title: Synthesis and evaluation of 1,7-diheteroarylhepta-1,4,6-trien-3-ones as curcumin-based anticancer agents.
abstract: Thirty (1E,4E,6E)-1,7-diaryl-1,4,6-heptatrien-3-ones, featuring a central linear trienone linker and two identical nitrogen-containing heteroaromatic rings, were designed and synthesized as curcumin-based anticancer agents on the basis of their structural similarity to the enol-tautomer of curcumin, in addition to taking advantage of the possibly enhanced pharmacokinetic profiles contributed by the basic nitrogen-containing heteroaromatic rings. Their cytotoxicity and antiproliferative activity were evaluated towards both androgen-dependent and androgen-independent prostate cancer cell lines, as well as HeLa human cervical cancer cells. Among them, the ten most potent analogues are 5- to 36-fold more potent than curcumin in inhibiting cancer cell proliferation. The acquired structure-activity relationship data indicate (i) that (1E,4E,6E)-1,7-diaryl-1,4,6-heptatrien-3-ones represent a potential scaffold for development of curcumin-based agents with substantially improved cytotoxicity and anti-proliferative effect; and (ii) 1-alkyl-1H-imidazol-2-yl and 1-alkyl-1H-benzo[d]imidazole-2-yl serve as optimal heteroaromatic rings for increased in vitro potency of this scaffold. Two of most potent compounds displayed no apparent cytotoxicity toward MCF-10A normal mammary epithelial cells at 1 μM concentration. Treatment of PC-3 prostate cancer cells with the most potent compound led to appreciable cell cycle arrest at a G1/G0 phase and cell apoptosis induction.
authors.affiliation: Department of Chemistry, California State University, Fresno, 2555 E. San Ramon, M/S SB70, Fresno, CA 93740, USA.
authors.forename: Rubing
authors.initials: R
authors.lastname: Wang
authors.affiliation: Department of Chemistry, California State University, Fresno, 2555 E. San Ramon, M/S SB70, Fresno, CA 93740, USA.
authors.forename: Xiaojie
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Chemistry, California State University, Fresno, 2555 E. San Ramon, M/S SB70, Fresno, CA 93740, USA.
authors.forename: Chengsheng
authors.initials: C
authors.lastname: Chen
authors.affiliation: Department of Chemistry, California State University, Fresno, 2555 E. San Ramon, M/S SB70, Fresno, CA 93740, USA.
authors.forename: Guanglin
authors.initials: G
authors.lastname: Chen
authors.affiliation: RCMI Cancer Research Center, Xavier University of Louisiana, 1 Drexel Drive, New Orleans, LA 70125, USA.
authors.forename: Qiu
authors.initials: Q
authors.lastname: Zhong
authors.affiliation: RCMI Cancer Research Center, Xavier University of Louisiana, 1 Drexel Drive, New Orleans, LA 70125, USA.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: RCMI Cancer Research Center, Xavier University of Louisiana, 1 Drexel Drive, New Orleans, LA 70125, USA.
authors.forename: Shilong
authors.initials: S
authors.lastname: Zheng
authors.affiliation: RCMI Cancer Research Center, Xavier University of Louisiana, 1 Drexel Drive, New Orleans, LA 70125, USA; Department of Chemistry, Xavier University of Louisiana, 1 Drexel Drive, New Orleans, LA 70125, USA.
authors.forename: Guangdi
authors.initials: G
authors.lastname: Wang
authors.affiliation: Department of Chemistry, California State University, Fresno, 2555 E. San Ramon, M/S SB70, Fresno, CA 93740, USA. Electronic address: qchen@csufresno.edu.
authors.forename: Qiao-Hong
authors.initials: QH
authors.lastname: Chen
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D003474:Curcumin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology*; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006367:HeLa Cells; D006801:Humans; D008297:Male; D009369:Neoplasms / Q000188:drug therapy; D011471:Prostatic Neoplasms / Q000188:drug therapy; D013329:Structure-Activity Relationship; D014266:Trientine / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000494:pharmacology; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy
chemical_list: D000970:Antineoplastic Agents; D003474:Curcumin; D014266:Trientine
keywords: 1,7-Diaryl-1,4,6-heptatrien-3-one; Anti-proliferative activity; Curcumin analogue; Cytotoxicity
references.citation: Biochem Pharmacol. 2008 Feb 15;75(4):787-809
references.pmid: 17900536
references.citation: Molecules. 2011;16(2):1888-900
references.pmid: 21343891
references.citation: J Nat Prod. 2002 Sep;65(9):1227-31
references.pmid: 12350137
references.citation: Cell Cycle. 2007 Dec 1;6(23):2953-61
references.pmid: 18156803
references.citation: Anticancer Agents Med Chem. 2015;15(2):138-56
references.pmid: 25594891
references.citation: Cancer Lett. 1996 Oct 1;107(1):109-15
references.pmid: 8913274
references.citation: J Org Chem. 2009 Sep 18;74(18):6973-9
references.pmid: 19705839
references.citation: Life Sci. 2004 Jan 9;74(8):969-85
references.pmid: 14672754
references.citation: Genes Nutr. 2010 Mar;5(1):61-74
references.pmid: 19806380
references.citation: Biochem Pharmacol. 2008 Dec 1;76(11):1590-611
references.pmid: 18775680
references.citation: Nutr Cancer. 2010;62(3):379-89
references.pmid: 20358476
references.citation: J Med Chem. 2011 Oct 27;54(20):7030-54
references.pmid: 21866910
references.citation: Br J Cancer. 2004 Mar 8;90(5):1011-5
references.pmid: 14997198
references.citation: Int J Cancer. 1978 Mar 15;21(3):274-81
references.pmid: 631930
references.citation: J Nat Prod. 2007 Feb;70(2):143-6
references.pmid: 17315954
references.citation: Eur J Med Chem. 2014 Mar 21;75:123-31
references.pmid: 24531225
references.citation: Invest Urol. 1979 Jul;17(1):16-23
references.pmid: 447482
references.citation: Prostate Cancer Prostatic Dis. 2000 Aug;3(2):84-93
references.pmid: 12497104
references.citation: Br J Pharmacol. 1998 Jul;124(6):1029-40
references.pmid: 9720770
references.citation: Planta Med. 2001 Aug;67(6):550-2
references.pmid: 11509978
references.citation: Bioorg Med Chem. 2010 Sep 15;18(18):6701-7
references.pmid: 20728364
references.citation: Anticancer Res. 2003 Jan-Feb;23(1A):363-98
references.pmid: 12680238
references.citation: Nat Prod Rep. 2011 Nov;28(12):1937-55
references.pmid: 21979811
references.citation: Cancer Res. 1983 Apr;43(4):1809-18
references.pmid: 6831420
references.citation: J Biol Chem. 2005 May 20;280(20):20059-68
references.pmid: 15738001
references.citation: Bioorg Med Chem Lett. 2014 Jul 1;24(13):2839-44
references.pmid: 24857542
references.citation: J Med Chem. 2015 Jun 11;58(11):4713-26
references.pmid: 25961334
references.citation: Cancer Lett. 1985 Nov;29(2):197-202
references.pmid: 4075289
references.citation: Org Lett. 2012 Dec 7;14(23):6104-7
references.pmid: 23157440