Granted Patent
B2
US 12,383,518 · App. 17/668,810 · Granted Aug 12, 2025
Disulfide-masked pro-chelator compositions and methods of use
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Abstract
Pro-chelator compositions featuring disulfide masks that upon activation yield active chelators. The pro-chelator compositions may be activated intracellularly, for example within cells featuring metal ion dysregulation, cells that proliferate abnormally, etc. The pro-chelators of the present invention include thiosemicarbazones, semicarbazones, and aroyl hydrazones. The pro-chelator compositions of the present invention may be used for a variety of purposes including inhibiting cell proliferation, or treating conditions associated with metal ion dysregulation or abnormal cell proliferation.
Claims (28)
1. A metal pro-chelator comprising at least one pro-ligand and a disulfide bond, wherein the disulfide bond is connected to an aromatic ring of the pro-ligand at an ortho position, and wherein each pro-ligand comprises at least two donor atoms; wherein the metal pro-chelator excludes formulations according to:
2. The pro-chelator of claim 1 , wherein the pro-chelator comprises two pro-ligands, connected by the disulfide bond.
3. The pro-chelator of claim 1 , wherein the pro-chelator comprises one pro-ligand and a solubilizing or biologically active moiety, connected by the disulfide bond.
4. The pro-chelator of claim 1 , wherein the pro-chelator is activated to transform each pro-ligand to an active bidentate, tridentate, or polydentate chelator.
5. The pro-chelator of claim 4 , wherein the pro-chelator is activated by reduction of the disulfide bond.
6. The pro-chelator of claim 4 , wherein each active chelator comprises a semicarbazone, a thiosemicarbazone, a hydrazone, or a thiohydrazone moiety.
7. The pro-chelator of claim 4 , wherein each active chelator comprises an iminic position, and comprises an electron-withdrawing group at the iminic position.
8. The pro-chelator of claim 4 , wherein each active chelator is configured to coordinate Fe to form a metal complex.
9. The pro-chelator of claim 1 , wherein the pro-chelator comprises a structure according to Formula II, Formula III, Formula IV, or Formula V;
wherein R is H, alkyl, trifluoromethyl, aryl, or a derivative thereof;
wherein R is H, alkyl, aryl or a derivative thereof;
wherein:
if X 1 =O,
then R 1 =Ph, pyridyl, p-CF 3 -Ph, p-NO 2 -Ph, CCl 3 , or CF 3 ;
X 2 =H, alkyl, alkoxy, halo, CF 3 , or NO 2 ;
R 2 =H, alkyl, aryl, or substituted aryl; and
R 3 =H, alkyl, aryl, or substituted aryl;
or if X 1 =S,
then R 1 =Ph, pyridyl, p-CF 3 -Ph, p-NO 2 -Ph, CCl 3 , or CF 3 ;
X 2 =H, alkyl, alkoxy, halo, CF 3 , or NO 2 ;
R 2 =alkyl, aryl, or substituted aryl; and
R 3 =alkyl, aryl, or substituted aryl;
wherein: X 1 =O, or S;
R 1 =Ph, pyridyl, p-CF 3 -Ph, p-NO 2 -Ph, CCl 3 , or CF3;
X 2 =H, alkyl, alkoxy, halo, CF 3 , or NO 2 ; and
X 3 =H, alkyl, alkoxy, halo, CF 3 , or NO 2 .
10. A pro-chelator according to Formula III, wherein R is H, alkyl, aryl or a derivative thereof
11. The pro-chelator of claim 10 , wherein the pro-chelator is redox-activated.
Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST
Recorded Sep 6, 2022
From: TOMAT, ELISA; AKAM, EMAN A.
To: ARIZONA BOARD OF REGENTS ON BEHALF OF THE UNIVERSITY OF ARIZONA
Reel/Frame 061000/0497 →
Continuity (11)
Continuation In Part
16632217
Continuation In Part
PCTUS2016068061
· Dec 21, 2016
Provisional Application
62533964
· Jul 18, 2017
Provisional Application
62270246
· Dec 21, 2015
Provisional Application
61899262
· Nov 3, 2013
References Cited (200)
US 5246821A
· Abe et al.
· 1993
[cited by applicant]
US 6030846A
· Simons et al.
· 2000
[cited by applicant]
US 7488747B2
· Fang et al.
· 2009
[cited by applicant]
US 7825226B2
· Schultz et al.
· 2010
[cited by applicant]
US 8551976B2
· Franz et al.
· 2013
[cited by applicant]
US 8680077B2
· Franz et al.
· 2014
[cited by applicant]
US 8685955B2
· Youdim et al.
· 2014
[cited by applicant]
US 9486423B2
· Tomat et al.
· 2016
[cited by applicant]
US 20060252798A1
· Richardson et al.
· 2006
[cited by applicant]
US 20140073645A1
· Linder et al.
· 2014
[cited by applicant]
US 20170112788A1
· Tomat et al.
· 2017
[cited by applicant]
WO WO2015200916A2
· 2015
[cited by applicant]
WO WO2017112787A1
· 2017
[cited by applicant]
Database Registry Chemical Abstracts Service, Columbus, Ohio, Accession No. RN 1440088-73-2 Entered STN: Jun. 21, 2013.
[cited by examiner]
“Investigations on Structural and Elctrochemical Properties of some Disulfides Prepared by Schiff Base Reactions” Stephan Kotte, Ingo Jolk, and Bernt Krebs J. Prakt. Chem. 2000, 342, No. 1, (Year: 2000).
