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The indolin-2-one fused-ring system and the 2,4-dimethylpyrrole unit represent key structural motifs in the anticancer drug sunitinib (Sutent®) and predecessor angiogenesis inhibitors that have undergone anticancer clinical trials (e.g. semaxanib, SU5416). In pursuit of novel anti-angiogenic scaffolds, we were interested in identifying whether the indolin-2-one group in these structures could be modified without losing activity. This paper describes novel condensation chemistry used to prepare a test series of (E)- and (Z)-alkenes related to SU5416 that retain the 2,4-dimethylpyrrole unit while incorporating ring-opened indolin-2-ones. Unique structural characteristics were identified in the compounds, such as intramolecular hydrogen bonds in the (Z)-alkenes, and several examples were shown to possess significant anti-angiogenic activity in a rat aorta in vitro model of angiogenesis. The work demonstrates that the indolin-2-one moiety is not an absolute requirement for angiogenesis inhibition in the sunitinib/SU5416 class.

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. Key words mangostin analog; chemical modification; anti-tuberculosis activity Tuberculosis (TB) remains a currently serious problem worldwide due to the rapid spread of TB strains resistant to all the major anti-tuberculosis drugs on the market, and the association of TB with the human immunodeficiency virus (HIV) leading to infection and death. 1) Nearly 2 million die from it and more than 9 million people per annum are infected.2)It is now generally accepted that new drugs to cure TB are urgently needed due to the recent increment of multidrugresistant mycobacteria. The drug discovery based on structure modification of natural products is a challenging strategy for new antitubercular drugs which are different from the drugs currently used. In this regard, the naturally occurring bioactive molecules constitute ideal starting material templates and natural-product like libraries synthesis in particular is of increasing interest. 3,4) Prenylated xanthones, secondary metabolites from higher plants, display a wide spectrum of biological profiles 5-7) such as antioxidant, 8) antiinflammatory, 9) hepatoprotective, 10) cancer preventive, 11) antimalarial 12) and antibacterial activities, 13) based on their diverse structures. α-, β-and γ-Mangostins (1-3), the major prenylated xanthones of Garcinia mangoatana L. 14) and some other Garcinia plants, 6) revealed interesting antimycobacterial potential against Mycobacterium tuberculosis at the respective minimal inhibitory concentrations (MICs) of 6.25, 6.25 and 50 µg/mL. 15) Our preliminary study on antimycobacterial xanthones of G. mangostana showed that the most active compounds were those oxygenated in the 1,3,6,7-positions and prenylated in the 2 and 8-positions and together with the 1-hydroxyl and 7-methoxyl groups on the xanthone nucleus. In addition, increase in hydrophilicity at the prenyl side chain in garcinone D (4) and mangostenol (5), structures of which relate with α-mangostin (1), decreased the activity with MICs of 25 and 100 µg/mL, respectively. 15) In order to investigate structural requirements for antituberculosis activity of mangostin, we were interested in exploiting the 1-, 3-and 6-positions in the hydroxyl moieties and the isopentenyl moiety of α-mangostin as an extende...

. (2016). Synthesis and preliminary evaluation of 5,7-dimethyl-2-aryl-3H-pyrrolizin-3-ones as angiogenesis inhibitors. Bioorganic and Medicinal Chemistry Letters, 26 (7), 1813-1816. Synthesis and preliminary evaluation of 5,7-dimethyl-2-aryl-3H-pyrrolizin-3-ones as angiogenesis inhibitors Abstract 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 nonindoline-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 nonindoline-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 10 μg/mL, confirming that 5,7-dimethyl-2-aryl-3H-pyrrolizin-3-ones represent a new class of angiogenesis inhibitors. Disciplines Medicine and Health Sciences Publication DetailsKirk, N. S., Bezos, A., Willis, A. C., Sudta, P., Suksamrarn, S., Parish, C. R., Ranson, M. & Kelso, M. J. (2016). Synthesis and preliminary evaluation of 5,7-dimethyl-2-aryl-3H-pyrrolizin-3-ones as angiogenesis inhibitors.