Abstract
1,2,4-Benzotriazine 1,4-di-N-oxides are potent antitumor drug candidates that undergo in vivo bioreduction leading to selective DNA damage in the low oxygen (hypoxic) cells found in tumors. Tirapazamine (TPZ) is the lead compound in this family. Here we report on the synthesis, crystal structure, and conformational analysis of a new analog, 3-cyclopropyl-1,2,4-benzotriazine 1,4-di-N-oxide (3). Compound 3 (C10H10N3O2) crystallized in the monoclinic space group C2/c. Unit cell parameters for 3: a = 16.6306 (12), b = 7.799 (5), c = 16.0113 (11) Å, α = 90, β = 119.0440 (10), γ = 90, and z = 8.
Keywords: Crystal structure, N-oxide, tirapazamine, cyclopropyl group, rotational energy profile
Introduction
3-Amino-1,2,4-benzotriazine 1,4-di-N-oxide (tirapazamine, TPZ, 1) is currently undergoing a variety of phase I, II, and III clinical trials for the treatment of various human cancers.1,2 TPZ derives its medicinal activity by inducing DNA damage in poorly oxygenated tumor cells.3–18 During the preclinical development of second generation analogues of TPZ it has become clear that 3-alkyl-1,2,4-benzotriazine 1,4-di-N-oxides have activities comparable to TPZ and may possess superior extravascular transport properties.9,10 Accordingly, we prepared 3-cyclopropyl-1,2,4-benzotriazine 1,4-dioxide (Scheme 1). An additional interesting aspect of compound 3 is that the cyclopropyl substituent has the potential to profoundly influence the reaction pathways available to the key radical intermediates generated in the bioactivation of 1,2,4-triazine 1,4-dioxides.3–18 We report here the synthesis, X-ray crystal structure, and conformational analysis of this new 3-cyclopropyl-1,2,4-benzotriazine 1,4-dioxide (3). To the best of our knowledge this is the first 3-alkyl-1,2,4-benzotriazine 1,4-dioxide that has been crystallographically characterized. The crystal structure of 3 may contribute to understanding of the chemistry and biology of 3-cyclopropyl-1,2,4-benzotriazine 1,4-dioxide.
Scheme 1.
Synthetic route for the preparation of 3-cyclopropyl-1,2,4-benzotriazine 1,4-di-N-oxide
Experimental
Oxidation of 3-cyclopropyl-1,2,4-benzotriazine (2) with m-chloroperbenzoic acid
To a solution of 3-cyclopropyl-1,2,4-benzotriazine 2 (50 mg, 0.25 mmol) in dichloromethane (10 mL), m-chloroperbenzoic acid (mCPBA, 2–6 equiv) was added and the resulting mixture stirred at room temperature until all starting material was consumed.21 The solvent was then evaporated and the residue purified using gravity column chromatography on silica gel eluted with ethyl acetate-hexanes (1:1) to provide a 10–15% yield of 3 as deep yellow powder. 1H-NMR (CDCl3, 500 MHz): δ 8.55 (dd, J = 8.5, 1 Hz, 1H), 8.43 (dd, J = 8.5, 1 Hz, 1H), 8.00 (ddd, J = 8.5, 7, 1 Hz, 1H), 7.79 (ddd, J = 8.5, 7, 1 Hz, 1H), 3.14 (tt, J = 8.0, 5.0 Hz, 1H), 1.36 (m, 4H); 13C-NMR (125 MHz, CDCl3): δ 157.1, 139.0, 135.4, 133.9, 131.1, 121.5, 119.4, 10.1, 9.3; HRMS (ESI) m/z calc for C10H10N3O2 (M+H+) 204.0773, found 204.0765.
Crystallography
Slow evaporation of dilute solutions of 3 in ethyl acetate-hexane afforded crystals suitable for X-ray diffraction analysis. Data was collected on Bruker SMART system at 173 K. Crystal structures were solved using SHELX programs.19,20 Details of the data collection and of the structure refinement are provided in Table 1.