[cited by examiner]
Calvaresi et al., “Glucose conjugation for the specific targeting and treatment of cancer,” Chem. Sci. 4, Jun. 1, 2014, 2319-2333.
[cited by applicant]
Younes et al., “Overexpression of the human erythrocyte glucose transporter occurs as a late event in human colorectal carcinogenesis and is associated with an increased incidence of lymph node metastases,” Clin. Cancer…
[cited by applicant]
Haber et al., “GLUT1 glucose transporter expression in colorectal carcinoma—A marker for poor prognosis,” Feb. 2, 1998, Cancer 83, 34-40.
[cited by applicant]
Shen et al., “Overexpression of GLUT1 in colorectal cancer is independently associated with poor prognosis,” Int. J. Biol. Markers 26, Jun. 22, 2011, 166-172.
[cited by applicant]
Graziano et al., “Glycolysis gene expression analysis and selective metabolic advantage in the clinical progression of colorectal cancer,” Pharmacogenomics J. Mar. 1, 2016, DOI: 10.1038/tpj.2016.13.
[cited by applicant]
Mikata et al., “Metal Complexes of Carbohydrate-targeted Ligands in Medicinal Inorganic Chemistry,” Ligand Design In Medicinal Inorganic Chemistry (Storr, T., Ed.) 2014, pp. 145-173, Chapter 6, John Wiley & Sons, Ltd, C…
[cited by applicant]
Liu et al., “Highly water-soluble platinum(II) complexes as GLUT substrates for targeted therapy: improved anticancer efficacy and transporter-mediated cytotoxic properties,” Chem. Commun. 49, Feb. 1, 2013, 2421-2423.
[cited by applicant]
Patra et al., “A Potent Glucose-Platinum Conjugate Exploits Glucose Transporters and Preferentially Accumulates in Cancer Cells,” Angew. Chem. Int. Ed. 55, 2016, 2550-2554.
[cited by applicant]
Storr et al., “Glycosylated tetrahydrosalens as multifunctional molecules for Alzheimer's therapy,” Dalton Trans., Feb. 16, 2009, 3034-3043.
[cited by applicant]
Cao et al., “Targeted Cancer Therapy with a 2-Deoxyglucose-Based Adriamycin Complex,” Cancer Res. 73, Feb. 8, 2013, 1362-1373.
[cited by applicant]
Halmos et al., “Synthesis of glucose-chlorambucil derivatives and their recognition by the human GLUT1 glucose transporter,” Eur. J. Pharmacol. 318, Oct. 4, 1996, 477-484.
[cited by applicant]
Guenin et al., “Synthesis and Anaphylactogenicity of Monohaptenic Carbohydrate Conjugates,” Helv. Chim. Acta 66, 1983, 1101-1109.
[cited by applicant]
Fan et al., “Design, synthesis and biological evaluation of brain-specific glucosyl thiamine disulfide prodrugs of naproxen,” Eur. J. Med. Chem. 46, May 20, 2011, 3651-3661.
[cited by applicant]
Cui et al., “Regioselective 6-detrimethylsilylation of per-O-TMS-protected carbohydrates in the presence of ammonium acetate,” Tetrahedron Lett. 54, May 18, 2013, 3831-3833.
[cited by applicant]
Jacob et al., “Glucose-aspirin: Synthesis and in vitro anti-cancer activity studies,” Bioorg. Med. Chem. Lett. 22, Mar. 23, 2012, 3168-3171.
[cited by applicant]
Peltier-Pain et al., “Warfarin Glycosylation Invokes a Switch from Anticoagulant to Anticancer Activity,” ChemMedChem 6, 2011, 1347-1350.
[cited by applicant]
Saaf et al., “Parallels between global transcriptional programs of polarizing caco-2 intestinal epithelial cells in vitro and gene expression programs in normal colon and colon cancer,” Mol. Biol. Cell 18, Aug. 8, 2007,…
[cited by applicant]
Harris et al., “Polarized Distribution of Glucose Transporter Isoforms in Caco-2 Cells,” Proc. Natl. Acad. Sci. U.S.A. 89, May 18, 1992, 7556-7560.
[cited by applicant]
O'Neil et al., “Uptake of a fluorescent deoxyglucose analog (2-NBDG) in tumor cells,” Mol. Imaging Biol. 7, Nov. 12, 2005, 388-392.
[cited by applicant]
Xintaropoulou et al., “A comparative analysis of inhibitors of the glycolysis pathway in breast and ovarian cancer cell line models,” Oncotarget 6, Jul. 16, 2015, 25677-25695.
[cited by applicant]
Barnett et al. “Structural Requirements for Binding to Sugar-Transport System of Human Erythrocyte,” Biochem. J. 131, Jul. 19, 1972, 211-221.
[cited by applicant]
Lin et al., “Targeting the Delivery of Glycan-Based Paclitaxel Prodrugs to Cancer Cells via Glucose Transporters,” J. Med. Chem. 51, May 26, 2008, 7428-7441.
[cited by applicant]
Sun et al. “Iron depletion decreases proliferation and induces apoptosis in a human colonic adenocarcinoma cell line, Caco2,” J. Inorg. Biochem. 103, May 20, 2009, 1074-1081.
[cited by applicant]
Lane et al., “Expanding horizons in iron chelation and the treatment of cancer: Role of iron in the regulation of ER stress and the epithelial-mesenchymal transition,” BBA Rev. Cancer 1845, Jan. 25, 2014, 166-181.
[cited by applicant]
Whitnall et al., “A class of iron chelators with a wide spectrum of potent antitumor activity that overcomes resistance to chemotherapeutics,” Proc. Natl. Acad. Sci. U.S.A. 103, Jun. 15, 2006, 14901-14906.
