TY - JOUR
T1 - Synthesis of new tricyclic thiolactams as potent antitumor agent for pancreatic cancer
AU - Okada, Takuya
AU - Minehira, Daisuke
AU - Takada, Minetatsu
AU - Urata, Hirokazu
AU - Kato, Atsushi
AU - Adachi, Isao
AU - Kurashima, Yukiko
AU - Kaji, Satoshi
AU - Ogura, Tsutomu
AU - Chiba, Shigeki
AU - Esumi, Hiroyasu
AU - Toyooka, Naoki
N1 - Publisher Copyright:
©2016 Elsevier Ltd. All rights reserved.
PY - 2016/6/1
Y1 - 2016/6/1
N2 - We synthesized the novel tricyclic thiolactams 2a-d, 3d-k, having a benzyl or substituted benzyl substituent on the nitrogen of indole subunit, and their preferential cytotoxicity under both nutrient-deprived medium (NDM) and Dulbecco's modified Eagle's medium (DMEM) was evaluated against a human pancreatic cancer cell line PANC-1. Among the tested compounds, the 4′-hydroxy derivative 3d showed the most potent cytotoxicity in NDM (PC50 1.68 μM) although the moderate preferential cytotoxicity (PC50 1.68 μM in NDM vs PC50 20 μM in DMEM). The 3′-hydroxy derivative 3e exhibited the most preferential cytotoxicity (PC50 1.96 μM in NDM vs less than 50% inhibition at 30 μM in DMEM). The benzyl 2a and halogenated benzyl derivatives 2b,c showed no cytotoxicity in NDM. In addition, the indole (10, PC50 173.7 μM), lactone (11, PC50 131.7 μM), and lactam (12, PC50 44.8 μM) derivatives showed week or moderate cytotoxicity in NDM. These results indicated that the hydroxy group on the benzyl substituent and tricyclic thiolactam ring were essential for the cytotoxicity in NDM against PANC-1 cell line. Moreover, 3′-hydroxy derivative 3e compound exhibited antitumor activity against the pancreatic ductal adenocarcinoma (PDAC) xenograft model in vivo.
AB - We synthesized the novel tricyclic thiolactams 2a-d, 3d-k, having a benzyl or substituted benzyl substituent on the nitrogen of indole subunit, and their preferential cytotoxicity under both nutrient-deprived medium (NDM) and Dulbecco's modified Eagle's medium (DMEM) was evaluated against a human pancreatic cancer cell line PANC-1. Among the tested compounds, the 4′-hydroxy derivative 3d showed the most potent cytotoxicity in NDM (PC50 1.68 μM) although the moderate preferential cytotoxicity (PC50 1.68 μM in NDM vs PC50 20 μM in DMEM). The 3′-hydroxy derivative 3e exhibited the most preferential cytotoxicity (PC50 1.96 μM in NDM vs less than 50% inhibition at 30 μM in DMEM). The benzyl 2a and halogenated benzyl derivatives 2b,c showed no cytotoxicity in NDM. In addition, the indole (10, PC50 173.7 μM), lactone (11, PC50 131.7 μM), and lactam (12, PC50 44.8 μM) derivatives showed week or moderate cytotoxicity in NDM. These results indicated that the hydroxy group on the benzyl substituent and tricyclic thiolactam ring were essential for the cytotoxicity in NDM against PANC-1 cell line. Moreover, 3′-hydroxy derivative 3e compound exhibited antitumor activity against the pancreatic ductal adenocarcinoma (PDAC) xenograft model in vivo.
KW - NDM
KW - Pancreatic cancer
KW - Tricyclic thiolactams
UR - http://www.scopus.com/inward/record.url?scp=84964663641&partnerID=8YFLogxK
U2 - 10.1016/j.bmcl.2016.04.035
DO - 10.1016/j.bmcl.2016.04.035
M3 - 学術論文
C2 - 27117432
AN - SCOPUS:84964663641
SN - 0960-894X
VL - 26
SP - 2577
EP - 2579
JO - Bioorganic and Medicinal Chemistry Letters
JF - Bioorganic and Medicinal Chemistry Letters
IS - 11
ER -
