The antitumour drug 7-ethyl-10-hy­droxycampto­thecin monohydrate and its solid-state hydrolysis mechanism on heating

7-Ethyl-10-hydroxy­camptothecin [systematic name: (4S)-4,11-diethyl-4,9-dihy­droxy-1H-pyrano[3′,4′:6,7]indolizino[1,2-b]quinoline-3,14(4H,12H)-dione, SN-38] is an antitumour drug which exerts activity through the inhibition of topoisomerase I. The crystal structure of SN-38 as the monohydrate, C₂₂H₂₀N₂O₅·H₂O, reveals that it is a monoclinic crystal, with one SN-38 mol­ecule and one water mol­ecule in the asymmetric unit. When the crystal is heated to 473 K, approximately 30% of SN-38 is hydrolyzed at its lactone ring, resulting in the formation of the inactive carboxyl­ate form. The mol­ecular arrangement around the water mol­ecule and the lactone ring of SN-38 in the crystal structure suggests that SN-38 is hydrolyzed by the water mol­ecule at (x, y, z) nucleophilically attacking the carbonyl C atom of the lactone ring at (x − 1, y, z − 1). Hydrogen bonding around the water mol­ecules and the lactone ring appears to promote this hydrolysis reaction: two carbonyl O atoms, which are hydrogen bonded as hydrogen-bond acceptors to the water mol­ecule at (x, y, z), might enhance the nucleophilicity of this water mol­ecule, while the water mol­ecule at (−x, y + , −z), which is hydrogen bonded as a hydrogen-bond donor to the carbonyl O atom at (x − 1, y, z − 1), might enhance the electrophilicity of the carbonyl C atom.

Computing details

Data collection: RAPID-AUTO (Rigaku, 1999); cell refinement: RAPID-AUTO (Rigaku, 1999); data reduction: RAPID-AUTO (Rigaku, 1999); program(s) used to solve structure: SHELXT (Sheldrick, 2015a); program(s) used to refine structure: SHELXL2014/7 (Sheldrick, 2015b), SHELXLE (Hübschle et al., 2011); molecular graphics: Mercury (Macrae et al., 2008); software used to prepare material for publication: publCIF (Westrip, 2010).

(4S)-4,11-Diethyl-4,9-dihydroxy-1H-pyrano[3',4':6,7] indolizino[1,2-b]quinoline-3,14(4H,12H)dione

Crystal data

C22H20N2O5·H2O	F(000) = 432
Mr = 410.41	Dx = 1.465 Mg m^−3
Monoclinic, P21	Synchrotron (SPring-8 BL02B1) radiation, λ = 0.70041 Å
a = 8.529 (2) Å	Cell parameters from 255 reflections
b = 7.352 (2) Å	θ = 1.2–6.7°
c = 15.075 (3) Å	µ = 0.11 mm^−1
β = 100.18 (3)°	T = 100 K
V = 930.3 (4) Å^3	Column, pale yellow
Z = 2	0.20 × 0.01 × 0.01 mm

Data collection

Rigaku Mercury2 four-circle diffractometer with CCD area detector	Rint = 0.056
Radiation source: synchrotron	θmax = 28.7°, θmin = 1.4°
ω scan	h = −11→8
13173 measured reflections	k = −6→9
4345 independent reflections	l = −20→20
3684 reflections with I > 2σ(I)

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)] = 0.043	Hydrogen site location: mixed
wR(F^2) = 0.120	H atoms treated by a mixture of independent and constrained refinement
S = 0.84	w = 1/[σ^2(Fo^2) + (0.1P)^2] where P = (Fo^2 + 2Fc^2)/3
4345 reflections	(Δ/σ)max < 0.001
281 parameters	Δρmax = 0.42 e Å^−3
16 restraints	Δρmin = −0.28 e Å^−3

Special details

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.

