%0 Journal Article
%T Synthesis and biologic properties of hydrophilic sapphyrins, a new class of tumor-selective inhibitors of gene expression
%A Zhong Wang
%A Philip S Lecane
%A Patricia Thiemann
%A Qing Fan
%A Cecilia Cortez
%A Xuan Ma
%A Danielle Tonev
%A Dale Miles
%A Louie Naumovski
%A Richard A Miller
%A Darren Magda
%A Dong-Gyu Cho
%A Jonathan L Sessler
%A Brian L Pike
%A Samantha M Yeligar
%A Mazen W Karaman
%A Joseph G Hacia
%J Molecular Cancer
%D 2007
%I BioMed Central
%R 10.1186/1476-4598-6-9
%X 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.Hydrophilic sapphyrins were found to display promise as novel agents that localize to tumors, generate oxidative stress, and inhibit gene expression.Sapphyrins are a class of expanded porphyrins that were first discovered as an unanticipated product during the synthesis of vitamin B12 [1]. Subsequently, efficient chemical synthesis of these compounds [2,3] led to the discovery that sapphyrins can function as highly effective anion binding receptors [4]. Sapphyrins possess a 22 ¦Ð-electron aromatic conjugation pathway and as a consequence are m
%U http://www.molecular-cancer.com/content/6/1/9