Triptycene (TT) is inactive but we synthesized new TT analogs (code names TT1 to TT16) that have antileukemic activity in the nM range in vitro. The lead compound, a TT bisquinone (TT2), not only inhibits macromolecule synthesis, induces DNA fragmentation, and decreases the growth and viability (IC50: 100 nM) of L1210 cells in vitro like the quinone antitumor drug daunomycin (DAU) but can also block the cellular transport of nucleosides, an effect which DAU cannot do. Since they have unique and highly useful dual effects on nucleoside transport and DNA cleavage, these TT analogs might be valuable to develop a novel synthetic class of bifunctional anticancer drugs effective in polychemotherapy. The major objectives are 1) to demonstrate the anticancer potential of TT2 in vivo, 2) to characterize its molecular mechanism of action, and 3) to identify more potent TT2 analogs.
The specific aims are: A) To establish that water-soluble TT2 derivatives can inhibit tumor development in vivo and prolong the survival of mice challenged with ascites (L1210) or solid tumors with metastatic potential (Lewis lung carcinoma and B16F10 melanoma). B) To elucidate the molecular mechanisms by which TT2 interacts with nucleoside transport (effects on equilibrative and Na+-dependent transporters, bidirectional fluxes of purines and pyrimidines, competition with nucleoside transport probes), DNA (binding, intercalation, strand breakage and crosslinks, topoisomerase activities), and tumor cells (drug uptake/retention/catabolism, cell cycle analysis, caspase-8 and -3 activation, apoptosis, potentiation of antimetabolite action, and effectiveness in P-glycoprotein-positive and -negative multidrug-resistant (MDR) cells). C) To synthesize new TT2 analogs and screen them in vitro to clarify structure-activity relationships for drug uptake, nucleoside transport/DNA synthesis, DNA fragmentation, and cell growth/viability. Because inhibition of nucleoside transport is unusual among DNA-damaging quinone antitumor drugs, the use of bifunctional TT2 analogs with antileukemic activity in the nM range in vitro might provide a considerable advantage in polychemotherapy to potentiate the action of antimetabolites and sensitize MDR tumor cells.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA086842-03
Application #
6514600
Study Section
Experimental Therapeutics Subcommittee 1 (ET)
Program Officer
Lees, Robert G
Project Start
2000-07-01
Project End
2005-06-30
Budget Start
2002-07-01
Budget End
2003-06-30
Support Year
3
Fiscal Year
2002
Total Cost
$196,425
Indirect Cost
Name
Kansas State University
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
City
Manhattan
State
KS
Country
United States
Zip Code
66506
Perchellet, Elisabeth M; Perchellet, Jean-Pierre H; Ganta, Chanran K et al. (2009) Synthesis, molecular targets, and antitumor activities of substituted tetrahydro-1-oxopyrano[4,3-b][1]benzopyrans and nanogels for drug delivery. Anticancer Agents Med Chem 9:864-76
Perchellet, Elisabeth M; Wang, Yang; Lou, Kaiyan et al. (2007) Novel substituted 1,4-anthracenediones with antitumor activity directly induce permeability transition in isolated mitochondria. Int J Oncol 31:1231-41
Perchellet, Elisabeth M; Wang, Yang; Lou, Kaiyan et al. (2007) Antitumor triptycene analogs directly interact with isolated mitochondria to rapidly trigger markers of permeability transition. Anticancer Res 27:3259-71
Wang, Yang; Perchellet, Elisabeth M; Ward, Mary M et al. (2006) Antitumor triptycene analogs induce a rapid collapse of mitochondrial transmembrane potential in HL-60 cells and isolated mitochondria. Int J Oncol 28:161-72
Hua, Duy H; Lou, Kaiyan; Battina, Srinivas K et al. (2006) Syntheses, molecular targets and antitumor activities of novel triptycene bisquinones and 1,4-anthracenedione analogs. Anticancer Agents Med Chem 6:303-18
Perchellet, Elisabeth M; Ward, Mary M; Skaltsounis, Alexios-Leandros et al. (2006) Antiproliferative and proapoptotic activities of pyranoxanthenones, pyranothioxanthenones and their pyrazole-fused derivatives in HL-60 cells. Anticancer Res 26:2791-804
Maezawa, Izumi; Hong, Hyun-Seok; Wu, Hui-Chuan et al. (2006) A novel tricyclic pyrone compound ameliorates cell death associated with intracellular amyloid-beta oligomeric complexes. J Neurochem 98:57-67
Wang, Yang; Perchellet, Elisabeth M; Ward, Mary M et al. (2005) Rapid collapse of mitochondrial transmembrane potential in HL-60 cells and isolated mitochondria treated with anti-tumor 1,4-anthracenediones. Anticancer Drugs 16:953-67
Perchellet, Elisabeth M; Perchellet, Jean-Pierre; Baures, Paul W (2005) Imidazole-4,5-dicarboxamide derivatives with antiproliferative activity against HL-60 cells. J Med Chem 48:5955-65
Perchellet, Elisabeth M; Wang, Yang; Weber, Rebeka L et al. (2004) Synthetic 1,4-anthracenedione analogs induce cytochrome c release, caspase-9, -3, and -8 activities, poly(ADP-ribose) polymerase-1 cleavage and internucleosomal DNA fragmentation in HL-60 cells by a mechanism which involves caspase-2 activation but not Fa Biochem Pharmacol 67:523-37

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