11-Methylpyrido[2,3-b]acridine-5,12-dione

The title molecule, C₁₇H₁₀N₂O₂, is a synthetic precursor to the cytotoxic marine alkaloid ascididemin and is also structurally related to cleistopholine, a plant-derived antifungal agent. The molecule was found to be essentially planar with the only significant deviations from planarity being for the quinone O atoms.

S1. Comment

The search for new human anticancer agents from the marine environment has resulted in the isolation of a large range of polycyclic alkaloids based upon the pyridoacridine framework (Molinski, 1993). Two such examples are the cytotoxic pentacyclic alkaloids ascididemin and its analogue 2-bromoleptoclinidinone (Kobayashi et al., 1988; Bloor & Schmitz, 1987; deGuzman & Schmitz, 1989; Bracher, 1997; Lindsay et al., 1998). Both molecules associate with DNA, probably via base-pair intercalation. In direct contrast to this, previous studies have noted that the tetracyclic synthetic precursor to ascididemin, 11-methylpyrido[2,3-b]acridine-5,12-dione, (I) (NSC 659780), exhibits only modest cytotoxicity (Bracher, 1997), and moderate antibacterial and antifungal properties (Lindsay et al., 1995). As part of our studies directed towards understanding the chemistry (Lindsay et al., 1997, 1998; Copp et al., 1999) and biological activities (Lindsay et al., 1995; Copp et al., 1999) of ascididemin and related marine alkaloids, we now report on the crystal structure of (I).

The title molecule was found to be highly planar, with the greatest deviations from the mean molecular plane being for the quinone atoms O1 [0.125 (4) Å] and O2 [0.195 (4) Å], thus making it a good DNA intercalating chromophore. There are few reported X-ray studies of the quinoline–quinone substructure present in rings AB of (I) although this fragment is present in many biologically active agents, including the antibiotic streptonigrin (Chiu & Lipscomb, 1975) and aza-analogues of the antitumour agent mitoxantrone (Krapcho et al., 1994). Bond lengths observed for rings A and B of (I) are comparable to those reported for other quinoline–quinone-bearing compounds (Chiu & Lipscomb, 1975; Kita et al., 1991; Gieren & Schanda, 1977). However, steric congestion between the quinone O1 and methyl C1' atoms is apparent in (I), as evidenced by bond angles of 118.8 (3) (O1—C12—C12a) and 122.6 (3)° (O1—C12—C11a). This interaction is presumably also responsible for the quinone O atoms bending out of the plane of the rings. Extensive π-π stacking was evident in the crystal of (I), with rings BCD of one molecule overlapping rings ABC of an adjacent molecule. The perpendicular separation between individual chromophores is 3.4 Å.

S2. Experimental

11-Methylpyrido[2,3-b]acridine-5,12-dione was prepared by a published route and yielded spectroscopic data identical in all respects with that previously reported (Bracher, 1989). Recrystallization from a methanol–dichloromethane solution yielded yellow–brown needles [m.p. 520–525 K, literature 513–521 K (Bracher, 1989)] suitable for X-ray analysis. Full assignment of ¹H and ¹³C NMR data were made by use of standard two-dimensional NMR techniques. ¹H NMR (200 MHz, CDCl₃): δ 9.16 (1H, dd, J = 4.6, 1.8 Hz, H-2), 8.73 (1H, dd, J = 8.0, 1.8 Hz, H-4), 8.45 (1H, dd, J = 8.5, 0.9 Hz, H-10), 8.38 (dd, J = 8.5, 0.9 Hz, H-7), 7.93 (1H, ddd, J = 8.3, 6.9, 1.4 Hz, H-8), 7.79 (1H, ddd, J = 8.3, 6.9, 1.4 Hz, H-9), 7.77 (1H, dd, J = 7.9, 4.6 Hz, H-3), 3.32 (3H, s, CH₃); ¹³C NMR (100 MHz, CDCl₃): δ 183.3 (s), 181.8 (d, J = 4 Hz, C-5), 155.6 (ddd, J = 183, 8, 4 Hz, C-2), 152.7 (dd, J = 6, 3 Hz, C-11), 150.2 (t, J = 5 Hz, C-12a), 148.6 (t, J = 8 Hz, C-6a), 147.5 (s, C-5a), 135.7 (dd, J = 170 Hz, 6, C-4), 132.7 (dd, J = 163 Hz, 9, C-8), 132.3 (dd, J = 165 Hz, 7, C-7), 130.0 (d, J = 7 Hz, C-4a), 125.5 (dd, J = 161 Hz, 8, C-10), 129.8 (dd, J = 163 Hz, 9, C-9), 129.8 (m, C-10a), 127.9 (dd, J = 167 Hz, 9, C-3), 125.5 (m, C-11a), 16.7 (q, J = 130 Hz, CH₃).

