RESUMO
Accelerated SuFEx Click Chemistry (ASCC) is a powerful method for coupling aryl and alkyl alcohols with SuFEx-compatible functional groups. With its hallmark favorable kinetics and exceptional product yields, ASCC streamlines the synthetic workflow, simplifies the purification process, and is ideally suited for discovering functional molecules. We showcase the versatility and practicality of the ASCC reaction as a tool for the late-stage derivatization of bioactive molecules and in the array synthesis of sulfonate-linked, high-potency, microtubule targeting agents (MTAs) that exhibit nanomolar anticancer activity against multidrug-resistant cancer cell lines. These findings underscore ASCC's promise as a robust platform for drug discovery.
RESUMO
hLDH-5 has emerged as a promising target for anti-glycolytic cancer chemotherapy. Here we report a first generation of bifunctional inhibitors, which show promising activity against hLDH-5.
Assuntos
Alcinos/farmacologia , L-Lactato Desidrogenase/antagonistas & inibidores , NAD/farmacologia , Ácido Oxâmico/farmacologia , Triazóis/farmacologia , Alcinos/síntese química , Alcinos/química , Domínio Catalítico/efeitos dos fármacos , Química Click , Cristalografia por Raios X , Glicólise , Humanos , Isoenzimas/antagonistas & inibidores , Isoenzimas/metabolismo , L-Lactato Desidrogenase/metabolismo , Lactato Desidrogenase 5 , Ligantes , Modelos Moleculares , Estrutura Molecular , NAD/síntese química , NAD/química , Ácido Oxâmico/síntese química , Ácido Oxâmico/química , Estereoisomerismo , Relação Estrutura-Atividade , Triazóis/síntese química , Triazóis/químicaRESUMO
The ability of two structurally diverse telomeric G-quadruplex-binding compounds to synergise the action of cis-platin has been investigated in two cancer cell lines. One compound is a trisubstituted acridine compound AS1410, a close analogue of BRACO-19, and the other is a non-polycyclic compound synthesised using click chemistry and containing two triazole rings. Both compounds produce growth arrest at sub-cytotoxic concentrations in the two cell lines (MCF7 and A549), with behaviour consistent with telomere targeting mechanisms. Synergistic behaviour was observed in both cell lines with both compounds in combination with cis-platin, but only when the ratio of AS1410:cis-platin is >1. In vivo tumour xenograft studies with the A549 lung cancer model and the trisubstituted acridine compound AS1410 showed only a modest anti-tumour effect when administered alone, but produced rapid and highly significant decreases in tumour volume when administered in combination with cis-platin.
Assuntos
Antineoplásicos/administração & dosagem , Cisplatino/administração & dosagem , Quadruplex G , Inibidores do Crescimento/administração & dosagem , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Animais , Antineoplásicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Linhagem Celular , Linhagem Celular Tumoral , Cisplatino/farmacologia , Sinergismo Farmacológico , Feminino , Inibidores do Crescimento/farmacologia , Humanos , Camundongos , Camundongos Nus , Fatores de Tempo , Ensaios Antitumorais Modelo de Xenoenxerto/métodosRESUMO
Maintenance of telomeres--specialized complexes that protect the ends of chromosomes, is undertaken by the enzyme complex telomerase, which is a key factor that is activated in more than 80% of cancer cells, but is absent in most normal cells. Targeting telomere maintenance mechanisms could potentially halt tumour growth across a broad spectrum of cancer types, with little cytotoxic effect outside cancer cells. Here, we describe in detail a new class of G-quadruplex binding ligands synthesized using a click chemistry approach. These ligands comprise a 1,3-di(1,2,3-triazol-4-yl)benzene pharmacophore, and display high levels of selectivity for interaction with G-quadruplex DNA vs. duplex DNA. The ability of these ligands to inhibit the enzymatic activity of telomerase correlates with their ability to stabilize quadruplex DNA, and with estimates of affinity calculated by molecular modeling.