[cited by applicant]
Medina et al., “Glucose transporters: expression, regulation and cancer,” Biol. Res. 35, Feb. 1, 2002, 9-26.
[cited by applicant]
Jung et al., “Improved synthesis of 4-amino-7-nitrobenz-2,1,3-oxadiazoles using NBD fluoride (NBD-F),” Tetrahedron Lett. 52, Mar. 2, 2011, 2533-2535.
[cited by applicant]
Widdison et al., “Semisynthetic maytansine analogues for the targeted treatment of cancer,” J. Med. Chem. 49, Mar. 20, 2006, 4392-4408.
[cited by applicant]
Sungaran et al. “Localization and regulation of thrombopoietin mRNa expression in human kidney, liver, bone marrow, and spleen using in situ hybridization.” Blood, The Journal of the American Society of Hematology 89.1 …
[cited by applicant]
Perez et al. “Iron chelators as potential therapeutic agents for Parkinson's disease.” Current bioactive compounds 4.3 (2008): 150-158.
[cited by applicant]
Dayani et al., “Desferoxamine (DFO)-medialed iron chelation: Rationale for a novel approach to therapy for brain cancer,” J_ Neuro-Oncol. 2004, 67, 367-377.
[cited by applicant]
Nutting et al., “Phase II study of 3-AP Triapine in patients with recurrent or metastatic head and neck squamous cell carcinoma,” Ann. Oncol. Dec. 5, 2008, 20, 1275-1279.
[cited by applicant]
Kontoghiorghes, “Ethical issues and risk/benefit assessment of iron chelation therapy: Advances with Deferiprone/Deferoxamine combinations and concerns about the safety, efficacy and costs of Deferasirox,” Hemoglobin 20…
[cited by applicant]
Lee et al., “Direct Fluorescence Monitoring of the Delivery and Cellular Uptake of a Cancer-Targeted RGD Peptide-Appended Naphthalimide Theragnostic Prodrug,” J_ Am. Chem. Soc. 2012, 134, 12668-12674.
[cited by applicant]
Wu et al. “In vivo and in situ tracking cancer chemotherapy by highly photostable NIR fluorescent theranostic prodrug.” Journal of the American Chemical Society 136.9 (2014): 3579-3588.
[cited by applicant]
Spasojevic et al., “Electrochemical Behavior of the Fe(III) complexes of the Cyclic Hydroxamate Siderophores Alcaligin and Desferrioxamine E,” Inorg. Chem. 1999, 38, 449-454.
[cited by applicant]
Bernhardt “Coordination chemistry and biology of chelators for the treatment of iron overload disorders,” Dalton Trans. Jun. 18, 2007, 3214-3220.
[cited by applicant]
Ornstein et al., “Iron stimulates urokinase plasminogen activator expression and activates NF-,appa Bin human prostate cancer cells,” Nutr. Cancer 2007, 58, 115-126.
[cited by applicant]
Kalinowski et al., “Design, synthesis, and characterization of novel iron chelators: Structure-activity relationships of the 2-benzoylpyridine lhiosemicarbazone series and their 3-nilrobenzoyl analogues as potent antitu…
[cited by applicant]
Richardson et al., “2-Acetylpyridine Thiosemicarbazones are Potent Iron Chelators and Antiproliferative Agents: Redox Activity, Iron Complexation and Characterization of their Antitumor Activity,” J_ Med. Chem. Dec. 15,…
[cited by applicant]
Choi et al., “Iron intake, oxidative stress-related genes (MnSOD and MPO) and prostate cancer risk in CARET cohort,” Carcinogenesis Feb. 22, 2008, 29, 964-970.
[cited by applicant]
Ben-Haim et al. “(18)F-FDG PET and PET/CT in the Evaluation of Cancer Treatment Response,” J_ Nucl. Med. Jan. 2009, 50, 88-99.
[cited by applicant]
Liu et al., “Synthesis of 2 ′-paclitaxel methyl 2-Glucopyranosyl succinate for specific targeted delivery to cancer cells. Bioorg,” Med. Chem. Lett. Nov. 7, 2006, 17, 617-620.
[cited by applicant]
Bensinger et al., “New aspects of the Warburg effect in cancer cell biology,” Semin. Cell Dev. Biol. Mar. 8, 2012, 23, 352-361.
[cited by applicant]
Yoshioka et al., “A novel fluorescent derivative of glucose applicable to the assessment of glucose uptake activity of
[cited by applicant]
Heath et al., “Iron Deprivation in Cancer-Potential Therapeutic Implications,” Nutrients. Jul. 24, 2013; 5(8): 2836-2859.
[cited by applicant]
Kovacevic et al., “Iron Chelators: Development of Novel Compounds with High and Selective Anti-Tumour Activity,” Current Drug Delivery, vol. 7, No. 3, Jul. 2010, pp. 194-207(14).
[cited by applicant]
Buss et al., “Iron chelators in cancer chemotherapy,” Curr Top Med Chem. 2004;4(15):1623-35.
[cited by applicant]
Chitambar et al. “Iron-targeting antitumor activity of gallium compounds and novel insights into triapine{®)-meta complexes,” Antioxid Redox Signal. Mar. 10, 2013;18(8):956-72.