Computing details

Data collection: SMART (Siemens, 1994); cell refinement: SAINT (Siemens, 1994); data reduction: SAINT; program(s) used to solve structure: SHELXS97 (Sheldrick, 1997a); program(s) used to refine structure: SHELXL97 (Sheldrick, 1997b); molecular graphics: SHELXTL (Siemens, 1994); software used to prepare material for publication: SHELXL97.

Figures

Fig. 1. The structure of (I) showing 50% probability displacement ellipsoids.

11-Methylpyrido[2,3-b]acridine-5,12-dione

Crystal data

C17H10N2O2	Dx = 1.479 Mg m^−3
Mr = 274.27	Mo Kα radiation, λ = 0.71073 Å
Orthorhombic, Pca21	Cell parameters from 5243 reflections
a = 25.7526 (17) Å	θ = 1.5–25.0°
b = 4.2348 (3) Å	µ = 0.10 mm^−1
c = 11.2966 (7) Å	T = 293 K
V = 1231.97 (14) Å^3	Needle, brown
Z = 4	0.94 × 0.18 × 0.18 mm
F(000) = 568

Data collection

Siemens SMART CCD diffractometer	2040 independent reflections
Radiation source: fine-focus sealed tube	1845 reflections with I > 2σ(I)
Graphite monochromator	Rint = 0.057
Area–detector ω scans	θmax = 25°, θmin = 1.6°
Absorption correction: multi-scan (Blessing, 1995; Sheldrick, 1998)	h = −25→30
Tmin = 0.912, Tmax = 0.982	k = −5→5
6391 measured reflections	l = −14→12

Refinement

Refinement on F^2	Primary atom site location: structure-invariant direct methods
Least-squares matrix: full	Secondary atom site location: difference Fourier map
R[F^2 > 2σ(F^2)] = 0.054	Hydrogen site location: inferred from neighbouring sites
wR(F^2) = 0.141	H-atom parameters constrained
S = 1.02	Calculated w = 1/[σ^2(Fo^2) + (0.0608P)^2 + 0.3024P] where P = (Fo^2 + 2Fc^2)/3
2040 reflections	(Δ/σ)max = 0.032
190 parameters	Δρmax = 0.16 e Å^−3
1 restraint	Δρmin = −0.18 e Å^−3

Special details

Refinement. The structure was determined by direct methods and refined by full-matrix least squares on F². Hydrogen atoms were placed geometrically and refined with a riding model (including free rotation about C—C bonds for the methyl group), and with U_iso constrained to be 1.2 (1.5 for the methyl group) times U_eq of the carrier atom.