Table 1.
Crystallographic data
| Compound 3 | |
|---|---|
| Chemical formula | C10H10N3O2 |
| CCDC no. | CCDC-752258 |
| Color/shape | yellow/prism |
| Formula weight | 203.21 |
| Crystal system | Monoclinic |
| Space group | C2/c |
| Temperature, K | 173 (2) K |
| Unit cell dimensions | a = 16.6306(12) Å |
| b = 7.799(5) Å | |
| c = 16.0133(11) Å | |
| α = 90° | |
| β = 119.0440(10)° | |
| γ = 90° | |
| Volume, Å3 | 1815.8(2) |
| Z | 8 |
| Density ( calculated), mg/m3 | 1.494 |
| Absorptioncefficient,mm−1 | |
| Diffractometer/scan | Bruker SMART/CCD area detector |
| θ range for data collection, deg. | 2.8 to 27.13 deg. |
| Reflections measured | |
| Independent/observed reflections | |
| Data/restraints/parameters | 2005/0/140 |
| Absorption correction | Semi-empirical |
| Goodness of fit on F2 | 1.066 |
| Tmin, Tmax | 0.73, 0.98 |
| Final R indices [ I > 2σ (I)] | R1 = 0.0581, ωR2 = 0.1495 |
| R indices ( all data) | R1 = 0.0721, ωR2 = 0.1614 |
Results and Discussion
Compound 3 crystallized in the monoclinic space group C2/c. Atomic coordinates and equivalent isotropic displacement parameters of the non-hydrogen atoms are given in Table 2, bond lengths and bond angles are shown in Tables 3 and 4, respectively, and an ORTEP drawing of 3 is shown in Figure 1.
Table 2.
Final Coordinates and Equivalent Isotropic Displacement Parameters of the non-Hydrogen atoms for compound 3
| Atom | x | y | z | U(eq) [Å2] |
|---|---|---|---|---|
| O1 | 1562 | 6515 | 94 | 40 |
| O4 | 2930 | 12320 | 1959 | 39 |
| N1 | 1489 | 9327 | 187 | 32 |
| N2 | 1911 | 7887 | 555 | 30 |
| N3 | 2617 | 10892 | 1512 | 31 |
| C1 | 1838 | 10786 | 655 | 31 |
| C2 | 2735 | 7833 | 1431 | 25 |
| C3 | 3170 | 6272 | 1796 | 30 |
| C4 | 3992 | 6277 | 2635 | 37 |
| C5 | 4380 | 7830 | 3109 | 39 |
| C6 | 3939 | 9354 | 2760 | 35 |
| C7 | 3099 | 9362 | 1911 | 27 |
| C8 | 1345 | 12393 | 220 | 38 |
| C9 | 317 | 12358 | −388 | 34 |
| C10 | 894 | 12598 | −851 | 39 |
Table 3.
Bond Distances (Å) for compounds 3
| O(1)-N(2) | 1.270(2) |
| O(4)-N(3) | 1.289(2) |
| N(1)-N(2) | 1.303(2) |
| N(1)-C(1) | 1.331(3) |
| N(2)-C(2) | 1.407(2) |
| N(3)-C(1) | 1.357(3) |
| N(3)-C(7) | 1.407(2) |
| C(1)-C(8) | 1.474(3) |
| C(2)-C(7) | 1.388(3) |
| C(2)-C(3) | 1.391(3) |
| C(3)-C(4) | 1.375(3) |
| C(3)-H(3) | 0.9500 |
| C(4)-C(5) | 1.409(3) |
| C(4)-H(4) | 0.9500 |
| C(5)-C(6) | 1.366(3) |
| C(5)-H(5) | 0.9500 |
| C(6)-C(7) | 1.399(3) |
| C(6)-H(6) | 0.9500 |
| C(8)-C(9) | 1.502(3) |
| C(8)-C(10) | 1.509(3) |
| C(8)-H(8) | 1.0000 |
| C(9)-C(10) | 1.479(3) |
| C(9)-H(9A) | 0.9900 |
| C(9)-H(9B) | 0.9900 |
| C(10)-H(10A) | 0.9900 |
| C(10)-H(10B) | 0.9900 |
Table 4.
