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Pyrido[3,4-d]pyrimidin-4(3H)-one metabolism mediated by aldehyde oxidase is blocked by C2-substitution.

ABSTRACT: 1. We have previously described C8-substituted pyrido[3,4-d]pyrimidin-4(3H)-one derivatives as cell permeable inhibitors of the KDM4 and KDM5 subfamilies of JmjC histone lysine demethylases. 2. Although exemplar compound 1 exhibited moderate clearance in mouse liver microsomes, it was highly cleared in vivo due to metabolism by aldehyde oxidase (AO). Similar human and mouse AO-mediated metabolism was observed with the pyrido[3,4-d]pyrimidin-4(3H)-one scaffold and other C8-substituted derivatives. 3. We identified the C2-position as the oxidation site by LC-MS and ¹H-NMR and showed that C2-substituted derivatives are no longer AO substrates. 4. In addition to the experimental data, these observations are supported by molecular modelling studies in the human AO protein crystal structure.

SUBMITTER: Hayes A

PROVIDER: S-EPMC5526139 | biostudies-literature |

REPOSITORIES: biostudies-literature

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8-Substituted Pyrido[3,4-d]pyrimidin-4(3H)-one Derivatives As Potent, Cell Permeable, KDM4 (JMJD2) and KDM5 (JARID1) Histone Lysine Demethylase Inhibitors.

Project description:We report the discovery of N-substituted 4-(pyridin-2-yl)thiazole-2-amine derivatives and their subsequent optimization, guided by structure-based design, to give 8-(1H-pyrazol-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-ones, a series of potent JmjC histone N-methyl lysine demethylase (KDM) inhibitors which bind to Fe(II) in the active site. Substitution from C4 of the pyrazole moiety allows access to the histone peptide substrate binding site; incorporation of a conformationally constrained 4-phenylpiperidine linker gives derivatives such as 54j and 54k which demonstrate equipotent activity versus the KDM4 (JMJD2) and KDM5 (JARID1) subfamily demethylases, selectivity over representative exemplars of the KDM2, KDM3, and KDM6 subfamilies, cellular permeability in the Caco-2 assay, and, for 54k, inhibition of H3K9Me3 and H3K4Me3 demethylation in a cell-based assay.

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Project description:The mol-ecular structure of the title compound, C(8)H(12)N(2)O, indicates that 2-isopropyl-6-methyl-pyrimidin-4-ol (the enol-form) undergoes an enol-to-keto tautomerism during the crystallization process. The pyrimidin-4(3H)-one group is essentially planar, with a maximum deviation of 0.081 (1) Å for the O atom. In the crystal structure, symmetry-related mol-ecules are linked into centrosymmetic dimers via pairs of inter-molecular N-H⋯O hydrogen bonds, generating R(2) (2)(8) rings. These dimers are stacked along the a axis.

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3,5,6-Trimethyl-thieno[2,3-d]pyrimidin-4(3H)-one.

Project description:In the title compound, C(9)H(10)N(2)OS, the thienopyrimidine ring system is almost planar [greatest deviation from the mean plane = 0.0318 (13) Å for the S atom]. The crystal packing features C-H⋯O hydrogen bonds and π-π stacking inter-actions between inversion-related pairs of mol-ecules with a centroid-centroid distance of 3.530 (3) Å.

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2-Diethyl-amino-6-methyl-pyrimidin-4(3H)-one.

Project description:The title compound, C(9)H(15)N(3)O, contains four mol-ecules (A, B, C and D) in the asymmetric unit. In the crystal, the A+A and D+D pairs form inversion dimers linked by pairs of N-H⋯O hydrogen bonds. The B+C pairing is linked by the same bonds. The dimers are further linked by weak C-H⋯O inter-actions.

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6-Ethyl-5-fluoro-2-methoxy-pyrimidin-4(3H)-one.

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6-Amino-2,5-bis-(pivaloylamino)pyrimidin-4(3H)-one dihydrate.