[cited by applicant]
Yu et al. “The Potent and Novel Thiosemicarbazone Chelators Di-2-pyridylketone-4, 4-dimethyl-3-thiosemicarbazone and 2-Benzoylpyridine-4, 4-dimethyl-3-thiosemicarbazone Affect Crucial Thiel Systems Required or Ribonucle…
[cited by applicant]
Siriwardana et al., “Two cell cycle blocks caused by iron chelation of neuroblastoma cells: separating cell cycle events associated with each block,” Physiol Rep. Dec. 1, 2013; 1(7): e00176.
[cited by applicant]
Choi et al. “Effects of oral iron chelator deferasirox on human malignant lymphoma cells,” Korean J Hemalol. Sep. 2012; 47(3): 194-201.
[cited by applicant]
Loccufier et al., “Convenient Method for the Preparation of 3-(2-Pyridyl Dilhio) Propionic-Acid N-Hydroxy Succinimide Ester,” B Soc Chim Belg. Jul. 10, 1988, 97, 535-539.
[cited by applicant]
Wood et al., “Advances in the Chemistry of Dipyrrins and Their Complexes,” Chem. Rev. Apr. 13, 2007, 107, 1831-1861.
[cited by applicant]
Katayev et al. “Dioxygen activation by diiminodipyrromethane complexes of Ni, Pd, and Pt.” Inorganic chemistry 46.14 (2007): 5465-5467.
[cited by applicant]
Reid et al. “Tautomerisation and hydrogen-bonding interactions in four-coordinate metal halide and azide complexes of N-donor-extended dipyrromethanes.” Dalton Transactions 39.2 (2010): 418-425.
[cited by applicant]
Halper et al. “Heterometallic metal-organic frameworks based on tris (dipyrrinato) coordination complexes.” Inorganic chemistry 44.3 (2005): 486-488.
[cited by applicant]
King et al. “Co (III) imidos exhibiting spin crossover and C—H bond activation.” Journal of the American Chemical Society 134.43 (2012): 17858-17861.
[cited by applicant]
Hennessy et al. “Complex N-heterocycle synthesis via iron-catalyzed, direct C—H bond amination.” Science 340.6132 (2013): 591-595.
[cited by applicant]
Thoi et al. “Diamidodipyrrins: versatile bipyrrolic ligands with multiple metal binding modes.” Inorganic chemistry 47.22 (2008): 10533-10541.
[cited by applicant]
Patra, et al. “A thermally stable {FeNO} 8 complex: properties and biological reactivity of reduced MNO systems.” Chemical Science 3.2 (2012): 364-369.
[cited by applicant]
Sanders et al.“Synthesis, properties, and reactivity of a series of non-heme {FeNO} 7/8 complexes: Implications for Fe-nitroxyl coordination.” Journal of inorganic biochemistry 118 (2013): 115-127.
[cited by applicant]
Broring et al. “Preparation, Magnetic and Structural Study on Oxido-Bridged Diiron (III) Complexes with Open-Chain Tetrapyrrolic 2, 2′-Bidipyrrin Ligands.” (2009): 3628-3635.
[cited by applicant]
Sessler et al. “Synthesis and Characterization of a Tripyrrane-Copper (II) Complex.” Inorganic chemistry 35.23 (1996): 6636-6637.
[cited by applicant]
Bennett et al., “Seeing Red: The Story of Prodigiosin,” Adv. Appl. Microbiol. 2000, 47, 1-32.
[cited by applicant]
Furstner, “Chemistry and Biology of Roseophilin and the Prodigiosin Alkaloids: A Survey of the Last 2500 Years,” A., Angew. Chem., Int. Ed. 2003, 42, 3582-3603.
[cited by applicant]
D'Alessio et al., “Synthesis and Immunosuppressive Activity of Novel Prodigiosin Derivatives,” J_ Med. Chem. Jan. 4, 2000, 43, 2557-2565.
[cited by applicant]
Furstner et al., “Studies on DNA Cleavage by Cytotoxic Pyrrole Alkaloids Reveal the Distinctly Different Behavior of Roseophilin and Prodigiosin Derivatives,” ChemBioChem; Feb. 9, 2001, 2, 60-68.
[cited by applicant]
Marchal et al., “Antimicrobial activity of non-natural prodigiosenes,” RSC Adv. Oct. 4, 2013, 3, 22967-22971.
[cited by applicant]
Vázquez-Dorbatt et al. “Synthesis of a pyridyl disulfide end-functionalized glycopolymer for conjugation to biomolecules and patterning on gold surfaces.” Biomacromolecules 10.8 (2009): 2207-2212.
[cited by applicant]
Calvaresi et al. “Glucose conjugation for the specific targeting and treatment of cancer.” Chemical science 4.6 (2013): 2319-2333.
[cited by applicant]
Samukov, “A Simple Preparation of 3-(2-Pyridyldithio)-Propionic Acid,” Synthetic Communications, vol. 28, No. 17, 1998. pp. 3213-3217.
[cited by applicant]
Ferlay et al., “Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012,” Int. J. Cancer 136, Sep. 13, 2014, E359-386.
[cited by applicant]
Bingham et al., “Diet and cancer—the European Prospective Investigation into Cancer and Nutrition,” Nat. Rev. Cancer 4, Mar. 2004, 206-215. 10 pages.
[cited by applicant]
Nelson, “Iron and colorectal cancer risk: Human studies,” Nutr. Rev. 59, May 2001, 140-148. 9 pages.
[cited by applicant]
Chua et al., “Iron: an emerging factor in colorectal carcinogenesis,” World J. Gastroenterol. 16, Feb. 14, 2010, 663-672. 10 pages.
