title: Design, synthesis and in vitro cell-based evaluation of the anti-cancer activities of hispolon analogs.
abstract: Phytochemicals play an important role in cancer therapy. Hispolon and 26 of its analogs (9 known and 17 new) were synthesized and evaluated for their antiproliferative activities in a panel of six independent human cancer cell lines using the in vitro cell-based MTT assay. Among the hispolon analogs tested, compound VA-2, the most potent overall, produced its most significant effect in the colon cancer cell lines HCT-116 (IC₅₀ 1.4 ± 1.3 μM) and S1 (IC₅₀ 1.8 ± 0.9 μM) compared to its activity in the normal HEK293/pcDNA3.1 cell line (IC₅₀ 15.8±3.7 μM; p<0.01 for each comparison). Based on our results, VA-2 was about 9- to 11-times more potent in colon cancer cells and 2- to 3-times more potent in prostate cancer cells compared to HEK293/pcDNA3.1 cells. Morphological analysis of VA-2 showed significant reduction of cell number, while the cells' sizes were also markedly increased and were obvious at 68 h of treatment with 1 μM in HCT-116 (colon) and PC-3 (prostate) cancer cells. A known analog, compound VA-4, prepared by simple modifications on the aromatic functional groups of hispolon, inhibited prostate and colon cancer cell lines with IC₅₀ values <10 μM. In addition, hispolon isoxazole and pyrazole analogs, VA-7 and VA-15 (known), respectively, have shown significant activity with the mean ICv values in the range 3.3-10.7 μM in all the cancer cell lines tested. Activity varied among the analogs in which aromatic functional groups and β-diketone functional groups are modified. But the activity of analogs VA-16 to VA-27 was completely lost when the side chain double-bond was hydrogenated indicating the crucial role of this functionality for anticancer activity. Furthermore, many of the compounds synthesized were not substrates for the ABCB1-transporter, the most common cause of multidrug resistance in anti-cancer drugs, suggesting they may be more effective anticancer agents.
authors.affiliation: Natsol Laboratories Private Limited, II Floor, Research & Development Building, Ramky Commercial Hub, J. N. Pharmacity, Visakhapatnam, India.
authors.forename: Neduri V
authors.initials: NV
authors.lastname: Balaji
authors.affiliation: Natsol Laboratories Private Limited, II Floor, Research & Development Building, Ramky Commercial Hub, J. N. Pharmacity, Visakhapatnam, India.
authors.forename: Modukuri V
authors.initials: MV
authors.lastname: Ramani
authors.affiliation: Department of Biomedical Sciences, CVMNAH, Tuskegee University, Tuskegee, AL, USA.
authors.forename: Arabela G
authors.initials: AG
authors.lastname: Viana
authors.affiliation: Department of Biomedical Sciences, CVMNAH, Tuskegee University, Tuskegee, AL, USA.
authors.forename: Leticia P
authors.initials: LP
authors.lastname: Sanglard
authors.affiliation: Department of Biomedical Sciences, CVMNAH, Tuskegee University, Tuskegee, AL, USA.
authors.forename: Jason
authors.initials: J
authors.lastname: White
authors.affiliation: Department of Chemical Engineering, Tuskegee University, Tuskegee, AL, USA.
authors.forename: Vanisree
authors.initials: V
authors.lastname: Mulabagal
authors.affiliation: Department of Biomedical Sciences, CVMNAH, Tuskegee University, Tuskegee, AL, USA.
authors.forename: Crystal
authors.initials: C
authors.lastname: Lee
authors.affiliation: Biopharmatech Consulting, Inc., Leesburg, VA, USA.
authors.forename: Theophilus J
authors.initials: TJ
authors.lastname: Gana
authors.affiliation: Department of Chemical Engineering, University of Mississippi, MS, USA.
authors.forename: Nosa O
authors.initials: NO
authors.lastname: Egiebor
authors.affiliation: Natsol Laboratories Private Limited, II Floor, Research & Development Building, Ramky Commercial Hub, J. N. Pharmacity, Visakhapatnam, India.
authors.forename: Gottumukkala V
authors.initials: GV
authors.lastname: Subbaraju
authors.affiliation: Department of Biomedical Sciences, CVMNAH, Tuskegee University, Tuskegee, AL, USA.|Department of Pharmacology and Experimental Therapeutics, College of Pharmacy & Pharmaceutical Sciences, University of Toledo, OH, USA.
authors.forename: Amit K
authors.initials: AK
authors.lastname: Tiwari
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002396:Catechols / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D057809:HEK293 Cells; D006801:Humans; D061986:MCF-7 Cells; D061985:Madin Darby Canine Kidney Cells / Q000187:drug effects; D051379:Mice; D015394:Molecular Structure; D041681:NIH 3T3 Cells; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D002396:Catechols; C103442:hispolon
keywords: Anticancer; Chemotherapy; Curcumin analogs; Hispolon analogs; Multidrug resistance
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