METALLOCENE ANTITUMOR AGENTS - SOLUTION AND SOLID-STATE MOLYBDENOCENE COORDINATION CHEMISTRY OF DNA CONSTITUENTS

This contribution reports a solution and solid-state structural study of the aqueous nucleobase and nucleotide coordination chemistry of the organometallic antineoplastic agent, Cp2MoCl2 (1, Cp = eta-5-C5H5). In neutral aqueous solution, Cp2MoCl2 undergoes essentially complete chloride aquation within 60 min to yield what is formulated as Cp2Mo(H2O)OH+, while under the same conditions, the Mo-Cp bonds are hydrolytically stable. Reaction of aqueous Cp2MoCl2 with the alkylated nucleobases, 9-methyladenine and 1-methylcytosine yields two isomeric [Cp2Mo(9-methyladenyl)][PF6] complexes (3a and 3b) and a single isomer of [Cp2Mo(1-methylcytosyl)][PF6] (4). On the basis of solution NMR spectroscopy, 3a and 3b are assigned HN6-/N1 and HN6-/N7 chelation modes, respectively, while 4 involves an HN4-/N3 chelation mode. Complex 3a crystallizes in the triclinic space group P1BAR with a = 10.682 (3) angstrom, b = 11.619 (5) angstrom, c = 7.701 (5) angstrom, alpha = 106.93 (4)degrees, beta = 96.32 (3)degrees, gamma = 86.98 (3)degrees, V = 908.64 angstrom 3, Z = 2; R(F) = 0.045 for 3614 independent reflections having I > 3-sigma(I). The Cp2Mo2+ fragment is in a bent sandwich geometry with an average Mo-C distance of 2.309 (4) angstrom, a Mo-N1 distance of 2.173 (3) angstrom, a Mo-N6 distance of 2.145 (3) angstrom, a N1-Mo-N6 angle of 60.9 (1)degrees, and a ring centroid-Mo-ring centroid angle of 135.3-degrees. The 9-methyladenyl ligand in 3a lies in the plane which bisects the ring centroid-Mo-ring centroid angle. Chelation constricts the N6-C6-N1 angle to 108.5 (3)degrees. Complex 4 crystallizes in the monoclinic space group (P2(1)/c) with a = 11.703 (1) angstrom, b = 10.794 (2) angstrom, c = 14.416 (2) angstrom, beta = 111.28 (1)degrees, Z = 4, V = 1696.8 angstrom 3; R(F) = 0.047 for 3007 independent reflections having I > 3-sigma(I). The Cp2Mo2+ fragment is also in a bent sandwich geometry with an average Mo-C distance of 2.294 (7) angstrom, a Mo-N4 distance of 2.140 (5) angstrom, a Mo-N3 distance of 2.130 (5) angstrom, a N1-Mo-N6 angle of 59.9 (1)degrees, and a ring centroid-Mo-ring centroid angle of 136.5-degrees. The 1-methylcytosyl ligand in 4 lies in the plane which bisects the ring cen-troid-Mo-ring centroid angle, and chelation constricts the N4-C4-N3 angle to 106.8 (5)degrees. On the NMR time scale and in the absence of other competing ligands, complex 1 forms 1:1 complexes with the 2'-deoxyribonucleotide-5-monophosphates of guanosine (5'-dGMP), adenosine (5'-dAMP), cytosine (5'-dCMP), and thymidine (5'-dTMP). There is little selectivity in the complexation, and nucleotide-nucleotide exchange processes are detectable. Although nucleotide complexation is observed, there is no NMR evidence that Cp2MoCl2(aq) disrupts Watson-Crick base pairing in 5'-dGMP/5'-dCMP or 5-dAMP/5'-dTMP dimers. The Cp2Mo2+ adduct of 5'-dGMP (5) crystallizes in the triclinic space group P1 with a = 10.690 (3) angstrom, b = 14.567 (5) angstrom, c = 9.298 (3) angstrom, alpha, = 107.20 (2)degrees, beta = 99.22 (3)degrees, gamma = 77.62 (3)degrees, Z = 1, V = 1344 (2) angstrom 3; R(F) = 0.045 for 5491 independent reflections having I > 3-sigma(I). The crystal structure of complex 5 consists of dimeric [Cp2Mo(5'-dGMP)]2 units interconnected by water bridges. Each Cp2Mo2+ unit of the dimer is in a bent sandwich geometry and is coordinated to N7 and O(phosphate) of different 5'-dGMP moieties. Metrical parameters for 5 are as follows: Mo-C distance(av), 2.307 (9) angstrom; Mo-N7 distance, 2.20 (1) angstrom; Mo-O(phosphate) distance, 2.096 (9) angstrom; N7-Mo-O(phosphate) angle, 77.8 (2)degrees; and ring centroid-Mo-ring centroid angle, 133.8 (6)degrees. The 5'-dGMP unit has beta-gg and gamma-gt torsional conformers and exhibits an unusual syn glycosidic and C3'-endo sugar puckering conformation. Compound 1 forms a monomeric complex with 5'-dAMP (6) in aqueous solution via Mo-N7 and Mo-O(phosphate) chelation, two complexes with 5'-dCMP that both involve 0(phosphate) coordination, and a single complex with 5'-dTMP which involves O(phosphate) and N3 coordination. These results place significant ligational restrictions on the mode(s) by which Cp2MX2(aq) species might bind to DNA and, together with a molecular graphics investigation of Cp2Mo+2 coordination to a model oligonucleotide duplex, argue against cisplatinlike complexation motifs.