RESUMO
We describe N-alkyl carbamoylimidazoles as readily available and highly versatile synthons for synthesizing urea-based prostate-specific membrane antigen (PSMA) inhibitors. Urea formation proceeded in high yields (>80%) at room temperature under aqueous conditions. All novel compounds were tested for their PSMA inhibitory potency in a cell-based radiometric binding assay. Compound 17 was identified as a novel high-affinity PSMA inhibitor (IC50 = 0.013 µM) suitable for developing an 18F-labeled radioligand for PET imaging of PSMA in prostate cancer.
RESUMO
We have prepared and tested radioligand [18F]ONO-8430506 ([18F]8) as a novel ATX PET imaging agent derived from highly potent ATX inhibitor ONO-8430506. Radioligand [18F]8 could be prepared in good and reproducible radiochemical yields of 35 ± 5% (n = 6) using late-stage radiofluorination chemistry. ATX binding analysis showed that 9-benzyl tetrahydro-b-carboline 8 has about five times better inhibitory potency than clinical candidate GLPG1690 and somewhat less inhibitory potency than ATX inhibitor PRIMATX. The binding mode for compound 8 inside the catalytic pocket of ATX using computational modelling and docking protocols revealed that compound 8 resembled a comparable binding mode to that of ATX inhibitor GLPG1690. However, PET imaging studies with radioligand [18F]8 showed only relatively low tumour uptake and retention (SUV60min 0.21 ± 0.03) in the tested 8305C human thyroid tumour model reaching a tumour-to-muscle ratio of â¼ 2.2 after 60 min.
Assuntos
Neoplasias , Humanos , Tomografia por Emissão de Pósitrons , Carbolinas , Compostos Radiofarmacêuticos/farmacologia , Radioisótopos de Flúor/químicaRESUMO
The synthesis of new indolopyrrolobenzodiazepine derivatives is described. Six compounds were selected for evaluation of cytotoxicity towards acute myeloid leukemia (AML) cells and normal fibroblasts. One compound (29) showed selective AML cell death induction. Its action was only partly overcome by knock-down of p53 or Bcl-2 overexpression, suggesting a strong activation of intrinsic apoptotic pathways.
Assuntos
Benzodiazepinas/química , Benzodiazepinas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Benzodiazepinas/síntese química , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Humanos , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patologia , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Proteínas Proto-Oncogênicas c-pim-1/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-pim-1/metabolismo , Relação Estrutura-Atividade , Proteína Supressora de Tumor p53/antagonistas & inibidores , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismoRESUMO
The asymmetric unit of the title compound, C13H10N2O3, contains four independent mol-ecules (I, II, III and IV). Mol-ecule IV shows whole-mol-ecule disorder over two sets of adjacent sites in a 0.669â (10):0.331â (10) ratio. The dihedral angles between the aromatic rings are 32.30â (13)° in mol-ecule I, 2.24â (14)° in II, 41.61â (13)° in III, 5.0â (5)° in IV (major component) and 10.2â (3)° in IV (minor component). In the crystal, mol-ecules are linked into layers lying parallel to (024) by C-Hâ¯O and O-Hâ¯O inter-actions. The layers inter-act by C-Hâ¯π and weak aromatic π-π stacking inter-actions [centroid-centroid distances = 3.8476â (16), 3.725â (3) and 3.733â (5)â Å].
RESUMO
The effect of double asymmetric induction for the synthesis of new cis-ß-lactams by [2 + 2] cycloaddition reactions of chiral imines with a chiral ketene was investigated. The cycloaddition reaction was found to be totally diastereoselective leading exclusively to the formation of the cis-ß-lactam derivatives. The newly synthesized cycloadducts were evaluated for their antimalarial activities against Plasmodium falciparum K14 resistant strain with moderate to excellent IC50 values varying from 8 to 50 µM. Of the fifteen ß-lactams tested, four showed IC50 ≤ 11 µM.