[cited by applicant]
Padmanabhan et al., “Iron and colorectal cancer: evidence from in vitro and animal studies,” Nutr. Rev. 73, Apr. 7, 2015, 308-317. 10 pages.
[cited by applicant]
Brookes et al., “Modulation of iron transport proteins in human colorectal carcinogenesis,” Gut 55, Apr. 26, 2006, 1449-1460.
[cited by applicant]
Perez et al., “Minding metals: tailoring multifunctional chelating agents for neurodegenerative disease,” Dalton Trans. 39, Dec. 17, 2009, 2177-2187.
[cited by applicant]
Vander Heiden et al., “Targeting cancer metabolism: a therapeutic window opens,” Nat. Rev. Drug Discov. 10, Sep. 2011, 671-684.
[cited by applicant]
Akam et al. “Disulfide-masked iron prochelators: Effects on cell death, proliferation, and hemoglobin production.” Journal of inorganic biochemistry 180 (2018): 186-193.
[cited by applicant]
Torti et al., “Iron and cancer: more ore to be mined,” Nat Rev. Cancer, 2013, 13, 342-355.
[cited by applicant]
Habashy et al. “Transferrin receptor (CD71) is a marker of poor prognosis in breast cancer and can predict response to tamoxifen.” Breast cancer research and treatment 119.2 (2010): 283-293.
[cited by applicant]
Pinnix et al. “Ferroportin and iron regulation in breast cancer progression and prognosis.” Science translational medicine 2.43 (2010): 43ra56-43ra56.
[cited by applicant]
Ricolleau et al. “Surface-enhanced laser desorption/ionization time of flight mass spectrometry protein profiling identifies ubiquitin and ferritin light chain as prognostic biomarkers in node-negative breast cancer tum…
[cited by applicant]
Spangler et al. “A reactivity-based probe of the intracellular labile ferrous iron pool.” Nature chemical biology 12.9 (2016): 680-685.
[cited by applicant]
Kalinowski et al. “The evolution of iron chelators for the treatment of iron overload disease and cancer.” Pharmacological reviews 57.4 (2005): 547-583.
[cited by applicant]
Merlot et al. “Novel chelators for cancer treatment: where are we now?.” Antioxidants & redox signaling 18.8 (2013): 973-1006.
[cited by applicant]
Yu et al., “Thiosemicarbazones from the Old to New: Iron Chelators That Are More Than Just Ribonucleotide Reductase inhibitors,” J. Med. Chem., Apr. 30, 2009, 52, 5271-5294.
[cited by applicant]
Lovejoy et al. “Novel second-generation di-2-pyridylketone thiosemicarbazones show synergism with standard chemotherapeutics and demonstrate potent activity against lung cancer xenografts after oral and intravenous admi…
[cited by applicant]
Jansson et al. “Di-2-pyridylketone 4, 4-dimethyl-3-thiosemicarbazone (Dp44mT) overcomes multidrug resistance by a hovel mechanism involving the hijacking of lysosomal P-glycoprotein (Pgp).” Journal of Biological Chemist…
[cited by applicant]
Jansson et al. “The renaissance of polypharmacology in the development of anti-cancer therapeutics: Inhibition of the “Triad of Death” in cancer by Di-2-pyridylketone thiosemicarbazones.” Pharmacological research 100 (2…
[cited by applicant]
Wang et al. “Stimulus-responsive prochelators for manipulating cellular metals.” Accounts of chemical research 49.11 (2016): 2468-2477.
[cited by applicant]
Chang et al. “Disulfide/thiol switches in thiosemicarbazone ligands for redox-directed iron chelation.” Dalton Transactions 42.22 (2013): 7846-7849.
[cited by applicant]
Akam et al. “Intracellular reduction/activation of a disulfide switch in thiosemicarbazone iron chelators.” Metallomics 6.10 (2014): 1905-1912.
[cited by applicant]
Pujol et al. “A Sulfur Tripod Glycoconjugate that Releases a High-Affinity Copper Chelator in Hepatocytes.” Angewandte Chemie International Edition 51.30 (2012): 7445-7448.
[cited by applicant]
Schafer et al. “Redox environment of the cell as viewed through the redox state of the glutathione disulfide/glutathione couple.” Free radical biology and medicine 30.11 (2001): 1191-1212.
[cited by applicant]
Gamcsik et al. “Glutathione levels in human tumors.” Biomarkers 17.8 (2012): 671-691.
[cited by applicant]
Lee et al. “Disulfide-cleavage-triggered chemosensors and their biological applications.” Chemical reviews 113.7 (2013): 5071-5109.
[cited by applicant]
Lee et al. “Disulfide-based multifunctional conjugates for targeted theranostic drug delivery.” Accounts of chemical research 48.11 (2015): 2935-2946.
[cited by applicant]
Ballatori et al. “Glutathione dysregulation and the etiology and progression of human diseases.” (2009): 191-214.
[cited by applicant]
Akam “Targeting iron in colon cancer via glycoconjugation of thiosemicarbazone prochelators.” Bioconjugate chemistry 27.8 (2016): 1807-1812.
[cited by applicant]
Mertens et al. “Intracellular iron chelation modulates the macrophage iron phenotype with consequences on tumor progression.” PLoS One 11.11 (2016): e0166164.
[cited by applicant]
Potůčková et al. “Structure-activity relationships of novel salicylaldehyde isonicotinoyl hydrazone (SIH) analogs: iron chelation, antioxidant and cytotoxic properties.” PLoS One 9.11 (2014): e112059.
[cited by applicant]
Soares et al. “Evaluation of thiosemicarbazones and semicarbazones as potential agents anti-Trypanosoma cruzi.” Experimental parasitology 129.4 (2011): 381-387.