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

	x	y	z	Uiso*/Ueq
O1	0.3063 (2)	0.4942 (3)	0.14614 (11)	0.0191 (5)
H1	0.3636	0.4929	0.1062	0.023*
N1	0.6918 (2)	0.4835 (3)	0.48097 (12)	0.0109 (4)
C1	0.4001 (3)	0.4971 (4)	0.22858 (15)	0.0136 (5)
O2	0.5040 (2)	0.4379 (3)	0.83245 (11)	0.0148 (4)
N2	0.5875 (2)	0.4670 (3)	0.69791 (12)	0.0101 (4)
C2	0.5673 (3)	0.4941 (5)	0.23798 (15)	0.0159 (6)
H2	0.6159	0.4925	0.1859	0.019*
C3	0.6596 (3)	0.4934 (4)	0.32162 (15)	0.0138 (5)
H3	0.7723	0.4927	0.3272	0.017*
O3	0.9750 (2)	0.2875 (3)	0.94861 (12)	0.0178 (4)
C4	0.5905 (3)	0.4938 (4)	0.40030 (14)	0.0109 (5)
O4	1.2123 (2)	0.2186 (3)	0.92289 (13)	0.0216 (5)
C5	0.4212 (3)	0.5057 (4)	0.39111 (14)	0.0099 (5)
O5	1.1680 (2)	0.3924 (3)	0.76177 (11)	0.0150 (5)
H5	1.2640	0.4005	0.7866	0.018*
OW1	0.4846 (2)	0.5435 (4)	0.01413 (13)	0.0259 (6)
HW1A	0.488 (4)	0.500 (5)	−0.0369 (14)	0.031*
HW1B	0.562 (3)	0.614 (5)	0.027 (2)	0.031*
C6	0.3287 (3)	0.5077 (4)	0.30356 (15)	0.0128 (5)
H6	0.2160	0.5165	0.2963	0.015*
C21	1.1135 (3)	0.6280 (4)	0.86604 (17)	0.0157 (6)
H21A	1.0606	0.6433	0.9190	0.019*
H21B	1.2300	0.6325	0.8877	0.019*
C20	0.8278 (3)	0.3921 (4)	0.92659 (16)	0.0146 (6)
H20A	0.8416	0.5105	0.9583	0.018*
H20B	0.7408	0.3256	0.9481	0.018*
C19	1.0918 (3)	0.3042 (4)	0.90154 (16)	0.0146 (6)
C18	1.0696 (3)	0.4405 (4)	0.82395 (14)	0.0117 (5)
C17	0.6166 (3)	0.4422 (4)	0.78970 (15)	0.0105 (5)
C16	0.7825 (3)	0.4245 (4)	0.82765 (15)	0.0117 (5)
C15	0.8984 (3)	0.4369 (4)	0.77579 (15)	0.0102 (5)
C14	0.8595 (3)	0.4540 (4)	0.68131 (14)	0.0111 (5)
H14	0.9396	0.4564	0.6448	0.013*
C13	0.7028 (3)	0.4669 (4)	0.64496 (14)	0.0106 (5)
C12	0.4254 (3)	0.4900 (4)	0.64572 (14)	0.0115 (5)
H12A	0.3755	0.6036	0.6625	0.014*
H12B	0.3564	0.3854	0.6541	0.014*
C11	0.6212 (3)	0.4838 (4)	0.55175 (14)	0.0098 (5)
C10	0.4570 (3)	0.4985 (4)	0.55105 (15)	0.0108 (5)
C7	0.3531 (3)	0.5150 (4)	0.47127 (15)	0.0100 (5)
C8	0.1777 (3)	0.5392 (4)	0.46971 (16)	0.0128 (5)
H8A	0.1328	0.6163	0.4175	0.015*
H8B	0.1623	0.6039	0.5251	0.015*
C22	1.0666 (4)	0.7842 (5)	0.8020 (2)	0.0258 (7)
H22A	0.9502	0.7935	0.7882	0.031*
H22B	1.1080	0.7631	0.7462	0.031*
H22C	1.1112	0.8976	0.8300	0.031*
C9	0.0871 (3)	0.3616 (5)	0.4636 (2)	0.0206 (6)
H9A	−0.0263	0.3862	0.4619	0.025*
H9B	0.1280	0.2863	0.5162	0.025*
H9C	0.1010	0.2971	0.4086	0.025*

