Synthesis and preliminary evaluation of 5,7-dimethyl-2-aryl-3H-pyrrolizin-3-ones as angiogenesis inhibitors

Abstract

. (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.

Unexpected synthesis of 3-imino-2-(pyrrol-2-yl) isatogen derivatives affords facile access to a 2-pyrrolyl isatogen

“…[10] We also recently reported a divergent one-pot synthesis of substituted 5,7-dimethyl-2-aryl-3H-pyrrolizin-3-ones and showed that these too, constitute a new class of angiogenesis inhibitors. [11] Acids (E)-5 and (Z)-5 were obtained for the current work in identical yields (84%) from the reported allyl esters (Z)-7 and (E)-7 [10] via Pd-catalysed deallylation in the presence of morpholine (Scheme 1(a)). Crystals of (Z)-5 suitable for X-ray analysis were obtained from Et 2 O/pet spirit and its structure was determined.…”

Synthesis and Biological Evaluation of Indole‐2‐carbohydrazide Derivatives as Anticancer Agents with Anti‐angiogenic and Antiproliferative Activities

“…However, Kelso et al. demonstrated that the indolin‐2‐one moiety is not an absolute requirement for angiogenesis inhibition in the sunitinib/SU5416 class . For example, ring‐opened indole‐2‐one derivatives (Figure ) have exhibited effective angiogenesis inhibition.…”

“…[17][18][19][20][21][22] However,K elso et al demonstrated that the indolin-2-one moiety is not an absolute requirement forangiogenesis inhibition in the sunitinib/SU5416 class. [17,23] For example, ring-opened indole-2-one derivatives (Figure 1) have exhibited effective angiogenesis inhibition. Recently,i ndole derivatives bearing ac arbohydrazide moiety have been found to exhibit potent anticancer, [24,25] antibacterial, [26,27] anti-inflammatory, [28] and antitubercular [29] effects.…”