[cited by applicant]
Potůčková et al. “In vitro characterization of the pharmacological properties of the anti-cancer chelator, Bp4eT, and its phase I metabolites.” PloS one 10.10 (2015): e0139929.
[cited by applicant]
Jansson et al. “The iron complex of Dp44mT is redox-active and induces hydroxyl radical formation: an EPR study.” Journal of inorganic biochemistry 104.11 (2010): 1224-1228.
[cited by applicant]
Kalyanaraman et al. “Measuring reactive oxygen and nitrogen species with fluorescent probes: challenges and imitations.” Free radical biology and medicine 52.1 (2012): 1-6.
[cited by applicant]
Franks et al. “A prochelator with a modular masking group featuring hydrogen peroxide activation with concurrent fluorescent reporting.” Chemical Communications 50.77 (2014): 11317-11320.
[cited by applicant]
Charkoudian et al. “Iron prochelator BSIH protects retinal pigment epithelial cells against cell death induced by hydrogen peroxide.” Journal of inorganic biochemistry 102.12 (2008): 2130-2135.
[cited by applicant]
Karlsson et al. “What does the commonly used DCF test for oxidative stress really show?.” Biochemical Journal 428.2 (2010): 183-190.
[cited by applicant]
Le et al. “The role of iron in cell cycle progression and the proliferation of neoplastic cells.” Biochimica et Biophysica Acta (BBA)—Reviews on Cancer 1603.1 (2002): 31-46.
[cited by applicant]
Eriksson et al. “Cell cycle-dependent regulation of mammalian ribonucleotide reductase. The S phase-correlated Increase in subunit M2 is regulated by de novo protein synthesis.” Journal of Biological Chemistry 259.19 (1…
[cited by applicant]
Cooper et al. “The relationship of intracellular iron chelation to the inhibition and regeneration of human ribonucleotide reductase.” Journal of Biological Chemistry 271.34 (1996): 20291-20299.
[cited by applicant]
Eberhard et al. “Chelation of intracellular iron with the antifungal agent ciclopirox olamine induces cell death in eukemia and myeloma cells.” Blood, The Journal of the American Society of Hematology 114.14 (2009): 306…
[cited by applicant]
Aye et al. “Mechanistic studies of semicarbazone triapine targeting human ribonucleotide reductase in vitro and in mammalian cells: tyrosyl radical quenching not involving reactive oxygen species.” Journal of Biological…
[cited by applicant]
Popović-Bijelić et al. “Ribonucleotide reductase inhibition by metal complexes of Triapine (3-aminopyridine-2-carboxaldehyde thiosemicarbazone): a combined experimental and theoretical study.” Journal of inorganic bioch…
[cited by applicant]
Macková et al. “Methyl and ethyl ketone analogs of salicylaldehyde isonicotinoyl hydrazone: novel iron chelators with selective antiproliferative action.” Chemico-biological interactions 197.2-3 (2012): 69-79.
[cited by applicant]
Pan et al. “Increased GADD153 gene expression during iron chelation-induced apoptosis in Jurkat T-lymphocytes.” Biochimica et Biophysica Acta (BBA)—Molecular Cell Research 1691.1 (2004): 41-50.
[cited by applicant]
Regis et al. “Iron regulates T-lymphocyte sensitivity to the IFN-γ/STAT1 signaling pathway in vitro and in vivo.” Blood 105.8 (2005): 3214-3221.
[cited by applicant]
Noulsri et al. “Antitumor activity and mechanism of action of the iron chelator, Dp44mT, against leukemic cells.” American journal of hematology 84.3 (2009): 170-176.
[cited by applicant]
Ponka, Prem. “Tissue-specific regulation of iron metabolism and heme synthesis: distinct control mechanisms in erythroid cells.” Blood, The Journal of the American Society of Hematology 89.1 (1997): 1-25.
[cited by applicant]
Muckenthaler et al. “A red carpet for iron metabolism.” Cell 168.3 (2017): 344-361.
[cited by applicant]
Ohta et al. “Erythroid cell differentiation: murine erythroleukemia cell variant with unique pattern of induction by polar compounds.” Proceedings of the National Academy of Sciences 73.4 (1976): 1232-1236.
[cited by applicant]
Marcero et al. “Rapid and sensitive quantitation of heme in hemoglobinized cells.” Biotechniques 61.2 (2016): 83-91.
[cited by applicant]
Chan et al. “Regulation of transferrin receptor mRNA expression: distinct regulatory features in erythroid cells.” European journal of biochemistry 220.3 (1994): 683-692.
[cited by applicant]
Schranzhofer et al. “Remodeling the regulation of iron metabolism during erythroid differentiation to ensure efficient heme biosynthesis.” Blood 107.10 (2006): 4159-4167.
[cited by applicant]
Sheftel et al. “Direct interorganellar transfer of iron from endosome to mitochondrion.” Blood, The Journal of the American Society of Hematology 110.1 (2007): 125-132.
[cited by applicant]
Hamdi et al. “Erythroid cell mitochondria receive endosomal iron by a “kiss-and-run” mechanism.” Biochimica Et Biophysica Acta (BBA)—Molecular Cell Research 1863.12 (2016): 2859-2867.
[cited by applicant]
Schultz et al. “Iron and porphyrin trafficking in heme biogenesis.” Journal of Biological Chemistry 285.35 (2010): 26753-26759.