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Ų)

	x	y	z	Uiso*/Ueq
O1	0.28702 (9)	0.3026 (9)	0.5575 (3)	0.0962 (11)
O2	0.48874 (8)	0.5722 (8)	0.5260 (3)	0.0817 (9)
N1	0.34850 (11)	0.0947 (7)	0.7290 (2)	0.0599 (8)
N6	0.42610 (9)	0.8471 (6)	0.3681 (2)	0.0462 (6)
C1'	0.25969 (11)	0.6673 (9)	0.3689 (3)	0.0618 (9)
H1'A	0.2474	0.6526	0.4499	0.093*
H1'B	0.2515	0.4735	0.3271	0.093*
H1'C	0.2429	0.8438	0.3298	0.093*
C2	0.38132 (16)	−0.0077 (10)	0.8124 (3)	0.0675 (10)
H2A	0.3678	−0.1344	0.8733	0.081*
C3	0.43368 (16)	0.0600 (10)	0.8150 (3)	0.0646 (10)
H3A	0.4546	−0.0145	0.8772	0.077*
C4a	0.42160 (11)	0.3458 (8)	0.6366 (3)	0.0475 (8)
C4	0.45459 (13)	0.2366 (8)	0.7262 (3)	0.0566 (9)
H4A	0.4903	0.2838	0.7251	0.068*
C5a	0.40490 (10)	0.6646 (8)	0.4488 (3)	0.0440 (7)
C5	0.44264 (11)	0.5311 (8)	0.5361 (3)	0.0506 (8)
C6a	0.39462 (11)	0.9673 (8)	0.2828 (3)	0.0434 (7)
C7	0.41800 (12)	1.1609 (8)	0.1966 (3)	0.0515 (8)
H7A	0.4538	1.2038	0.2009	0.062*
C8	0.38911 (13)	1.2867 (9)	0.1070 (3)	0.0580 (9)
H8A	0.4049	1.4165	0.0499	0.070*
C9	0.33586 (13)	1.2215 (8)	0.1005 (3)	0.0594 (9)
H9A	0.3163	1.3056	0.0377	0.071*
C10a	0.34025 (11)	0.9066 (8)	0.2783 (3)	0.0453 (7)
C10	0.31194 (12)	1.0397 (8)	0.1830 (3)	0.0537 (8)
H10A	0.2761	1.0014	0.1768	0.064*
C11a	0.35069 (11)	0.5933 (8)	0.4544 (3)	0.0434 (7)
C11	0.31773 (10)	0.7174 (7)	0.3687 (3)	0.0451 (7)
C12a	0.36933 (11)	0.2704 (8)	0.6431 (3)	0.0477 (7)
C12	0.33125 (11)	0.3865 (8)	0.5514 (3)	0.0501 (8)

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
O1	0.0360 (12)	0.156 (3)	0.097 (2)	−0.0227 (15)	−0.0073 (13)	0.051 (2)
O2	0.0325 (11)	0.131 (3)	0.0818 (18)	−0.0131 (13)	−0.0113 (12)	0.0239 (19)
N1	0.0532 (16)	0.077 (2)	0.0491 (16)	−0.0020 (14)	0.0040 (14)	−0.0017 (15)
N6	0.0319 (11)	0.0553 (15)	0.0515 (15)	−0.0049 (11)	−0.0003 (11)	−0.0093 (14)
C1'	0.0362 (16)	0.082 (2)	0.068 (2)	−0.0032 (15)	−0.0036 (15)	0.002 (2)
C2	0.068 (2)	0.082 (3)	0.052 (2)	0.005 (2)	0.0014 (18)	−0.002 (2)
C3	0.067 (2)	0.076 (3)	0.050 (2)	0.0108 (19)	−0.0119 (17)	−0.002 (2)
C4a	0.0381 (14)	0.0543 (19)	0.0500 (17)	0.0039 (12)	−0.0026 (13)	−0.0148 (16)
C4	0.0472 (16)	0.063 (2)	0.059 (2)	0.0013 (16)	−0.0111 (16)	−0.0047 (18)
C5a	0.0319 (13)	0.0503 (18)	0.0498 (17)	−0.0008 (12)	−0.0007 (13)	−0.0121 (15)
C5	0.0336 (15)	0.062 (2)	0.057 (2)	−0.0043 (14)	−0.0048 (14)	−0.0100 (17)
C6a	0.0317 (15)	0.0507 (18)	0.0476 (16)	0.0016 (13)	0.0008 (13)	−0.0105 (14)
C7	0.0381 (15)	0.0595 (19)	0.0569 (19)	−0.0021 (14)	0.0054 (14)	−0.0062 (17)
C8	0.0520 (17)	0.067 (2)	0.055 (2)	0.0029 (16)	0.0081 (16)	−0.0009 (18)
C9	0.0526 (18)	0.071 (2)	0.055 (2)	0.0076 (17)	−0.0030 (16)	−0.0008 (19)
C10a	0.0340 (15)	0.0523 (19)	0.0497 (17)	0.0007 (13)	0.0007 (14)	−0.0164 (15)
C10	0.0370 (15)	0.067 (2)	0.057 (2)	0.0044 (14)	−0.0054 (14)	−0.0084 (17)
C11a	0.0308 (12)	0.0510 (18)	0.0485 (17)	−0.0009 (12)	0.0008 (13)	−0.0145 (14)
C11	0.0295 (13)	0.0542 (18)	0.0517 (18)	−0.0001 (12)	0.0012 (12)	−0.0128 (15)
C12a	0.0416 (16)	0.0538 (18)	0.0478 (17)	−0.0012 (13)	0.0020 (14)	−0.0105 (14)
C12	0.0332 (15)	0.067 (2)	0.0496 (18)	−0.0028 (13)	0.0019 (13)	−0.0021 (17)

