Crystal structures of five 6-mercaptopurine derivatives

Three of five 6-mercaptopurine derivatives are isomorphous and accordingly their molecular and supramolecular structures are similar. In the remaining two derivatives, the purine and exocyclic phenyl rings are essentially planar, but that in the case of the three isomorphous compounds, these rings are twisted.


Chemical context
Purines, purine nucleosides and their analogs, are nitrogencontaining heterocycles ubiquitous in nature and present in biological systems like man, plants and marine organisms (Legraverend, 2008). These types of heterocycles take part of the core structure of guanine and adenine in nucleic acids (DNA and RNA) being involved in diverse in vivo catabolic and anabolic metabolic pathways.
6-Mercaptopurine is a water insoluble purine analogue, which attracted attention due to its antitumor and immunosuppressive properties. The drug is used, among others, in the treatment of rheumathologic disorders, cancer and prevention of rejection of organ transplantation. The main problem associated with the pharmacological treatment with 6mercaptopurine is the low bioavailability of the oral absorption and the short half-life in plasma. Strategies that have been adopted to circumvent those problems include the administration of 6-mercaptopurine analogues that act as prodrugs or by the chemical protection of the thiol group.
These compounds can be envisaged as two building blocks, a substituted phenylethanone grouping and a substituted 6mercaptopurine moiety, bonded together by the mercapto ethanone residue. Since both purine and phenyl rings are essentially planar, the structural conformations of those compounds are conditioned by the -SCH 2 CO spacer ( Fig. 6) which permits rotations around the following bonds: Pu-S6, S6-C61, C61-C62 and C62-Ph bonds. The sp 3 character of the central carbon atom may also direct the relative positions of the acetophenone residue out of the main plane constituted by the mercaptopurine, which is not the case of the present compounds. Selected geometric parameters for compounds (1)-(5) are given in Tables 1-5, respectively.
The Pu-S6 bond tends to be coplanar with the purine residue. In fact, the 6-mercaptopurine itself may appear in the thione form, e.g. 3,7-dihydropurine-6-thione, as a consequence of the high degree of electron delocalization within the 6- A view of the asymmetric unit of (1), with displacement ellipsoids are drawn at the 70% probability level.

Figure 2
A view of the asymmetric unit of (2), with displacement ellipsoids are drawn at the 70% probability level.

Figure 3
A view of the asymmetric unit of (3), with displacement ellipsoids are drawn at the 70% probability level.

Figure 4
A view of the asymmetric unit of (4), with displacement ellipsoids are drawn at the 70% probability level.

Figure 5
A view of the asymmetric unit of (5), with displacement ellipsoids are drawn at the 70% probability level.
1 is the dihedral angle between the mean planes of the purine and phenyl rings and the phenyl ring. 2 is the dihedral angles between the mean planes of the purine ring and the plane defined by the S6/C61/C62/O6 atoms. 3 is the dihedral angle between the mean planes of the phenyl ring and the plane defined by the S6/C61/C62/O6 atoms. (1) 2.95 (7) 8.45 (8) (8) The maximum deviations from the mean plane of the S-C-C-O bridging unit are for compounds (1)-(5) are 0.0457 (13), À0.041 (2), À0.023 (11), À0.017 (2) and 0.0302 (8) Å respectively. In all cases it is atom C42 which shows the maximum deviation.
(0, 1 2 , 1 2 ) are involved instacking in which the purine ring stacks above the exocyclic phenyl ring. In (2), (3) and (4), the stacking is between imidazole rings while in (1) and (5), the contact is between an imidazole ring and a benzyl ring. In particular, in (1) and (5) two molecules centrosymmetrically related across the centre of symmetry at (0, 1 2 , 1 2 ) are involved in stacking in which the purine rings stack above the exocyclic phenyl ring, Table 11.
The R-S bond distances for these compounds are similar to those of the studied compounds and they assume a partial double-bond character with the exception of UGITUA where the S atom is bonded to a phenyl ring, suggesting a tendency for delocalization of the electron density through the sulfur atom when the ring has heteroatoms. The S-CH 2 bond distances vary between 1.80 and 1.81 Å with exception of SILGAW (1.79 Å ) and ETEWOP (1.82 Å ). The supplementary figure also gives information about the distances of the -CH 2 -carbon atom to the best plane made up of the atoms of the heterocycles (CH 2 -distance). These values were computed in order to evaluate the degree of bending of the S-CH 2 bond with respect to the main plane of the substituted rings. There are two main groups of compounds, one in which the distance is shorter than 0.3 Å and the other, which contains the CNH fragment in the heterocyclic ring, in which this distance is greater than 1.2 Å . As noted above, the sp 3 character of the -carbon atom of the ethanone fragment may also direct the relative positions of the acetophenone residue out of the main plane constituted by the substituted heteroaromatic ring. This is the case for SILGAW and IKAXOI. Thus, despite the small sample size, there is a wide range of adopted conformations.
CgI(J) is plane I(J); CgÁ Á ÁCg is the distance between ring centroids; is the dihedral angle between planes I and J; CgI perp is the perpendicular distance of Cg(I) on ring J; CgJ perp is the perpendicular distance of Cg(J) on ring I; Slippage is the distance between Cg(I) and the perpendicular projection of Cg(J) on ring I. Plane 1 is through the imadazole ring, plane 2 the pyrimidine ring and plane 3 the exocyclic benzene ring.