1. 3-Aroylindoles display antitumor activity in vitro and in vivo: Effects of N1-substituents on biological activity.
- Author
-
Lee HY, Lee JF, Kumar S, Wu YW, HuangFu WC, Lai MJ, Li YH, Huang HL, Kuo FC, Hsiao CJ, Cheng CC, Yang CR, and Liou JP
- Subjects
- Animals, Antineoplastic Agents chemistry, Antineoplastic Agents pharmacology, Cell Line, Tumor, Drug Design, HeLa Cells, Histone Deacetylase 6, Histone Deacetylase Inhibitors chemistry, Histone Deacetylase Inhibitors pharmacology, Histone Deacetylases metabolism, Humans, Hydroxamic Acids chemistry, Hydroxamic Acids pharmacology, Hydroxamic Acids therapeutic use, Indoles chemistry, Indoles pharmacology, Male, Mice, Nude, Prostate drug effects, Prostate metabolism, Prostate pathology, Prostatic Neoplasms metabolism, Prostatic Neoplasms pathology, Tubulin metabolism, Tubulin Modulators chemistry, Tubulin Modulators pharmacology, Antineoplastic Agents therapeutic use, Histone Deacetylase Inhibitors therapeutic use, Indoles therapeutic use, Prostatic Neoplasms drug therapy, Tubulin Modulators therapeutic use
- Abstract
A series of 3-aroylindole hydroxamic acids (10-17) were developed based on the concept of a structural combination of tubulin and histone deacetylase (HDAC) inhibitors. This was accomplished by introducing hydroxamic acid-containing moieties at the N1 position of the tubulin assembly inhibitor, compound 9 (SCB01A, BPR0L075, phase II trial). Most of synthetic compounds produced in this way displayed comparable HDAC inhibitory activity, and four (10, 12-14) of them also inhibit tubulin assembly. Notably, compound 12 possesses not only tubulin and HDAC inhibitory activity but also shows HDAC6 selectivity over other HDAC isoforms. In addition, it exhibits remarkable inhibitory activity against the growth cancer cells in vitro and in vivo (PC3 and RPMI-8226 cells). Notably, it suppresses the growth of multiple myeloma xenografts without leading to the death of teated animals like reference compound. In sum, this study provided potential compounds with safer profiles for cancer treatment., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)
- Published
- 2017
- Full Text
- View/download PDF