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1.
ACS Med Chem Lett ; 14(7): 943-948, 2023 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-37465305

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.

2.
Bioorg Med Chem Lett ; 90: 129345, 2023 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-37217023

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 âˆ¼ 2.2 after 60 min.


Assuntos
Neoplasias , Humanos , Tomografia por Emissão de Pósitrons , Carbolinas , Compostos Radiofarmacêuticos/farmacologia , Radioisótopos de Flúor/química
3.
Bioorg Med Chem ; 23(22): 7313-23, 2015 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-26526744

RESUMO

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/metabolismo
4.
Acta Crystallogr E Crystallogr Commun ; 71(Pt 2): o113-4, 2015 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-25878858

RESUMO

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 0.669 (10):0.331 (10) ratio. The dihedral angles between the aromatic rings are 32.30 (13)° in mol-ecule I, 2.24 (14)° in II, 41.61 (13)° in III, 5.0 (5)° in IV (major component) and 10.2 (3)° in IV (minor component). In the crystal, mol-ecules are linked into layers lying parallel to (024) by C-H⋯O and O-H⋯O inter-actions. The layers inter-act by C-H⋯π and weak aromatic π-π stacking inter-actions [centroid-centroid distances = 3.8476 (16), 3.725 (3) and 3.733 (5) Å].

5.
Eur J Med Chem ; 87: 364-71, 2014 Nov 24.
Artigo em Inglês | MEDLINE | ID: mdl-25282260

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 química
6.
Molecules ; 15(1): 515-31, 2010 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-20110906

RESUMO

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/química
7.
Acta Crystallogr Sect E Struct Rep Online ; 65(Pt 10): o2522-3, 2009 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-21577969

RESUMO

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 = 0.003 (3) Å] and makes dihedral angles of 87.07 (15), 59.80 (16) and 20.81 (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-H⋯O and C-H⋯N hydrogen bonds. The crystal structure features weak C-H⋯π inter-actions.

8.
Acta Crystallogr Sect E Struct Rep Online ; 65(Pt 3): o501-2, 2009 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-21582166

RESUMO

The ß-lactam ring of the title compound, C(35)H(23)NO(2), is nearly planar with a maximum deviation of 0.003 (3) Šfrom the mean plane. It makes dihedral angles of 17.4 (2), 85.22 (17) and 65.39 (16)°, respectively, with the phenyl, xanthene and anthracene ring systems. In the crystal structure, there are intra-molecular C-H⋯O and C-H⋯N contacts and mol-ecules are also linked by C-H⋯π inter-actions.

9.
Acta Crystallogr Sect E Struct Rep Online ; 65(Pt 3): o626-7, 2009 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-21582278

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 31.5 (2)°. Its ß-lactam ring is essentially planar, with a maximum deviation of -0.021 (1) Å. The ß-lactam ring makes dihedral angles of 18.815 (9), 83.33 (7) and 53.62 (8)° with the mean planes of the benzene, xanthene and anthracene ring systems, respectively. The structure is stabilized by C-H⋯π, C-H⋯N and C-H⋯O inter-actions.

10.
Acta Crystallogr Sect E Struct Rep Online ; 65(Pt 7): o1623-4, 2009 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-21582891

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 0.001 (2) and 0.017 (2) Šin the two mol-ecules. The crystal structure is stabilized by inter-molecular C-H⋯O and C-H⋯N contacts, as well as by weak C-H⋯π inter-actions.

11.
Acta Crystallogr Sect E Struct Rep Online ; 64(Pt 5): o902-3, 2008 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-21202385

RESUMO

In the title mol-ecule, C(36)H(25)NO(3), the ß-lactam ring is essentially planar, with a dihedral angle of 3.3 (2)° between the two separate three-atom N/C/C planes. The ß-lactam ring makes dihedral angles of 28.45 (14), 87.4 (1) and 51.8 (1)° with the mean planes of the benzene, xanthene and anthracene ring systems, respectively. In addition to a weak intra-molecular C-H⋯N hydrogen bond, the crystal structure is stabilized by two weak inter-molecular C-H⋯O hydrogen bonds.

12.
Acta Crystallogr Sect E Struct Rep Online ; 64(Pt 12): o2466-7, 2008 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-21581434

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 0.012 (2) Šfrom the mean plane] and makes dihedral angles of 36.41 (13), 88.87 (13) and 54.16 (12)°, respectively, with the naphthalene, xanthene and anthracene ring systems. The mol-ecular conformation is stabilized by intra-molecular C-H⋯O and C-H⋯N contacts. The complete solvent mol-ecule is generated by inversion. In the crystal structure, mol-ecules are linked to each other by C-H⋯π inter-actions.

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