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1.
Bioorg Med Chem ; 69: 116911, 2022 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-35792402

RESUMO

A series of 10-alkoxy-Anthryl-isoxazole-pyrrole-doubletails (RO-AIMs) were synthesized using a crown ether assisted nucleophilic aromatic substitution followed by a modified Schotten-Baumann reaction. The novel RO-AIMs described here exhibit robust growth inhibition for the human SNB19 CNS glioblastoma cell line, and biphenyl analog 8c had activity in the nanomolar regime, which represents the most efficacious compound in the AIM series to date. Computational modeling for RO-AIMs binding in a ternary complex with c-myc quadruplex DNA and its helicase DHX36 is presented which represents our current working hypothesis.


Assuntos
Quadruplex G , Glioblastoma , Álcoois , Linhagem Celular , Linhagem Celular Tumoral , Glioblastoma/tratamento farmacológico , Humanos , Isoxazóis
2.
Bioorg Med Chem Lett ; 25(8): 1765-1770, 2015 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-25782743

RESUMO

Using the structure-activity relationship emerging from previous Letter, and guided by pharmacokinetic properties, new AIMs have been prepared with both improved efficacy against human glioblastoma cells and cell permeability as determined by fluorescent confocal microscopy. We present our first unambiguous evidence for telomeric G4-forming oligonucleotide anisotropy by NMR resulting from direct interaction with AIMs, which is consistent with both our G4 melting studies by CD, and our working hypothesis. Finally, we show that AIMs induce apoptosis in SNB-19 cells.


Assuntos
Amidas/química , Antineoplásicos/química , Amidas/metabolismo , Amidas/farmacologia , Antineoplásicos/metabolismo , Antineoplásicos/farmacologia , Apoptose , Sítios de Ligação , Linhagem Celular Tumoral , Dicroísmo Circular , Cristalografia por Raios X , Quadruplex G , Humanos , Simulação de Dinâmica Molecular , Conformação de Ácido Nucleico , Relação Estrutura-Atividade , Telômero/química
3.
Tetrahedron ; 68(50): 10360-10364, 2012 Dec 16.
Artigo em Inglês | MEDLINE | ID: mdl-23526841

RESUMO

A critical comparison of methods to prepare sterically hindered 3-aryl isoxazoles containing fused aromatic rings using the nitrile oxide cycloaddition (NOC) reveal that modification of the method of Bode, Hachisu, Matsuura, and Suzuki (BHMS), utilizing either triethylamine as base or sodium enolates of the diketone, ketoester, and ketoamide dipolarophiles, respectively, was the method of choice for this transformation.

4.
Tetrahedron Lett ; 52(43): 5656-5658, 2011 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-21966033

RESUMO

A procedure for benzylic Suzuki-Miyaura cross-coupling under microwave conditions has been developed. These conditions allowed for heterocyclic compounds to be coupled. Optimum conditions found were Pd(OAc)(2), JohnPhos as the catalyst and ligand, potassium carbonate as base, and DMF as the solvent. Using these conditions, a library of structurally diverse compounds was synthesized.

5.
Bioorg Med Chem Lett ; 19(15): 4067-9, 2009 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-19560922

RESUMO

Dimeric analogs of Anthracenyl Isoxazole Amides (AIMs) (the designation AIM is in honor of the memory of Professor Albert I. Meyers) were prepared and dimer 6 exhibited the highest efficacy to date for this class of anti-tumor compounds against the human glioma Central Nervous System cell line SNB-19.


Assuntos
Amidas/farmacologia , Antineoplásicos/síntese química , Neoplasias Encefálicas/tratamento farmacológico , Química Farmacêutica/métodos , Glioma/tratamento farmacológico , Amidas/síntese química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , DNA/química , Dimerização , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Concentração de Íons de Hidrogênio , Modelos Químicos , Conformação Molecular
6.
Bioorg Med Chem ; 17(4): 1671-80, 2009 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-19167892

RESUMO

The synthesis and in vitro anti-tumor 60 cell lines screen of a novel series of anthracenyl isoxazole amides (AIMs) (While not a strict acronym, the designation AIM is in honor of the memory of Professor Albert I. Meyers.) (22-33) are described. The molecules consist of an isoxazole that pre-organizes a planar aromatic moiety and a simple amide and/or lexitropsin-oligopeptide. The new conjugate molecules were prepared via doubly activated amidation modification of Weinreb's amide formation technique, using SmCl(3) as an activating agent which produces improved yields for sterically hindered 3-aryl-4-isoxazolecarboxylic esters. The results of the National Cancer Institute's (NCI) 60 cell line screening assay show a distinct structure activity relationship (SAR), wherein a trend of the highest activity for molecules with one N-methylpyrrole peptide. Evidence consistent with a mechanism of action via the interaction of these compounds with G-quadruplex (G4) DNA and a structural based rational for the observed selectivity of the AIMs for G4 over B-DNA is presented.


Assuntos
Antracenos/síntese química , Antracenos/farmacologia , Antineoplásicos/síntese química , Azóis/síntese química , Azóis/farmacologia , Netropsina/análogos & derivados , Antracenos/química , Antineoplásicos/química , Antineoplásicos/farmacologia , Azóis/química , Linhagem Celular Tumoral , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Espectroscopia de Ressonância Magnética , Netropsina/síntese química , Netropsina/química , Netropsina/farmacologia , Espectrometria de Massas por Ionização por Electrospray , Relação Estrutura-Atividade
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