[cited by applicant]
Sung et al. “Albumin Conjugates of Thiosemicarbazone and Imidazole-2-thione Prochelators: Iron Coordination and Antiproliferative Activity.” ChemMedChem 16.18 (2021): 2764-2768.
[cited by applicant]
Jávorfi et al. “Quantitative spectrophotometry using integrating cavities.” Journal of Photochemistry and Photobiology B: Biology 82.2 (2006): 127-131.
[cited by applicant]
Ongena et al. “Determining cell number during cell culture using the Scepter cell counter.” JoVE (Journal of Visualized Experiments) 45 (2010): e2204.
[cited by applicant]
Papireddy et al., “Antimalarial Activity of Natural and Synthetic Prodiginines,” J_ Med. Chem. Jul. 8, 2011, 54, 5296-5306.
[cited by applicant]
Perez-Tomas et al., “New Insights on the Antitumoral Properties of Prodiginines,” Curr. Med. Chem. Jul. 1, 2010, 17, 2222-2231.
[cited by applicant]
Regourd et al., “Synthesis and Anti-Cancer Activity of C-Ring-FtmctionaHzed Prodigiosin Analogues,” J_ Med. Chem. 2007, 50, 1528-1536.
[cited by applicant]
Diaz et al., “Amido-Functionalised Prodigiosenes: Synthesis and Anticancer Properties,” ChemMedChem 2009, 4, 742-745.
[cited by applicant]
Smithen et al., “Investigations regarding the utility of prodigiosenes to treat leukemia,” Org. Biomol. Chem. 2013, 11, 62-68.
[cited by applicant]
Melvin et al., “DNA Binding by 4-Methoxypyrrolic Natural Products. Preference for Intercalation at AT Sites by Tambjamine E and Prodigiosin,” J_ Org. Chem. Jun. 10, 1999, 64, 6861-6869.
[cited by applicant]
Sessler et al., “Synthesis, Anion-Binding Properties, and In Vitro Anticancer Activity of Prodigiosin Analogues,” Angew. Chem., Int. Ed. 2005, 44, 5989-5992.
[cited by applicant]
Davis et al., “Using small molecules to facilitate exchange of bicarbonate and chloride anions cross liposomal membranes,” Nat. Chem. Apr. 19, 2009, 1, 138-144.
[cited by applicant]
Busschaert et al., “Small-Molecule Lipid-Bilayer Anion Transporters for Biological Applications,” Angew. Chem., Int. Ed. 2013, 52, 1374-1382.
[cited by applicant]
Melvin et al., “Double-Strand DNA Cleavage by Copper-Prodigiosin,” J. Am. Chem. Soc. Jan. 6, 2000, 122, 6333-6334.
[cited by applicant]
Melvin et al., “Copper-nuclease efficiency correlates with cytotoxicity for the 4-methoxypyrrolic natural products,” J_ Inorg. Biochem. Aug. 14, 2001, 87, 129-135.
[cited by applicant]
Diaz et al., “Chloride anion transport and copper-1nediated I)NA cleavage by C-ring functionalized prodigiosenes,” Chem. Commun. Feb. 12, 2007, 2701-2703.
[cited by applicant]
Furstner et al., “Synthesis and Biological Evaluation of Nonylprodigiosin and Macrocyclic Prodigiosin Analogues,” ChemBioChem 2001, 2, 706-709.
[cited by applicant]
Melvin et al., “Influence of the A-Ring on the Proton Affinity and Anticancer Properties of the Prodigiosins,” Chem. Res. Toxicol. 2002, 15, 734-741.
[cited by applicant]
Zhang et al., “One-pot efficient synthesis of pyrrolyIBODIPY dyes from pyrrole and acyl chloride,” RSC Advances 2012, 2, 11215-11218.
[cited by applicant]
Zhang et al., “Synthesis of pyrrolyldipyrrinato BF 2 complexes by oxidative nudeophilk substitution of boron dipyrromethene with pyrrole,” Org. Biomol. Chem. 2012, 10, 2139-2145.
[cited by applicant]
Park et al., “Zinc and Copper Complexes of Prodigiosin: Implications for Copper-Mediated Double-Strand DNA Cleavage,” Org. Lett. 2003, 5, 113-116.
[cited by applicant]
Crawford et al., “Synthesis and Characterization of Fluorescent Pyrrolyldipyrrinato Sn(IV) Complexes,” Inorg. Chem. 2011, 50, 8207-8213.
[cited by applicant]
Hong et al., “Syntheses of mono- and diacylated bipyrroles with rich substitution modes and development of a prodigiosin derivative as a fluorescent Zn(11) probe,” RSC Adv. 2014, 4, 6133-6140.
[cited by applicant]
Murakami., “Transition-metal Complexes of Pyrrole Pigments. Part VI. Some Bivalent Metal Complexes of 3,3′ ,4′,4′-Tetrachloro-5,5′-diethoxycarb-onyldipyrromethene,” J_ Chem. Soc., Dalton Trans. 1973, 1729-1734.
[cited by applicant]
Smithen et al., “Use of f-BODIPYs as a Protection Strategy for Dipyrrins: Optimization of BF2 Removal,” J_ Org. Chem. 2012, 77, 3439-3453.
[cited by applicant]
Wallace et al., “Rational Tetraarylporphyrin Syntheses: Tetraarylporphyrins from the MacDonald Route,” J_ Org. Chem. Jul. 14, 1993, 58, 7245-7257.
[cited by applicant]
Garcia-Valverde et al., “Conformational Analysis of a Model Synthetic Prodiginine,” J_ Org. Chem. 2012, 77, 6538-6544.