Bond Angles (deg) for compounds 3
| N(2)-N(1)-C(1) | 119.39(16) |
| O(1)-N(2)-N(1) | 117.99(15) |
| O(1)-N(2)-C(2) | 120.24(16) |
| N(1)-N(2)-C(2) | 121.76(16) |
| O(4)-N(3)-C(1) | 122.96(17) |
| O(4)-N(3)-C(7) | 119.57(16) |
| C(1)-N(3)-C(7) | 117.46(16) |
| N(1)-C(1)-N(3) | 124.22(18) |
| N(1)-C(1)-C(8) | 118.12(17) |
| N(3)-C(1)-C(8) | 117.66(18) |
| C(7)-C(2)-C(3) | 121.39(17) |
| C(7)-C(2)-N(2) | 118.54(17) |
| C(3)-C(2)-N(2) | 120.06(17) |
| C(4)-C(3)-C(2) | 118.42(19) |
| C(4)-C(3)-H(3) | 120.8 |
| C(2)-C(3)-H(3) | 120.8 |
| C(3)-C(4)-C(5) | 120.44(19) |
| C(3)-C(4)-H(4) | 119.8 |
| C(5)-C(4)-H(4) | 119.8 |
| C(6)-C(5)-C(4) | 120.88(18) |
| C(6)-C(5)-H(5) | 119.6 |
| C(4)-C(5)-H(5) | 119.6 |
| C(5)-C(6)-C(7) | 119.10(19) |
| C(5)-C(6)-H(6) | 120.4 |
| C(7)-C(6)-H(6) | 120.5 |
| C(2)-C(7)-C(6) | 119.70(18) |
| C(2)-C(7)-N(3) | 118.58(16) |
| C(6)-C(7)-N(3) | 121.69(18) |
| C(1)-C(8)-C(9) | 119.14(19) |
| C(1)-C(8)-C(10) | 118.86(19) |
| C(9)-C(8)-C(10) | 58.86(14) |
| C(1)-C(8)-H(8) | 116.0 |
| C(9)-C(8)-H(8) | 116.0 |
| C(10)-C(8)-H(8) | 116.0 |
| C(10)-C(9)-C(8) | 60.84(15) |
| C(10)-C(9)-H(9A) | 117.7 |
| C(8)-C(9)-H(9A) | 117.7 |
| C(10)-C(9)-H(9B) | 117.7 |
| C(8)-C(9)-H(9B) | 117.7 |
| H(9A)-C(9)-H(9B) | 114.8 |
| C(9)-C(10)-C(8) | 60.31(14) |
| C(9)-C(10)-H(10A) | 117.7 |
| C(8)-C(10)-H(10A) | 117.7 |
| C(9)-C(10)-H(10B) | 117.7 |
| C(8)-C(10)-H(10B) | 117.7 |
| H(10A)-C(10)-H(10B) | 114.9 |
Fig. 1.
ORTEP diagram of 3
Figure 2 shows a diagram of packing viewed normal to the a–c plane. It can be seen that approximately coplanar molecules form layers along the a–c diagonal with considerable overlap of the aromatic rings. The final difference Fourier map shows peaks of electron density which appear to result from a minor contribution of a “whole body disorder” wherein the molecule is rotated normal to the approximate plane of the aromatic portion. This disordered component was not included in the final model.
Fig. 2.