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
O1	0.0172 (8)	0.0388 (14)	0.0013 (7)	0.0003 (10)	0.0016 (6)	0.0001 (8)
N1	0.0113 (8)	0.0186 (13)	0.0034 (8)	−0.0004 (9)	0.0030 (7)	0.0013 (8)
C1	0.0161 (11)	0.0200 (15)	0.0045 (10)	−0.0002 (11)	0.0010 (8)	0.0010 (10)
O2	0.0136 (8)	0.0293 (12)	0.0031 (7)	−0.0004 (8)	0.0059 (6)	−0.0008 (7)
N2	0.0091 (8)	0.0187 (13)	0.0032 (8)	0.0007 (9)	0.0031 (6)	−0.0004 (8)
C2	0.0176 (11)	0.0268 (17)	0.0048 (9)	0.0008 (12)	0.0061 (8)	0.0002 (10)
C3	0.0118 (10)	0.0246 (16)	0.0062 (9)	0.0001 (11)	0.0048 (8)	0.0016 (10)
O3	0.0151 (8)	0.0331 (13)	0.0062 (7)	0.0032 (8)	0.0047 (6)	0.0080 (8)
C4	0.0124 (10)	0.0173 (15)	0.0035 (9)	−0.0005 (11)	0.0028 (8)	0.0008 (9)
O4	0.0191 (10)	0.0324 (14)	0.0143 (9)	0.0067 (9)	0.0052 (7)	0.0084 (8)
C5	0.0112 (10)	0.0149 (14)	0.0042 (9)	0.0000 (10)	0.0028 (7)	0.0011 (9)
O5	0.0085 (8)	0.0340 (14)	0.0039 (7)	0.0037 (8)	0.0048 (6)	−0.0018 (7)
OW1	0.0227 (10)	0.0524 (17)	0.0046 (8)	−0.0111 (10)	0.0075 (7)	−0.0076 (9)
C6	0.0117 (10)	0.0206 (15)	0.0058 (10)	−0.0007 (11)	0.0010 (8)	0.0001 (10)
C21	0.0153 (12)	0.0241 (16)	0.0080 (10)	−0.0014 (11)	0.0028 (9)	−0.0026 (10)
C20	0.0133 (11)	0.0270 (18)	0.0045 (10)	0.0018 (11)	0.0039 (8)	0.0009 (10)
C19	0.0152 (12)	0.0233 (16)	0.0055 (10)	−0.0002 (11)	0.0023 (9)	0.0001 (10)
C18	0.0102 (10)	0.0237 (15)	0.0024 (9)	0.0009 (10)	0.0044 (7)	0.0003 (9)
C17	0.0124 (10)	0.0166 (14)	0.0035 (9)	−0.0004 (10)	0.0042 (8)	−0.0007 (9)
C16	0.0126 (10)	0.0202 (15)	0.0029 (9)	0.0000 (10)	0.0034 (8)	0.0005 (9)
C15	0.0116 (10)	0.0146 (14)	0.0047 (9)	0.0010 (10)	0.0026 (8)	0.0011 (9)
C14	0.0123 (10)	0.0185 (15)	0.0037 (9)	−0.0005 (10)	0.0046 (8)	−0.0001 (9)
C13	0.0127 (10)	0.0169 (15)	0.0035 (9)	−0.0009 (10)	0.0048 (7)	0.0004 (9)
C12	0.0097 (9)	0.0230 (16)	0.0024 (9)	0.0014 (11)	0.0030 (7)	−0.0004 (10)
C11	0.0099 (9)	0.0157 (14)	0.0040 (9)	0.0003 (10)	0.0021 (7)	0.0008 (9)
C10	0.0129 (10)	0.0160 (14)	0.0046 (9)	−0.0011 (11)	0.0045 (8)	0.0001 (9)
C7	0.0112 (10)	0.0138 (14)	0.0059 (10)	−0.0010 (10)	0.0040 (8)	0.0006 (9)
C8	0.0111 (11)	0.0203 (16)	0.0073 (10)	0.0029 (10)	0.0029 (8)	−0.0002 (9)
C22	0.0238 (14)	0.0229 (18)	0.0296 (16)	−0.0054 (13)	0.0013 (12)	0.0025 (13)
C9	0.0123 (12)	0.0255 (18)	0.0243 (14)	−0.0011 (11)	0.0048 (10)	0.0016 (12)

Geometric parameters (Å, º)

