2. Academic Validation
  3. Design, synthesis and in vitro cell-based evaluation of the anti-cancer activities of hispolon analogs

Design, synthesis and in vitro cell-based evaluation of the anti-cancer activities of hispolon analogs

  • Bioorg Med Chem. 2015 May 1;23(9):2148-2158. doi: 10.1016/j.bmc.2015.03.002.
Neduri V Balaji # 1,  Modukuri V Ramani # 1,  Arabela G Viana # 2,  Leticia P Sanglard 2,  Jason White 2,  Vanisree Mulabagal 3,  Crystal Lee 2,  Theophilus J Gana 4,  Nosa O Egiebor 5,  Gottumukkala V Subbaraju 1,  Amit K Tiwari 2 6
Affiliations

Affiliations

  • 1 Natsol Laboratories Private Limited, II Floor, Research & Development Building, Ramky Commercial Hub, J. N. Pharmacity, Visakhapatnam, India.
  • 2 Department of Biomedical Sciences, CVMNAH, Tuskegee University, Tuskegee, AL, USA.
  • 3 Department of Chemical Engineering, Tuskegee University, Tuskegee, AL, USA.
  • 4 Biopharmatech Consulting, Inc., Leesburg, VA, USA.
  • 5 Department of Chemical Engineering, University of Mississippi, MS, USA.
  • 6 Department of Pharmacology and Experimental Therapeutics, College of Pharmacy & Pharmaceutical Sciences, University of Toledo, OH, USA.
  • # Contributed equally.
PMID: 25842364 DOI: 10.1016/j.bmc.2015.03.002
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.

Keywords

Anticancer; Chemotherapy; Curcumin analogs; Hispolon analogs; Multidrug resistance.

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