Project description:The asymmetric unit of the title compound, C(14)H(23)N(5)O(3)·2H(2)O, contains two crystallographically independent 6-amino-2,5-bis-(pivaloylamino)pyrimidin-4(3H)-one mol-ecules (A and B) with similar geometry and four water mol-ecules. In both independent mol-ecules, one of the amide groups is almost coplanar with the pyrimidine ring [dihedral angle of 12.85?(9) in A and 12.30?(10)° in B], whereas the other amide group is significantly twisted away from it [dihedral angle is 72.18?(7) in A and 71.29?(7)° in B]. In each independent mol-ecule, an intra-molecular N-H?O hydrogen bond generates an S(6) ring motif. Mol-ecules A and B are linked into chains along the a axis by N-H?O and C-H?O hydrogen bonds. Adjacent chains are linked into a two-dimensional network parallel to the ac plane by water mol-ecules via N-H?O and O-H?O hydrogen bonds.

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7-Benzyl-3-(4-fluoro-phen-yl)-2-propyl-amino-5,6,7,8-tetra-hydro-pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4(3H)-one.

Project description:In the title compound, C(25)H(25)FN(4)OS, the thienopyrimidine fused-ring system is close to planar (r.m.s. deviation = 0.0089?Å), with a maximum deviation of 0.0261?(17)?Å for the N atom adjacent to the benzene ring. This thienopyrimidine fused-ring system forms dihedral angles of 64.73?(3) and 81.56?(5)° with the adjacent benzyl and fluoro-phenyl rings, respectively. Inter-molecular N-H?F and C-H?F hydrogen bonding, as well as C-F?? inter-actions [F?centroid = 3.449?(3)?Å; C-F?centroid = 91.87?(15)°], help to stabilize the crystal structure.

| S-EPMC3344049 | biostudies-literature

7-Benzyl-2-[(cyclo-propyl-meth-yl)amino]-3-phenyl-5,6,7,8-tetra-hydro-pyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4(3H)-one.

Project description:There are two independent mol-ecules in the asymmetric unit of the title compound, C(26)H(26)N(4)OS. In each mol-ecule, the thienopyrimidine fused-ring system is essentially planar with a maximum deviation of 0.0409?(18) for the N atom. In one mol-ecule, this ring system forms diherdral angles of 84.8?(1) and 67.6?(1)° with the adjacent phenyl and benzyl rings, respectively, while the corresponding angles in the other mol-ecule are 77.9?(1) and 66.5?(1)°.

| S-EPMC3213622 | biostudies-literature

Design, synthesis, and anti-cancer evaluation of new pyrido[2,3-d]pyrimidin-4(3H)-one derivatives as potential EGFRWT and EGFRT790M inhibitors and apoptosis inducers.

Project description:A new series of pyrido[2,3-d]pyrimidin-4(3H)-one derivatives having the essential pharmacophoric features of EGFR inhibitors has been designed and synthesised. Cell viability screening was performed for these compounds against A-549, PC-3, HCT-116, and MCF-7 cell lines at a dose of 100 μM. The highest active derivatives (8a, 8 b, 8d, 9a, and 12b) were selected for IC50 screening. Compounds 8a, 8 b, and 9a showed the highest cytotoxic activities and were further investigated for wild EGFRWT and mutant EGFRT790M inhibitory activities. Compound 8a showed the highest inhibitory activities against EGFRWT and EGFRT790M with IC50 values of 0.099 and 0.123 µM, respectively. In addition, it arrested the cell cycle at pre-G1 phase and induced a significant apoptotic effect in PC-3 cells. Furthermore, compound 8a induced a 5.3-fold increase in the level of caspase-3 in PC-3 cells. Finally, docking studies were carried out to examine the binding mode of the synthesised compounds against both EGFRWT and EGFRT790M.

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3-(2-Chloro-ethyl)-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one.

Project description:In the title mol-ecule, C(11)H(11)ClN(2)O, the pyrido[1,2-a]pyrimidine ring system is planar (maximum deviation = 0.0148?Å) and the methyl C and carbonyl O atoms are nearly coplanar to it. The chloro-ethyl side chain is in a synclinal conformation, nearly orthogonal to the pyrimidine ring, with a dihedral angle between the chloro-ethyl side chain and the pyrimidine ring of 88.5?(1)°. Weak inter-molecular C-H?N and C-H?Cl hydrogen bonds along with ?-? inter-actions between the pyrimidine and pyridine rings [centroid-centroid distance is 3.538?(2)?Å] form a three-dimensional network. The crystal is a racemic twin with a 0.68?(12):0.32?(12) domain ratio. MOPAC AM1 and density functional theory (DFT) theoretical calculations at the B3-LYP/6-311+G(d,p) level support these observations.

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