Synthesis of new tricyclic thiolactams as potent antitumor agent for pancreatic cancer. Issue 11 (1st June 2016)

• Record Type: Journal Article
• Authors: Okada, Takuya; Minehira, Daisuke; Takada, Minetatsu; Urata, Hirokazu; Kato, Atsushi; Adachi, Isao; Kurashima, Yukiko; Kaji, Satoshi; Ogura, Tsutomu; Chiba, Shigeki; Esumi, Hiroyasu; Toyooka, Naoki
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 26:Issue 11(2016)
• Page Start: 2577
• Page End: 2579
• Publication Date: 2016-06-01
• Subjects: Tricyclic thiolactams -- Pancreatic cancer -- NDM; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2016.04.035
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: We synthesized the novel tricyclic thiolactams2a –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 derivative3d 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 derivative3e exhibited the most preferential cytotoxicity (PC50 1.96 μM in NDM vs less than 50% inhibition at 30 μM in DMEM). The benzyl2a and halogenated benzyl derivatives2b, 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 derivative3e compound exhibited antitumor activity against the pancreatic ductal adenocarcinoma (PDAC) xenograft model in vivo.