title: Cellular uptake and anticancer activity of carboxylated gallium corroles.
abstract: 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: IC50values 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 IC50values (<20 µM) relative to previous analogs against all four cancer cell lines, displayed high efficacy (Emax= 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.
authors.affiliation: Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA 91125;
authors.forename: Melanie
authors.initials: M
authors.lastname: Pribisko
authors.affiliation: Verrix, LLC, Pasadena, CA 91107;
authors.forename: Joshua
authors.initials: J
authors.lastname: Palmer
authors.affiliation: Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA 91125;
authors.forename: Robert H
authors.initials: RH
authors.lastname: Grubbs
authors.affiliation: Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA 91125; hbgray@caltech.edu JTermini@coh.org PLim@coh.org.
authors.forename: Harry B
authors.initials: HB
authors.lastname: Gray
authors.affiliation: Department of Molecular Medicine, Beckman Research Institute of the City of Hope, Duarte, CA 91010 hbgray@caltech.edu JTermini@coh.org PLim@coh.org.
authors.forename: John
authors.initials: J
authors.lastname: Termini
authors.affiliation: Department of Molecular Medicine, Beckman Research Institute of the City of Hope, Duarte, CA 91010 hbgray@caltech.edu JTermini@coh.org PLim@coh.org.
authors.forename: Punnajit
authors.initials: P
authors.lastname: Lim
mesh_terms: D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000494:pharmacology; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D005260:Female; D005708:Gallium / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D008297:Male; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D011166:Porphyrins / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D011166:Porphyrins; C431863:corrole; D005708:Gallium
keywords: anticancer agents; carboxylated metallocorroles; corroles; gallium(III); macrocycles