Event Title

Synthesis and Anti-Cancer Activity of Benzisoxazolo[2,3-a]azinium Tetrafluoroborates

Poster Number

34

Presenter Information

Jamie Murakami, Winthrop University

Faculty Mentor

James M. Hanna, Jr., Ph.D. and Takita Sumter, Ph.D.

College

College of Arts and Sciences

Department

Chemistry, Physics and Geology

Location

Richardson Ballroom

Start Date

24-4-2015 3:20 PM

End Date

24-4-2015 4:50 PM

Description

Despite the success of genomics in identifying new essential oncogenic signaling pathways, there have been a limited number of sustainable leads in anticancer drug discovery to address increasing chemoresistance. To improve progress in this area, our lab synthesized several novel benzisoxazoloazinium tetrafluoroborates with structural characteristics similar to clinically effective DNA binding drugs. From a series of eight tricyclic pyridinium compounds with various substituents, a methyl-substituted compound effectively inhibits proliferation in colon cancer cell lines (IC50 = 2.95 micromolar) and shows significant in silico and in vitro DNA binding affinity. Incorporation of a fourth ring generated quinolinium derivatives that recapitulate DNA binding activity of ellipticine. Preliminary IC50 values for these compounds range from 52 to 202 micromolar. To evaluate the impact of a second nitrogen, we synthesized and evaluated a quinoxalinium analog; results for this compound (IC50 of 18 micromolar) show increased cytotoxicity compared to the quinolinium analog. All compounds induce cell death via non-apoptotic pathways. Future work will involve the synthesis and evaluation of other quinoxalinium analogs, as well as evaluation of their activity against PC3 human prostate cancer cells.

Comments

Presented at the Annual Meeting of the American Society for Biochemistry and Molecular Biology, March 2015

Supported by an NIH-INBRE grant from the National Center for Research Resources and the National Institute of General Medical Sciences and a grant from the Winthrop University Research Council

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Apr 24th, 3:20 PM Apr 24th, 4:50 PM

Synthesis and Anti-Cancer Activity of Benzisoxazolo[2,3-a]azinium Tetrafluoroborates

Richardson Ballroom

Despite the success of genomics in identifying new essential oncogenic signaling pathways, there have been a limited number of sustainable leads in anticancer drug discovery to address increasing chemoresistance. To improve progress in this area, our lab synthesized several novel benzisoxazoloazinium tetrafluoroborates with structural characteristics similar to clinically effective DNA binding drugs. From a series of eight tricyclic pyridinium compounds with various substituents, a methyl-substituted compound effectively inhibits proliferation in colon cancer cell lines (IC50 = 2.95 micromolar) and shows significant in silico and in vitro DNA binding affinity. Incorporation of a fourth ring generated quinolinium derivatives that recapitulate DNA binding activity of ellipticine. Preliminary IC50 values for these compounds range from 52 to 202 micromolar. To evaluate the impact of a second nitrogen, we synthesized and evaluated a quinoxalinium analog; results for this compound (IC50 of 18 micromolar) show increased cytotoxicity compared to the quinolinium analog. All compounds induce cell death via non-apoptotic pathways. Future work will involve the synthesis and evaluation of other quinoxalinium analogs, as well as evaluation of their activity against PC3 human prostate cancer cells.