane, is less bulky than the cyclohexane in androstenedione; however, this is well balanced with a 6β-methyl group. Moreover, the C6 functionality is similar to that in exemestane, which can interact with a hydrophobic pocket within the active site of the enzyme delimited by Phe 221, Trp 224, Val 369, Val 370 and Leu 477 (Ghosh et al., 2009), increasing the anti-aromatase potency. Futhermore, according to the same authors, the C19 methyl group is another important interaction position between the inhibitor and the aromatase heme Fe. On this basis, the detailed knowledge of the crystal structure of 6β-methyl-B-norandrostenedione is important for the design of new potent aromatase inhibitors.
The X-ray study of (I) shows that the distance between the terminal atoms O3 and O17 is 10.408 (3) Å, which can be compared with 10.401 (2) and 10.681 Å for exemestane and androstenedione, respectively. The agreement between the B-nor and the exemestane values is notable and certainly consistent with their similar biological activity. Considering possible variations in C═O···H hydrogen-bond lengths (Jeffrey, 1997), a difference of about 0.28 Å in length for the androstenedione molecule is not sufficient to prevent the establishment of such bonds both with the head and the tail of the steroid. For the B-nor structure, ring A, with a C═C double bond, addopts a 1α-sofa conformation [asymmetry parameters (Duax & Norton, 1975): ΔCs(1) = 3.7 (2), ΔC2(3,4) = 22.2 (3) and ΔC2(2,3) = 51.9 (3)°]. Ring C has a slightly flattened chair conformation evidenced by an average torsion angle value of 56.7 (3)°. The five membered D ring assumes a 14α-envelope conformation [puckering parameters (Cremer & Pople, 1975): q2=0.427 (3) Å and ϕ2=211.0 (4) °; pseudorotation (Altona et al., 1968) and asymmetry parameters (Duax & Norton, 1975): Δ = 25.6 (2), ϕm = 43.6 (2), ΔCs(14) = 4.7 (3), ΔC2(13,14) = 15.3 (3)°]. The conformational parameters of these three rings are very similar to the corresponding androstenedione values, and to those of exemestane if one considers only rings C and D.
The cyclopentane B-nor ring assumes a 9α-envelope conformation [puckering parameters (Cremer & Pople, 1975): q2=0.435 (2) Å and ϕ2=288.2 (3) °; pseudorotation (Altona et al., 1968) and asymmetry parameters (Duax & Norton, 1975): Δ = 181.3 (2), ϕm = 44.2 (1), ΔCs(9) = 1.0 (2), ΔC2(8,9) = 22.4 (2)°]. The pseudo-torsion angle C19—C10···C13—C18 of 6.9 (2)° indicates that the B-nor steroid molecule is twisted compared with androstenedione or exemestane, for which values of -1.57 and 0.1 (2)°, respectively, were determined by Busetta et al. (1972) and Gorlitzer et al. (2006). This twist can be understood as a normal consequence of the replacement of the six-membered B-ring by a five-membered ring.
For the B-nor structure the 6-methyl group is in a β-bisectional position, with an angle of 51.6 (1)°, which can be compared with the quasi-equatorial position of the 6β-CH2 group in exemestane, with an angle 68.19 (9)°. The C19···C66 distances for the B-nor steroid and the exemestane molecules are, respectively, 3.994 (3) and 3.995 (2) Å. Moreover, when one tries to superimpose the three molecules it is possible to have atoms O3, O17 and C19 almost coincident. However, the positions of the C6 hydrophobic groups for the B-nor steroid and exemestane are clearly distinct, as indicated by the C19—C10···C6—C66 pseudo-torsion angles for both molecules [24.6 (3) and 48.4 (2)°, respectively]. This apparently indicates that the hydrophobic crevice in the aromatase active site is large enough to accommodate groups in different orientations. Since there are no strong intermolecular bonds, the crystal packing can only be the result of weak van der Waals interactions, which do not appear to be responsible for the conformational aspects of the molecule.