Packing diagram of 3
Conformation and Rotational Energy Profile
The cyclopropyl group attached to a benzene ring adopts a bisected conformation, that is, the C–H bond of the cyclopropyl carbon that is attached to the benzene ring is coplanar with the arene; τ = ∠(Cortho–Cipso–CCP–H) = 0°.22 In the bisected conformation the molecular orbital overlap between the cyclopropyl group and the arene π-system is maximal. The bisected conformation is exemplified, for example, by the crystal structures of cyclopropylbenzene 23,24 and of cyclopropyl acetophenone.25
Bisected structures also occur in heteroaryl-substituted cyclopropanes such as 2-cyclopropylpyridine 26 and, in such cases, there are two possible bisected conformations. In the case of heteroaryl cyclopropane 3, the two conformational possibilities are characterized by τ = ∠(N1–C2–CCP–H) = 0° and τ = 180°, and the crystal structure analysis shows that the first of these options is realized in the solid (τ = 0°).
Results of computational studies27,28 show that the conformation observed in the solid state also is the preferred conformation of free 3. We explored the potential energy surface of 3 with density functional theory, B3LYP/6-31+G(d), and also with second-order perturbation theory, MP2(full)/6-31+G(d), and the rotational energy profiles are shown in Figure 3. The DFT results are straightforward and they are as expected, that is, there are two minima M1 (τ1= 0°) and M2 (τ2 = 180°) and M1 is preferred over M2 by ΔErel = 1.97 kcal/mol. The rotational transition state structure RTS for rotation about the HAr–Cp bond also was located (Figure 4) and the activation energies are ΔE(M1→RTS) = 6.16 and ΔE(M2→RTS) = 4.19 kcal/mol, respectively.
Fig. 3.
Rotational profiles of 3 computed as a function of the dihedral angle τ = ∠(NO–C–CCP–H) at the theoretical levels B3LYP/6-31+G(d) (blue) and MP2(full)/6-31+G(d) (red). Energies are given in kcal/mol relative to the τ = 180° structure (M2).
Fig. 4.
B3LYP/6-31+G(d) optimized structures of conformers M1 and M2 of 3 and of the rotational transition state structure RTS for their interconversion.
In each conformation, the CCp–H bond is pointed toward the lone pair region of one heteroatom (d(H---ON1) = 2.327 Å in M1, d(H---N3) = 2.403 Å in M2) and the cyclopropyl-C2H4 moiety is placed close to the other (d(H---N3) = 2.672 Å in M1, d(H---ON1) = 2.445 Å in M2). The sums of the van der Waals radii of H (1.20 Å) and of O (1.52 Å) or N (1.55 Å), respectively, are 2.72 and 2.75 Å, respectively. Hence, HAr–Cp bonding suffers from steric repulsion and the steric problems are less severe in M1 (H---ON1 contact in 5-ring) than in M2 (H---N3 contact in 6-ring). This repulsion is clearly manifest in the ∠(C2–CH–CH2) angles of M1 (119.8°) and M2 (125.2°). Driving the cyclopropyl-CH2 moieties past ON1 is likely to be the major source of the rotational barrier; the RTS structure features (d(H---ON1) = 2.359 Å and ∠(C2–CH–CH2) angles of 125.5° and 119.5°.
The results obtained at the MP2 level are similar but also reveal some interesting new features. The comparison of the rotational energy profiles in Figure 3 shows that the preference for M1 is somewhat more pronounced at the MP2 level with ΔErel = 2.26 kcal/mol, and that the RTS structure is slightly shifted toward M2. While Cs-M2 is a minimum at both theoretical levels, the minimum M1 is not Cs-symmetric at the MP2 level and, instead, the optimized C1-structure deviates ever so slightly from planarity (τ = 3.49°). An unexpected observation was made in the search for the RTS structure on the MP2(full)/6-31+G(d) potential energy surface. The rotational energy profile scan provides a rather well defined expectation as to the location of the RTS structure and it should be routine to optimize the precise structure of the saddle point. Yet, even with excellent guesses of the initial structure and with the computation of the Hessian matrix at every point, searches for a stationary saddle point did not succeed. The black dot in the transition state region (Figure 3) corresponds to a nonstationary near-RTS structure and it appears slightly below the red curve. There are many such “nonstationary near-RTS structures”, they are essentially isoenergetic but differ in the specific combination of a great number of dihedral angles.
