TY - JOUR
T1 - Synthesis and evaluation of fuligocandin b derivatives with activity for overcoming TRAIL resistance
AU - Arai, Midori A.
AU - Masuda, Ayaka
AU - Suganami, Akiko
AU - Tamura, Yutaka
AU - Ishibashi, Masami
N1 - Funding Information:
Acknowledgments This study was supported by KAKENHI Grant Numbers 18H02582, 17H03992 and 15H04650 from Japan Society for the Promotion of Science, Takeda Science Foundation, Astellas Foundation for Research on Metabolic Disorders, the Naito Foundation, Strategic Priority Research Promotion Program, Chiba University, “Phytochemical Plant Molecular Sciences,” JSPS A3 Foresight Program, and a Workshop on Chirality at Chiba University (WCCU). This work was inspired by the international and interdisciplinary environment of the JSPS Core-to-Core Program “Asian Chemical Biology Initiative.”
Publisher Copyright:
© 2018 The Pharmaceutical Society of Japan.
PY - 2018
Y1 - 2018
N2 - 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 30µM compared to without TRAIL. This activity was better than that of fuligocandin B (2).
AB - 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 30µM compared to without TRAIL. This activity was better than that of fuligocandin B (2).
KW - Cancer
KW - Cytotoxicity
KW - Inhibitor
KW - Natural product
KW - Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)
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U2 - 10.1248/cpb.c18-00308
DO - 10.1248/cpb.c18-00308
M3 - Article
C2 - 30068801
AN - SCOPUS:85054930258
SN - 0009-2363
VL - 66
SP - 810
EP - 817
JO - Chemical and Pharmaceutical Bulletin
JF - Chemical and Pharmaceutical Bulletin
IS - 8
ER -
