Synthesis and Evaluation of Fuligocandin B Derivatives with Activity for Overcoming TRAIL Resistance

Abstract

The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) signaling pathway induces apoptosis in cancer cells but not in normal cells. Therefore, this pathway has attracted attention regarding possible clinical treatment of cancer. However, many cancer cells demonstrate TRAIL resistance. To overcome this problem, small molecules that sensitize cancer cells to TRAIL are desired. Heterocyclic derivatives of the natural product, fuligocandin B (2), with activity for overcoming TRAIL resistance were synthesized, and their activity was evaluated. Of the synthetic molecules, the quinoline derivative (10g) showed potent activity against TRAIL-resistant gastric adenocarcinoma cells. After a docking study of the target protein valosin-containing protein, 7'-amino fuligocandin B (10m) was designed and synthesized. Compound 10m also showed good activity for overcoming TRAIL resistance. 10m produced a 49.7% difference in viability with TRAIL at 30 µM compared to without TRAIL. This activity was better than that of fuligocandin B (2).

Screening for natural products that affect Wnt signaling activity

“…In our efforts to identify bioactive natural products [1], we recently examined screening programs to isolate compounds targeting biological pathways such as Wnt, Hedgehog, Notch [2], and TRAIL [3] from various natural resources, including microorganisms (Myxomycetes [4] and Actinomycetes [5]) and plants collected from South Asian countries [6, 7]. We also used a synthetic-compound library with natural product-based structures that was constructed by our group for screening studies [8–10]. Here, we describe our recent studies screening for natural products that affect the Wnt signaling pathway [11].…”