STRUCTURAL STUDIES OF THE NOVEL ANTITUMOR AGENTS 4-AMINO-8-(BETA-D-RIBOFURANOSYLAMINO)PYRIMIDO(5,4-D) PYRIMIDINE AND 4-METHOXY-8-(BETA-D-RIBOFURANOSYLAMINO)PYRIMIDO[5,4-D]PYRIMIDINE AND THEIR ALPHA-ANOMERS USING X-RAY, H-1-NMR, AND THEORETICAL METHODS

The structural properties of the new antitumor agents 4-amino-(ARPP, 1a) and 4-methoxy-8-(β-D-ribofuranosylamino) pyrimido[5,4-d]pyrimidines (MRPP, 1b) and the corresponding α-anomers 2a and 2b were studied by using molecular mechanics, molecular orbital (AMI) calculations, X-ray diffraction, and 1H NMR spectral data. In the 1H NMR spectra of 1a and 1b at elevated temperature, substantial upfield shifts for the exocyclic NH proton resonance were observed as compared to the spectra of the -anomers. The crystal structures of MRPP (C12H15NO5·H2O, 1b) and its a-anomer (C12H15NO5·H2O, 2b) have been determined by single-crystal X-ray diffraction techniques employing Cu Kα radiation. Nucleoside 1b crystallized in the monoclinic space group C2 with cell dimensions a = 13.309 (3) Å, b = 8.211 (2) Å, c = 14.025 (5) Å, β = 112.37 (3)°, and Z = 4. The structure was refined to a conventional R value of 0.0346 for 2369 reflections (F ≥ 4σF). The α-anomer 2b crystallized in the monoclinic space group I2 with cell dimensions a = 14.543 (2) Å, b = 4.7405 (13) Å, c = 21.355 (7) Å, β = 95.041 (14)°, and Z = 4 and was refined to R = 0.0338 for 2524 reflections (F ≥ 4σF). The sugar conformations and puckering parameters are 3T2 472 (C3'-endo/C2'-exo), P = -1.3°, and τm = 36.5° for 1b and 2T3 (C2'-exo/C3'-endo), P = 0.6°, and τm = 38.9° for 2b. The dihedral angles between the fused pyrimidine rings are 2.55 (10)° for 1b and 1.09 (9)° for 2b. In each structure (1b and 2b), all hydroxyl and amino hydrogen atoms are involved in intermolecular hydrogen bonding; no intramolecular hydrogen bonding is observed. The 1H NMR spectrum of 5'-deoxy-MRPP (3d) also exhibited an upfield shift for the exocyclic NH proton signal at elevated temperature. An analysis of the molecular mechanics and molecular orbital conformational results together with X-ray crystallography and 1H NMR data indicates that the reversible upfield shift shown by the exocyclic NH proton of these β-nucleosides is a conformational property rather than an effect of intramolecular hydrogen bonding. © 1990, American Chemical Society. All rights reserved.