The results of the PES analysis are consistent with the measured 1H-NMR spectrum and in particular with the cyclopropyl hydrogen signals at 3.14 (m, 1H) and 1.36 (m, 4H) ppm. For the dominant conformer M1, one would expect the unique cyclopropyl-H (Hu) to couple with two pairs of equivalent methylene hydrogens (Hi and Ho oriented toward and away from the heterocycle, respectively) and a tt-type splitting pattern should result (3Jcis(Hu,Hi), 3Jtrans(Hu,Ho)) and such a multiplet is observed. The cyclopropyl methylene hydrogens of M1 should give two signals for the hydrogens that are cisoid (Ho) or transoid (Hi) with the unique cyclopropyl hydrogen, and each signal should feature a ddd-type splitting pattern (3Jcis(Hu,Ho) or 3Jtrans(Hu,Hi), 2Jgem(Hi,Ho), 3Jtrans(Hi,Ho)). NMR computations require large, well-polarized basis sets and we computed isotropic magnetic shielding and spin-spin coupling constants for M1 and M2 using the GIAO method at the B3LYP/6-311+G(2d,p) level.29,30,31 The computed shielding values are reported relative to TMS in parts per million (ppm) and computed J values are reported in Hertz (Hz). The data in Table 5 support the conclusion that the preferred gas phase conformer also is preferred in solution. The chemical shifts computed for M1 closely match the observed spectrum whereas those computed for M2 do not. First-order analysis of the Hu signal results in coupling constants of 8 and 5 Hz and these values are in good agreement with the computed coupling constants 3J(Hu,Hi) and 3J(Hu,Ho).
Table 5.
Computed isotropic magnetic shieldings and chemical shifts relative to TMS (in ppm) and spin-spin coupling constants J (in Hz)
| Mol. | Nucleus | σiso | δcalc | δexp | Computed J values | |
|---|---|---|---|---|---|---|
| M1 | Hu(CH) | 28.50 | 3.38 | 3.14 (tt) | ||
| Hi(CH2) | 30.65 | 1.23 | 1.36 (m) | 3J(Hu,Hi) = 4.07 | 3J(Hi,Ho) = 5.87 | |
| Ho(CH2) | 30.77 | 1.11 | 3J(Hu,Ho) = 8.24 | 2J(Hi,Ho) = −3.72 | ||
| M2 | Hu(CH) | 29.86 | 2.02 | |||
| Hi(CH2) | 29.22 | 2.66 | 3J(Hu,Hi) = 4.67 | 3J(Hi,Ho) = 5.49 | ||
| Ho(CH2) | 31.10 | 0.78 | 3J(Hu,Ho) = 8.62 | 2J(Hi,Ho) = −3.32 | ||
| TMS | H | 31.88 | 0.00 | |||
All values computed at the B3LYP/6-311+G(2d,p) level.
Conclusion
In conclusion, we found that the solid state conformation of 3 also is the preferred conformation in the gas phase and in solution. The crystallographic characterization of 1,2,4-benzotriazine di-N-oxide may be relevant to the properties of the 3-cyclopropyl-1,2,4-benzotriazine 1,4-dioxide radical where conformational isomerism will affect potential ring opening reactions.
Acknowledgements
We thank National Institutes of Health (CA 100757) for support of this work. MU Research Computing is supported by Federal Earmark NASA Funds for Bioinformatics Consortium Equipment and additional support from Dell, SGI, Sun Microsystems, TimeLogic and Intel.
Footnotes
Supplementary Material
X-ray crystallographic data have been deposited with the Cambridge Crystallographic Data Center as supplementary publication number CCDC 752258. Copies of available material can be obtained, free of charge, on application to the Director, CCDC, 12 Union Road, Cambridge CB21EZ, UK.
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