Geometric parameters (Å, º)

O1—C12	1.195 (4)	C5a—C11a	1.430 (4)
O2—C5	1.205 (4)	C5a—C5	1.496 (4)
N1—C12a	1.335 (4)	C6a—C7	1.408 (4)
N1—C2	1.338 (5)	C6a—C10a	1.424 (4)
N6—C5a	1.313 (4)	C7—C8	1.364 (5)
N6—C6a	1.358 (4)	C8—C9	1.401 (5)
C1'—C11	1.510 (4)	C9—C10	1.357 (5)
C2—C3	1.379 (5)	C10a—C10	1.417 (4)
C3—C4	1.363 (5)	C10a—C11	1.422 (5)
C4a—C12a	1.385 (4)	C11a—C11	1.391 (4)
C4a—C4	1.400 (5)	C11a—C12	1.489 (4)
C4a—C5	1.483 (5)	C12a—C12	1.509 (4)
C12a—N1—C2	116.0 (3)	C7—C8—C9	119.7 (3)
C5a—N6—C6a	117.7 (2)	C10—C9—C8	121.3 (3)
N1—C2—C3	124.4 (4)	C10—C10a—C11	124.0 (3)
C4—C3—C2	119.0 (3)	C10—C10a—C6a	117.5 (3)
C12a—C4a—C4	118.4 (3)	C11—C10a—C6a	118.5 (3)
C12a—C4a—C5	121.2 (3)	C9—C10—C10a	120.9 (3)
C4—C4a—C5	120.4 (3)	C11—C11a—C5a	119.0 (3)
C3—C4—C4a	118.3 (3)	C11—C11a—C12	121.9 (2)
N6—C5a—C11a	124.1 (3)	C5a—C11a—C12	119.0 (3)
N6—C5a—C5	114.2 (2)	C11a—C11—C10a	117.6 (2)
C11a—C5a—C5	121.7 (3)	C11a—C11—C1'	123.4 (3)
O2—C5—C4a	120.6 (3)	C10a—C11—C1'	119.0 (3)
O2—C5—C5a	121.6 (3)	N1—C12a—C4a	123.9 (3)
C4a—C5—C5a	117.9 (2)	N1—C12a—C12	114.8 (3)
N6—C6a—C7	117.0 (2)	C4a—C12a—C12	121.3 (3)
N6—C6a—C10a	123.0 (3)	O1—C12—C11a	122.6 (3)
C7—C6a—C10a	120.0 (3)	O1—C12—C12a	118.8 (3)
C8—C7—C6a	120.5 (3)	C11a—C12—C12a	118.6 (2)