Synthesis and biologic properties of hydrophilic sapphyrins, a new class of tumor-selective inhibitors of gene expression

dc.creatorWang, Zhongen
dc.creatorLecane, Philip S.en
dc.creatorThiemann, Patricaen
dc.creatorFan, Qingen
dc.creatorCortez, Ceciliaen
dc.creatorMa, Xuanen
dc.creatorTonev, Danielleen
dc.creatorMiles, Daleen
dc.creatorNaumovski, Louieen
dc.creatorMiller, Richard A.en
dc.creatorMagda, Darrenen
dc.creatorCho, Dong-Gyuen
dc.creatorSessler, Jonathan L.en
dc.creatorPike, Brian L.en
dc.creatorYeligar, Samantha M.en
dc.creatorKaraman, Mazen W.en
dc.creatorHacia, Joseph G.en
dc.date.accessioned2014-12-15T17:10:25Zen
dc.date.available2014-12-15T17:10:25Zen
dc.date.issued2007-01-19en
dc.descriptionZhong Wang, Philip S. Lecane, Patricia Thiemann, Quing Fan, Cecilia Cortez, Xuan Ma, Danielle Tonev, Dale Miles, Louie Naumovski, and Richard A. Miller, Darren Magda are with the Pharmacyclics, Inc., Sunnyvale, California, USA -- Dong-Gyu Cho and Jonathan L. Sessler are with the Department of Chemistry and Biochemistry, University of Texas at Austin, Austin, Texas, USA -- Brian L. Pike, Samantha M. Yeligar, Mazen W. Laraman and Joseph G. Hacia are with the Department of Biochemistry and Molecular Biology, University of Southern California, Los Angeles, California, USAen
dc.description.abstractBackground: Sapphyrin analogues and related porphyrin-like species have attracted attention as anticancer agents due to their selective localization in various cancers, including hematologic malignancies, relative to surrounding tissues. Sapphyrins are electron affinic compounds that generate high yields of singlet oxygen formation. Although initially explored in the context of photodynamic therapy, sapphyrins have intrinsic anticancer activity that is independent of their photosensitizing properties. However, the mechanisms for their anticancer activity have not been fully elucidated. -- Results: We have prepared a series of hydrophilic sapphyrins and evaluated their effect on proliferation, uptake, and cell death in adherent human lung (A549) and prostate (PC3) cancer cell lines and in an A549 xenograft tumor model. PCI-2050, the sapphyrin derivative with the highest in vitro growth inhibitory activity, significantly lowered 5-bromo-2'-deoxyuridine incorporation in S-phase A549 cells by 60% within eight hours and increased levels of reactive oxygen species within four hours. The growth inhibition pattern of PCI-2050 in the National Cancer Institute 60 cell line screen correlated most closely using the COMPARE algorithm with known transcriptional or translational inhibitors. Gene expression analyses conducted on A549 plateau phase cultures treated with PCI-2050 uncovered wide-spread decreases in mRNA levels, which especially affected short-lived transcripts. Intriguingly, PCI-2050 increased the levels of transcripts involved in RNA processing and trafficking, transcriptional regulation, and chromatin remodeling. We propose that these changes reflect the activation of cellular processes aimed at countering the observed wide-spread reductions in transcript levels. In our A549 xenograft model, the two lead compounds, PCI-2050 and PCI-2022, showed similar tumor distributions despite differences in plasma and kidney level profiles. This provides a possible explanation for the better tolerance of PCI-2022 relative to PCI-2050. -- Conclusion: Hydrophilic sapphyrins were found to display promise as novel agents that localize to tumors, generate oxidative stress, and inhibit gene expression.en
dc.description.catalogingnotedmagda@pcyc.comen
dc.description.departmentChemistryen
dc.description.departmentBiochemistryen
dc.description.sponsorshipen
dc.identifier.Filename1476-4598-6-9en
dc.identifier.citationWang, Zhong, Philip S. Lecane, Patricia Thiemann, Qing Fan, Cecilia Cortez, Xuan Ma, Danielle Tonev, et al. “Synthesis and Biologic Properties of Hydrophilic Sapphyrins, a New Class of Tumor-Selective Inhibitors of Gene Expression.” Molecular Cancer 6, no. 1 (January 19, 2007): 9. doi:10.1186/1476-4598-6-9.en
dc.identifier.doidoi:10.1186/1476-4598-6-9en
dc.identifier.urihttp://hdl.handle.net/2152/27878en
dc.language.isoEnglishen
dc.publisherMolecular Canceren
dc.rightsAdministrative deposit of works to UT Digital Repository: This works author(s) is or was a University faculty member, student or staff member; this article is already available through open access at http://www.biomedcentral.com. The public license is specified as CC-BY: http://creativecommons.org/licenses/by/4.0/. The library makes the deposit as a matter of fair use (for scholarly, educational, and research purposes), and to preserve the work and further secure public access to the works of the University.en
dc.subjecthydrophilic sapphyrinsen
dc.subjecttumor-selective inhibitorsen
dc.subjectgene expressionen
dc.subjectanticancer agentsen
dc.titleSynthesis and biologic properties of hydrophilic sapphyrins, a new class of tumor-selective inhibitors of gene expressionen
dc.typeArticleen

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