2. Academic Validation
  3. Synthesis and structure-activity relationship studies of novel 3,9-substituted α-carboline derivatives with high cytotoxic activity against colorectal cancer cells

Synthesis and structure-activity relationship studies of novel 3,9-substituted α-carboline derivatives with high cytotoxic activity against colorectal cancer cells

  • Eur J Med Chem. 2016 Mar 3:110:98-114. doi: 10.1016/j.ejmech.2016.01.004.
Yi-Chien Lin 1,  Yi-Fong Chen 2,  Li-Shin Tseng 1,  Yueh-Hsuan Lee 1,  Susan L Morris-Natschke 3,  Sheng-Chu Kuo 4,  Ning-Sun Yang 5,  Kuo-Hsiung Lee 6,  Li-Jiau Huang 7
Affiliations

Affiliations

  • 1 School of Pharmacy, China Medical University, Taichung, Taiwan.
  • 2 The Ph.D. Program for Cancer Biology and Drug Discovery, China Medical University and Academia Sinica, Taichung, Taiwan.
  • 3 Natural Products Research Laboratories, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC, USA.
  • 4 School of Pharmacy, China Medical University, Taichung, Taiwan; The Ph.D. Program for Cancer Biology and Drug Discovery, China Medical University and Academia Sinica, Taichung, Taiwan.
  • 5 The Ph.D. Program for Cancer Biology and Drug Discovery, China Medical University and Academia Sinica, Taichung, Taiwan; Agricultural Biotechnology Research Center, Academia Sinica, Taipei, Taiwan.
  • 6 Natural Products Research Laboratories, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC, USA; Chinese Medicine Research and Development Center, China Medical University and Hospital, Taichung, Taiwan. Electronic address: khlee@unc.edu.
  • 7 School of Pharmacy, China Medical University, Taichung, Taiwan; The Ph.D. Program for Cancer Biology and Drug Discovery, China Medical University and Academia Sinica, Taichung, Taiwan. Electronic address: ljhuang@mail.cmu.edu.tw.
PMID: 26820553 DOI: 10.1016/j.ejmech.2016.01.004
Abstract

In our continued focus on 1-benzyl-3-(5-hydroxymethyl-2-furyl)indazole (YC-1) analogs, we synthesized a novel series of 3,9-substituted α-carboline derivatives and evaluated the new compounds for antiproliferactive effects. Structure activity relationships revealed that a COOCH3 or CH2OH group at position-3 and substituted benzyl group at position-9 of the α-carboline nucleus were crucial for maximal activity. The most active compound, 11, showed high levels of cytotoxicity against HL-60, COLO 205, Hep 3B, and H460 cells with IC50 values of 0.3, 0.49, 0.7, and 0.8 μM, respectively. The effect of compound 11 on the cell cycle distribution demonstrated G2/M arrest in COLO 205 cells. Furthermore, mechanistic studies indicated that compound 11 induced Apoptosis by activating death receptor and mitochondria dependent apoptotic signaling pathways in COLO 205 cells. The new 3,9-substituted α-carboline derivatives exhibited excellent anti-proliferative activities, and compound 11 can be used as a promising pro-apoptotic agent for future development of new antitumor agents.

Keywords

Antiproliferative activity; Apoptosis; Structure-activity relationships (SARs); YC-1 analogs; α-Carboline derivatives.

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