title: Synthesis and structure-activity relationship studies of novel 3,9-substituted α-carboline derivatives with high cytotoxic activity against colorectal cancer cells.
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.
authors.affiliation: School of Pharmacy, China Medical University, Taichung, Taiwan.
authors.forename: Yi-Chien
authors.initials: YC
authors.lastname: Lin
authors.affiliation: The Ph.D. Program for Cancer Biology and Drug Discovery, China Medical University and Academia Sinica, Taichung, Taiwan.
authors.forename: Yi-Fong
authors.initials: YF
authors.lastname: Chen
authors.affiliation: School of Pharmacy, China Medical University, Taichung, Taiwan.
authors.forename: Li-Shin
authors.initials: LS
authors.lastname: Tseng
authors.affiliation: School of Pharmacy, China Medical University, Taichung, Taiwan.
authors.forename: Yueh-Hsuan
authors.initials: YH
authors.lastname: Lee
authors.affiliation: Natural Products Research Laboratories, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: Susan L
authors.initials: SL
authors.lastname: Morris-Natschke
authors.affiliation: 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.
authors.forename: Sheng-Chu
authors.initials: SC
authors.lastname: Kuo
authors.affiliation: 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.
authors.forename: Ning-Sun
authors.initials: NS
authors.lastname: Yang
authors.affiliation: 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.
authors.forename: Kuo-Hsiung
authors.initials: KH
authors.lastname: Lee
authors.affiliation: 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.
authors.forename: Li-Jiau
authors.initials: LJ
authors.lastname: Huang
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002243:Carbolines / Q000737:chemistry* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003106:Colon / Q000187:drug effects / Q000473:pathology; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000473:pathology; D004354:Drug Screening Assays, Antitumor; D018922:HL-60 Cells; D006801:Humans; D012007:Rectum / Q000187:drug effects / Q000473:pathology; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D002243:Carbolines; C055571:alpha-carboline
keywords: Antiproliferative activity; Apoptosis; Structure-activity relationships (SARs); YC-1 analogs; α-Carboline derivatives
references.citation: Bioorg Med Chem. 2004 Dec 15;12(24):6539-46
references.pmid: 15556770
references.citation: Mol Pharmacol. 1998 Jan;53(1):123-7
references.pmid: 9443939
references.citation: Cytometry. 1998 Jan 1;31(1):1-9
references.pmid: 9450519
references.citation: J Nat Prod. 1997 Jul;60(7):688-91
references.pmid: 9249972
references.citation: Blood. 1994 Dec 15;84(12):4226-33
references.pmid: 7527671
references.citation: J Immunol Methods. 1983 Dec 16;65(1-2):55-63
references.pmid: 6606682
references.citation: Arch Pharm (Weinheim). 2004 Aug;337(8):434-9
references.pmid: 15293262
references.citation: Mol Pharmacol. 2003 Dec;64(6):1419-27
references.pmid: 14645672
references.citation: J Med Chem. 2001 Oct 25;44(22):3746-9
references.pmid: 11606139
references.citation: Bioorg Med Chem. 1999 Nov;7(11):2457-64
references.pmid: 10632055
references.citation: Bioorg Med Chem Lett. 2015 Sep 15;25(18):3873-7
references.pmid: 26235951
references.citation: Eur J Med Chem. 2015 Jun 5;97:816-29
references.pmid: 25499235
references.citation: Eur J Med Chem. 2015 Jan 7;89:198-206
references.pmid: 25462240
references.citation: Eur J Med Chem. 2014 Nov 24;87:63-70
references.pmid: 25240096
references.citation: Br J Pharmacol. 2014 Sep;171(17):4010-25
references.pmid: 24697523
references.citation: Int J Oncol. 2013 Nov;43(5):1596-606
references.pmid: 23970288
references.citation: Bioorg Med Chem. 2013 Sep 1;21(17):5064-75
references.pmid: 23867385
references.citation: Eur J Med Chem. 2013 Aug;66:466-79
references.pmid: 23831809
references.citation: Oncol Rep. 2013 Apr;29(4):1501-9
references.pmid: 23443304
references.citation: Bioorg Med Chem. 2012 Aug 1;20(15):4820-9
references.pmid: 22748378
references.citation: Kaohsiung J Med Sci. 2010 Nov;26(11):593-602
references.pmid: 21126712
references.citation: Oncol Rep. 2010 Nov;24(5):1169-78
references.pmid: 20878107
references.citation: Bioorg Med Chem Lett. 2009 Jun 15;19(12):3225-8
references.pmid: 19435666
references.citation: Br J Pharmacol. 2008 Oct;155(4):505-13
references.pmid: 18641674
references.citation: Bioorg Med Chem. 2007 Feb 15;15(4):1732-40
references.pmid: 17189698
references.citation: Nat Rev Cancer. 2006 Oct;6(10):813-23
references.pmid: 16990858
references.citation: J Pharmacol Exp Ther. 2005 Jul;314(1):35-42
references.pmid: 15784655
references.citation: Anticancer Res. 2005 Jul-Aug;25(4):2857-68
references.pmid: 16080538
references.citation: Org Lett. 2006 Feb 2;8(3):415-8
references.pmid: 16435848