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Published April 19, 2016 | Published
Journal Article Open

Cellular uptake and anticancer activity of carboxylated gallium corroles


We report derivatives of gallium(III) tris(pentafluorophenyl)corrole, 1 [Ga(tpfc)], with either sulfonic (2) or carboxylic acids (3, 4) as macrocyclic ring substituents: the aminocaproate derivative, 3 [Ga(ACtpfc)], demonstrated high cytotoxic activity against all NCI60 cell lines derived from nine tumor types and confirmed very high toxicity against melanoma cells, specifically the LOX IMVI and SK-MEL-28 cell lines. The toxicities of 1, 2, 3, and 4 [Ga(3-ctpfc)] toward prostate (DU-145), melanoma (SK-MEL-28), breast (MDA-MB-231), and ovarian (OVCAR-3) cancer cells revealed a dependence on the ring substituent: IC_(50) values ranged from 4.8 to >200 µM; and they correlated with the rates of uptake, extent of intracellular accumulation, and lipophilicity. Carboxylated corroles 3 and 4, which exhibited about 10-fold lower IC_(50) values (<20 µM) relative to previous analogs against all four cancer cell lines, displayed high efficacy (E_(max) = 0). Confocal fluorescence imaging revealed facile uptake of functionalized gallium corroles by all human cancer cells that followed the order: 4 >> 3 > 2 >> 1 (intracellular accumulation of gallium corroles was fastest in melanoma cells). We conclude that carboxylated gallium corroles are promising chemotherapeutics with the advantage that they also can be used for tumor imaging.

Additional Information

© 2016 National Academy of Sciences. Contributed by Harry B. Gray, March 1, 2016 (sent for review September 1, 2015; reviewed by David Dolphin and Daniel T. Gryko). Published online before print April 4, 2016. The experimental assistance of Dr. Shane Mangold and software assistance of Dr. Ching Ouyang are gratefully acknowledged. We thank Dr. Brian Armstrong of the Light Microscopy Digital Imaging Core Facility and Dr. Gerald Wuenschell of the Translational Biomarker Discovery Core Facility of the City of Hope Comprehensive Cancer Center for their technical assistance, and the NCI Developmental Therapeutics Program for the 60 cell line screen. This work was supported by a Caltech/COH grant (to J.T. and H.B.G.) and by NIH Grant DK01038 (to H.B.G.). uthor contributions: M.P., J.P., R.H.G., H.B.G., J.T., and P.L. designed research; M.P. and P.L. performed research; M.P. and P.L. contributed new reagents/analytic tools; M.P., J.T., and P.L. analyzed data; and M.P., J.P., R.H.G., H.B.G., J.T., and P.L. wrote the paper. Reviewers: D.D., University of British Columbia; and D.T.G., Polish Academy of Sciences. The authors declare no conflict of interest.

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