RESUMO
Sunitinib (Sutent®) is a receptor tyrosine kinase (RTK) and angiogenesis inhibitor approved for the treatment of renal cell carcinomas, gastrointestinal stromal tumours and pancreatic neuroendocrine tumours. A key structural motif retained throughout medicinal chemistry efforts during sunitinib's development was the indoline-2-one group. In the search for new anti-angiogenic scaffolds, we previously reported that non-indoline-2-one-based derivatives of semaxanib (SU5416, a structurally simpler sunitinib predecessor that underwent Phase III trials) are active as angiogenesis inhibitors, indicating that the group is not essential for activity. This Letter describes the synthesis and structure-activity relationships of another class of non-indoline-2-one angiogenesis inhibitors related to sunitinib/semaxanib; the 5,7-dimethyl-2-aryl-3H-pyrrolizin-3-ones. A focussed library of 19 analogues was prepared using a simple novel process, wherein commercially available substituted arylacetic acids activated with an amide coupling reagent (HBTU) were reacted with the potassium salt of 3,5-dimethyl-1H-pyrrole-2-carbaldehyde in one-pot. Screening of the library using a cell-based endothelial tube formation assay identified 6 compounds with anti-angiogenesis activity. Two of the compounds were advanced to the more physiologically relevant rat aortic ring assay, where they showed similar inhibitory effects to semaxanib at 10µg/mL, confirming that 5,7-dimethyl-2-aryl-3H-pyrrolizin-3-ones represent a new class of angiogenesis inhibitors.
Assuntos
Inibidores da Angiogênese/química , Inibidores da Angiogênese/farmacologia , Indóis/química , Indóis/farmacologia , Pirróis/química , Pirróis/farmacologia , Inibidores da Angiogênese/síntese química , Animais , Aorta/efeitos dos fármacos , Aorta/fisiologia , Células Endoteliais da Veia Umbilical Humana , Humanos , Indóis/síntese química , Metilação , Modelos Moleculares , Neovascularização Fisiológica/efeitos dos fármacos , Pirróis/síntese química , Ratos , SunitinibeRESUMO
A new series of mangostin analogs of natural α-mangostin from mangosteen was prepared and their antimycobacterial activity was evaluated in vitro against Mycobacterium tuberculosis H(37)Ra. The results showed that the monoalkyl tetrahydro α-mangostin analogs displayed increased antimycobacterial activity as compared with the lead natural xanthone, α-mangostin. Among the tested compounds, 6-methoxytetrahydro α-mangostin (16) exhibited the most potent antimycobacterial activity with minimum inhibitory concentration (MIC) of 0.78 µg/mL. The activity of the monoalkylated and monoacylated tetrahydro α-mangostins decreases as the length of carbon chain increases. The methyl ether analog was also active against the multidrug-resistant (MDR) strains with pronounced MICs of 0.78-1.56 µg/mL.