RESUMO
Commercial porcine intestinal mucosal heparan sulfate (HS) is a valuable material for research into its biological functions. As it is usually produced as a side-stream of pharmaceutical heparin manufacture, its chemical composition may vary from batch to batch. We analysed the composition and structure of nine batches of HS from the same manufacturer. Statistical analysis of the disaccharide compositions placed these batches in three categories: group A had high GlcNAc and GlcNS, and low GlcN typical of HS; group B had high GlcN and GlcNS, and low GlcNAc; group C had high di- and trisulfated, and low unsulfated and monosulfated disaccharide repeats. These batches could be placed in the same categories based on their 1H NMR spectra and molecular weights. Anticoagulant and growth factor binding activities of these HS batches did not fit within these same groups but were related to the proportions of more highly sulfated disaccharide repeats.
Assuntos
Anticoagulantes/química , Heparitina Sulfato/química , Mucosa Intestinal/química , Animais , Dissacarídeos/análise , Fator Xa/química , Peptídeos e Proteínas de Sinalização Intercelular/química , SuínosRESUMO
The fungal metabolite TAN-2483B has a 2,6-trans-relationship across the pyran ring of its furo[3,4-b]pyran-5-one core, which has thwarted previous attempts at its synthesis. We have now developed a chiral pool approach to this core and prepared side-chain analogues of TAN-2483B. The synthesis relies on ring expansion of a reactive furan ring-fused dibromocyclopropane and alkynylation of the resulting pyran. The furan ring is constructed by palladium-catalysed carbonylative lactonisation. Various side-chains are appended through Wittig-type chemistry. The prepared analogues showed micromolar activity towards cancer cell lines HL-60, 1A9 and MCF-7 and certain human disease-relevant kinases, including Bruton's tyrosine kinase (Btk).
Assuntos
Antineoplásicos/síntese química , Lactonas/química , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/síntese química , Piranos/química , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Lactonas/síntese química , Lactonas/farmacologia , Estrutura Molecular , Fosfotransferases/antagonistas & inibidores , Fosfotransferases/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Piranos/síntese química , Piranos/farmacologia , Relação Estrutura-AtividadeRESUMO
Peloruside A is a macrocyclic natural product from a New Zealand marine sponge Mycale hentscheli. It has attracted significant attention in the synthetic chemistry, cellular and structural biology communities due to its complex structure and potent anticancer activity. Several natural congeners have since been isolated and synthetic analogues have been prepared. This review describes in detail the published syntheses of peloruside analogues and discusses the structure-activity relationships available to date.