Assuntos
Antimaláricos/química , Antimaláricos/farmacologia , Reação de Cicloadição , Etilenos/química , Iminas/química , Cetonas/química , beta-Lactamas/química , beta-Lactamas/farmacologia , Antimaláricos/síntese química , Técnicas de Química Sintética , Concentração Inibidora 50 , Plasmodium falciparum/efeitos dos fármacos , Estereoisomerismo , Relação Estrutura-Atividade , beta-Lactamas/síntese químicaRESUMO
Some new mono-and bis-polycyclic aromatic spiro-beta-lactams and bis-non spiro-polycyclic aromatic beta-lactams have been synthesized from imines derived from anthracene-9-carbaldehyde, 2-naphtaldehyde and a ketene derived from 9H-xanthene-9-carboxylic acid and phenoxyacetic acid by a [2+2] cycloaddition reaction. The cycloadducts were characterized by spectral data, including 1H-NMR, 13C-NMR, IR and elemental analyses. The configurations of some of these mono-spiro-beta-lactams were established by X-ray crystal analysis.
Assuntos
Compostos de Espiro/síntese química , beta-Lactamas/síntese química , Cristalografia por Raios X , Modelos Moleculares , Compostos de Espiro/química , beta-Lactamas/químicaRESUMO
In the title mol-ecule, C(35)H(22)BrNO(2), the four-membered ring of the ß-lactam unit is nearly planar [maximum deviation = 0.003â (3)â Å] and makes dihedral angles of 87.07â (15), 59.80â (16) and 20.81â (19)°, respectively, with the xanthene system, the anthracene system and the bromo-substituted benzene ring. The mol-ecular conformation is stabilized by weak intra-molecular C-Hâ¯O and C-Hâ¯N hydrogen bonds. The crystal structure features weak C-Hâ¯π inter-actions.
RESUMO
The ß-lactam ring of the title compound, C(35)H(23)NO(2), is nearly planar with a maximum deviation of 0.003â (3)â Å from the mean plane. It makes dihedral angles of 17.4â (2), 85.22â (17) and 65.39â (16)°, respectively, with the phenyl, xanthene and anthracene ring systems. In the crystal structure, there are intra-molecular C-Hâ¯O and C-Hâ¯N contacts and mol-ecules are also linked by C-Hâ¯π inter-actions.
RESUMO
The stabilized conformation of the title compound, C(36)H(25)NO(3), 4-(9-anthryl)-1-(2-methoxyphenyl)-spiro[azetid-in-3,9'-xanthen]-2-one, may be compared with that of the isomeric compound 4-(9-anthr-yl)-1-(4-methoxy-phen-yl)spiro-[azetidin-3,9'-xanthen]-2-one. In the title isomer, the meth-oxy group is slightly twisted out of the plane of the attached benzene ring, with a C-O-C-C torsion angle of 31.5â (2)°. Its ß-lactam ring is essentially planar, with a maximum deviation of -0.021â (1)â Å. The ß-lactam ring makes dihedral angles of 18.815â (9), 83.33â (7) and 53.62â (8)° with the mean planes of the benzene, xanthene and anthracene ring systems, respectively. The structure is stabilized by C-Hâ¯π, C-Hâ¯N and C-Hâ¯O inter-actions.
RESUMO
The title compound, C(37)H(27)NO(4), crystallizes with two mol-ecules in the asymmetric unit. The ß-lactam ring of each mol-ecule is very nearly planar, with maximum deviations of 0.001â (2) and 0.017â (2)â Å in the two mol-ecules. The crystal structure is stabilized by inter-molecular C-Hâ¯O and C-Hâ¯N contacts, as well as by weak C-Hâ¯π inter-actions.
RESUMO
In the title compound, C(39)H(25)NO(2)·0.5C(6)H(14), the ß-lactam ring is nearly planar [maximum deviation of 0.012â (2)â Å from the mean plane] and makes dihedral angles of 36.41â (13), 88.87â (13) and 54.16â (12)°, respectively, with the naphthalene, xanthene and anthracene ring systems. The mol-ecular conformation is stabilized by intra-molecular C-Hâ¯O and C-Hâ¯N contacts. The complete solvent mol-ecule is generated by inversion. In the crystal structure, mol-ecules are linked to each other by C-Hâ¯π inter-actions.
RESUMO
In the title mol-ecule, C(36)H(25)NO(3), the ß-lactam ring is essentially planar, with a dihedral angle of 3.3â (2)° between the two separate three-atom N/C/C planes. The ß-lactam ring makes dihedral angles of 28.45â (14), 87.4â (1) and 51.8â (1)° with the mean planes of the benzene, xanthene and anthracene ring systems, respectively. In addition to a weak intra-molecular C-Hâ¯N hydrogen bond, the crystal structure is stabilized by two weak inter-molecular C-Hâ¯O hydrogen bonds.