[cited by applicant]
Melvin et al., “Influence of the A-Ring on the Redox and Nuclease Properties of the Prodigiosins: Importance of the Bipyrrole Moiety in Oxidative DNA Cleavage,” Chem. Res. Toxicol. 2002, 15, 742-748.
[cited by applicant]
Rastogi et al., “Synthetic prodigiosenes and the influence of C-ring substitution on DNA cleavage, transmembrane chloride transport and basicity,” Org. Biomol. Chem. 2013, 11, 3834-3845.
[cited by applicant]
Yu et al. “Straightforward Acid-Catalyzed Synthesis of Pyrrolyl-dipyrromethenes,” Angew. Chem., Int. Ed. 2012, )1, 7688-7691.
[cited by applicant]
Jenkins et al., “Structural studies of C-ring substituted unnatural analogues of prodigiosin” CrystEngComm 2009, 11, 242-245.
[cited by applicant]
Davies, “A New Pulse Endor Technique” E. R., Phys. Lett. A Feb. 2, 1974, 47, 1-2.
[cited by applicant]
Holland et al., “Three-Coordinate Cu(II) Complexes: Structural Models of Trigonal-Planar Type I Copper Protein Active Sites,” J_ Am. Chem. Soc. May 10, 1999, 121, 7270-7271.
[cited by applicant]
Holland et al., “A Structural Model of the Type I Copper Protein Active Site: N2S(thiolate)S{thioether) Ligation in a Cu{H) Complex,” J_ Am. Chem. Soc. 2000, 122, 6331-6332.
[cited by applicant]
Pap et al. “Tetra-, penta-and hexacoordinate copper (II) complexes with N3 donor isoindoline-based ligands: Characterization and SOD-like activity.” Inorganica Chimica Acta 376.1 (2011): 158-169.
[cited by applicant]
Iwaizumi et al. “Correlation between the hyperfine coupling constants of donor nitrogens and the structures of the first coordination sphere in copper complexes as studied by nitrogen-14 ENDOR spectroscopy.” Inorganic C…
[cited by applicant]
Mitrikas et al. “Asymmetric Spin Density Distribution in the Copper (ii) Complex of N-Confused Tetraphenylporphyrin: A Multifrequency Continuous-Wave and Pulse EPR Study.” Angewandte Chemie International Edition 44.21 (…
[cited by applicant]
Heinze et al. “Heteroleptic Cu (II) dipyrromethene complexes linked via hydrogen bonds, coordinative bonds, and covalent bonds: probing the coordination environment by electron paramagnetic resonance spectroscopy.” Inor…
[cited by applicant]
Bailey et al. “Ethyl Pyrrole-2-Carboxylate: 1H-Pyrrole-2-carboxylic acid, ethyl ester.” Organic syntheses 51 (2003): 100-100.
[cited by applicant]
Sheldrick, George M. “A short history of SHELX.” Acta Crystallographica Section A: Foundations of Crystallography 64.1 (2008): 112-122.
[cited by applicant]
Macrae et al. “Mercury CSD 2.0—new features for the visualization and investigation of crystal structures.” Journal of Applied Crystallography 41.2 (2008): 466-470.
[cited by applicant]
Spek, A. L. J. “Single-crystal structure validation with the program PLATON.” Journal of applied crystallography 36.1 (2003): 7-13.
[cited by applicant]
Van der Sluis et al. “BYPASS: an effective method for the refinement of crystal structures containing disordered solvent regions.” Acta Crystallographica Section A: Foundations of Crystallography 46.3 (1990): 194-201.
[cited by applicant]
Astashkin et al. “26.5-40 GHz Ka-band pulsed EPR spectrometer.” Concepts in Magnetic Resonance Part B: Magnetic Resonance Engineering: An Educational Journal 29.3 (2006): 125-136.
[cited by applicant]
Humphlett, W. J. “4-(D-arabino-tetrahydroxybutyl)-4-thiazoline-2-thione synthesis of optical isomers and analogs.” Carbohydrate Research 7.4 (1968): 431-441.
[cited by applicant]
Humphlett, W. J. “A determination of the structure of 4-(d-arabino-tetrahydroxybutyl)-4-thiazoline-2-thione.” Carbohydrate Research 6.1 (1968): 25-33.
[cited by applicant]
Serra et al., “Thiosemicarbazide, a fragment with promising indolamine-2,3-dioxygenase (IDO) inhibition properties,” Eur. J.Med. Chem. 82, 2014, 96-105.
[cited by applicant]
Kwok et al., “The iron metabolism of neoplastic cells: Alterations that facilitate proliferation?” Crit. Rev. Oncol. Hemalol. 2002, 42, 65-78.
[cited by applicant]
Yu et al., “Chelators at the cancer coalface: Desferrioxamine to triapine and beyond,” Clin. Cancer Res.Dec. 1, 2006, 12, 6876-6883.
[cited by applicant]
Richardson et al. “Cancer cell iron metabolism and the development of potent iron chelators as anti-tumour agents.” Biochimica et Biophysica Acta (BBA)—General Subjects 1790.7 (2009): 702-717.
[cited by applicant]
Sutherland et al., “Ubiquitous cell-surface glycoprotein on tumor cells is proliferation-associated receptor for transferrin,” Proc. Nall. Acad. Sci. U. S. A. Mar. 17, 1981, 78, 4515-4519.
[cited by applicant]
Kontoghiorghes et al., “Chelators controlling metal metabolism and toxicity pathways: Applications in cancer prevention, diagnosis and treatment,” Hemoglobin 2008, 32, 217-227.
[cited by applicant]