Design and Synthesis of Biaryl and Biphenylamino Sulfonamides as Novel Anticancer Agents

Project: A - Government Institutionb - Ministry of Science and Technology

Project Details

Description

Based on our earlier works and literatures, both benzenesulfonamide moiety and biaryl moiety have been recognized as a crucial structure for anticancer activity of antimitotic agents. In addition, we have published 「N-sulfonyl-aminobiaryls as antitubulin agents and inhibitors of signal transducers and activators of transcription 3 (STAT3) signaling.」 on J. Med. Chem. 2015, 58, 6549-6558. We synthesized a serious of N-sulfonyl-aminobiaryl compounds derived from small-molecule antimitotic agent ABT-751 (clinical trial phase II), and lead compound 4 was as a novel anticancer agent. Lead 4 showed the antiproliferative activity against four human cancer cell lines, pancreatic carcinoma AsPC-1, lung carcinoma A549, hepatocellular carcinoma Hep3B, and prostatic carcinoma PC-3 with IC50 values of 20, 100, 30, and 80 nM, respectively. Besides, it inhibited not only tubulin polymerization but also STAT3 phosphorylation. Therefore, in this proposal, we use N-sulfonyl-aminobiaryl as core structure and precede further structure modification to design and synthesize novel anticancer agents. This proposal is planned to achieve two aims, aim A and B. Aim A: to execute chemical structure modification of biphenyl sulfonamides and study on structure-activity relationship; moreover, to maintain both tubulin and STAT3 inhibition. Aim B: to design and synthesis compounds with dual inhibition of tubulin and HDAC activity by structure modification of various linkages between biaryl groups with sulfonamide and hydroxamic acid or benzamide moiety. In our preliminary results, for antiproliferative activity against human lung carcinoma A549 and colon carcinoma HCT116, biphenylamino-sulfonamide hydroxamate 5 and phenyl-pyridylethane-sulfonamide benzamide 9 exhibited IC50 values of 1.46, 1.37 μM and 0.19, 0.13 μM. Hydroxamate 7 showed the apparent inhibition on HDAC6 (IC50=37.6 nM). Accordingly, the series of biaryl sulfonamide hydroxamates and benzamides both have potential for development of anticancer agents.
StatusFinished
Effective start/end date8/1/167/31/17

Keywords

  • anticancer
  • tubulin
  • STAT3
  • HDAC