O1—C1	1.354 (3)	C21—H21B	0.9900
O1—H1	0.8400	C20—C16	1.492 (3)
N1—C11	1.315 (3)	C20—H20A	0.9900
N1—C4	1.364 (3)	C20—H20B	0.9900
C1—C6	1.378 (3)	C19—C18	1.526 (4)
C1—C2	1.408 (3)	C18—C15	1.511 (3)
O2—C17	1.248 (3)	C17—C16	1.435 (3)
N2—C13	1.372 (3)	C16—C15	1.368 (3)
N2—C17	1.374 (3)	C15—C14	1.410 (3)
N2—C12	1.475 (3)	C14—C13	1.356 (3)
C2—C3	1.363 (3)	C14—H14	0.9500
C2—H2	0.9500	C13—C11	1.459 (3)
C3—C4	1.415 (3)	C12—C10	1.500 (3)
C3—H3	0.9500	C12—H12A	0.9900
O3—C19	1.327 (3)	C12—H12B	0.9900
O3—C20	1.460 (3)	C11—C10	1.403 (3)
C4—C5	1.428 (3)	C10—C7	1.367 (3)
O4—C19	1.200 (3)	C7—C8	1.502 (3)
C5—C6	1.413 (3)	C8—C9	1.511 (4)
C5—C7	1.432 (3)	C8—H8A	0.9900
O5—C18	1.409 (3)	C8—H8B	0.9900
O5—H5	0.8400	C22—H22A	0.9800
OW1—HW1A	0.839 (13)	C22—H22B	0.9800
OW1—HW1B	0.836 (13)	C22—H22C	0.9800
C6—H6	0.9500	C9—H9A	0.9800
C21—C22	1.508 (4)	C9—H9B	0.9800
C21—C18	1.536 (4)	C9—H9C	0.9800
C21—H21A	0.9900
C1—O1—H1	109.5	O2—C17—C16	125.9 (2)
C11—N1—C4	114.48 (18)	N2—C17—C16	113.8 (2)
O1—C1—C6	118.6 (2)	C15—C16—C17	121.8 (2)
O1—C1—C2	121.0 (2)	C15—C16—C20	119.7 (2)
C6—C1—C2	120.3 (2)	C17—C16—C20	118.4 (2)
C13—N2—C17	124.44 (19)	C16—C15—C14	121.2 (2)
C13—N2—C12	112.99 (18)	C16—C15—C18	117.46 (19)
C17—N2—C12	122.53 (19)	C14—C15—C18	121.2 (2)
C3—C2—C1	120.1 (2)	C13—C14—C15	117.0 (2)
C3—C2—H2	119.9	C13—C14—H14	121.5
C1—C2—H2	119.9	C15—C14—H14	121.5
C2—C3—C4	121.2 (2)	C14—C13—N2	121.5 (2)
C2—C3—H3	119.4	C14—C13—C11	131.6 (2)
C4—C3—H3	119.4	N2—C13—C11	106.93 (18)
C19—O3—C20	121.8 (2)	N2—C12—C10	101.73 (17)
N1—C4—C3	117.1 (2)	N2—C12—H12A	111.4
N1—C4—C5	124.07 (19)	C10—C12—H12A	111.4
C3—C4—C5	118.9 (2)	N2—C12—H12B	111.4
C6—C5—C4	118.62 (19)	C10—C12—H12B	111.4
C6—C5—C7	123.0 (2)	H12A—C12—H12B	109.3
C4—C5—C7	118.36 (19)	N1—C11—C10	126.5 (2)
C18—O5—H5	109.5	N1—C11—C13	124.9 (2)
HW1A—OW1—HW1B	107 (2)	C10—C11—C13	108.63 (19)
C1—C6—C5	120.7 (2)	C7—C10—C11	120.3 (2)
C1—C6—H6	119.6	C7—C10—C12	130.0 (2)
C5—C6—H6	119.6	C11—C10—C12	109.68 (19)
C22—C21—C18	113.7 (2)	C10—C7—C5	116.2 (2)
C22—C21—H21A	108.8	C10—C7—C8	120.8 (2)
C18—C21—H21A	108.8	C5—C7—C8	122.9 (2)
C22—C21—H21B	108.8	C7—C8—C9	113.3 (2)
C18—C21—H21B	108.8	C7—C8—H8A	108.9
H21A—C21—H21B	107.7	C9—C8—H8A	108.9
O3—C20—C16	111.8 (2)	C7—C8—H8B	108.9
O3—C20—H20A	109.3	C9—C8—H8B	108.9
C16—C20—H20A	109.3	H8A—C8—H8B	107.7
O3—C20—H20B	109.3	C21—C22—H22A	109.5
C16—C20—H20B	109.3	C21—C22—H22B	109.5
H20A—C20—H20B	107.9	H22A—C22—H22B	109.5
O4—C19—O3	119.8 (2)	C21—C22—H22C	109.5
O4—C19—C18	122.3 (2)	H22A—C22—H22C	109.5
O3—C19—C18	117.8 (2)	H22B—C22—H22C	109.5
O5—C18—C15	108.33 (18)	C8—C9—H9A	109.5
O5—C18—C19	109.7 (2)	C8—C9—H9B	109.5
C15—C18—C19	109.6 (2)	H9A—C9—H9B	109.5
O5—C18—C21	111.7 (2)	C8—C9—H9C	109.5
C15—C18—C21	111.0 (2)	H9A—C9—H9C	109.5
C19—C18—C21	106.5 (2)	H9B—C9—H9C	109.5
O2—C17—N2	120.3 (2)

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
O1—H1···OW1	0.84	1.91	2.734 (3)	168
O5—H5···O2^i	0.84	2.06	2.894 (3)	172
OW1—HW1A···O2^ii	0.84 (1)	2.05 (2)	2.879 (3)	170 (4)
OW1—HW1B···O4^iii	0.84 (1)	2.09 (2)	2.894 (3)	162 (4)

Symmetry codes: (i) x+1, y, z; (ii) x, y, z−1; (iii) −x+2, y+1/2, −z+1.