title: Novel analogs of antitumor agent calixarene 0118: Synthesis, cytotoxicity, click labeling with 2-[(18)F]fluoroethylazide, and in vivo evaluation.
abstract: Calixarene 0118 is a potent anti-angiogenic agent that effectively inhibited tumor growth in preclinical studies, and is currently being evaluated in a phase I clinical trial. We have designed two close mimetics of calixarene 0118 containing a terminal alkynyl-functional group, and developed an optimized semi-automated procedure for radiolabeling with 2-[(18)F]fluoroethylazide using click chemistry. Following semi-preparative HPLC purification and formulation, the lower-rim modified analog [(18)F]6 and the equatorially labeled [(18)F]13 were obtained in >97% radiochemical purity and overall decay-corrected isolated radiochemical yields of 18.7 ± 2.7% (n = 4) and 10.2 ± 5.0% (n = 4), respectively, in a total synthesis time of about 2 h. Preliminary in vivo studies in nude mice bearing human tumor xenografts revealed highest accumulation of both tracers in the liver, followed by spleen, kidney, lung and bone, with no substantial uptake in the tumor. Still, these first-in-class radiotracers are a valuable tool for pharmacokinetic profiling and improvement of calixarene-based anti-angiogenic therapeutics in the future, as similar radiolabeling strategies may be applied to other compounds in the calixarene series. The cold reference compounds of the radiotracers were characterized in terms of cytotoxicity and anti-proliferative effects on HUVEC cells and on MA148 human ovarian carcinoma cells, along with the respective precursors, a small series of 0118 analogs modified with short-chain linear alkyl substituents, and a PEG3-spaced calixarene dimer. While all of the new analogs proved at least equipotent to parent 0118, some of them inhibited HUVEC and MA148 cell growth almost 4- and 10-fold more effectively, rendering these analogs promising candidates for further evaluation in anti-angiogenic cancer therapy.
authors.affiliation: Department Minimally Invasive Healthcare, Philips Research, High Tech Campus 11, 5656 AE Eindhoven, The Netherlands. Electronic address: tilman.lappchen@philips.com.
authors.forename: Tilman
authors.initials: T
authors.lastname: Läppchen
authors.affiliation: Department of Biochemistry, Molecular Biology & Biophysics, University of Minnesota Health Sciences Center, 6-155 Jackson Hall, 321 Church Street, Minneapolis, MN 55455, USA; Department of Radiation Oncology, Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, 4301 W. Markham St., Slot 771, Little Rock, AR 72205-7199, USA.
authors.forename: Ruud P M
authors.initials: RP
authors.lastname: Dings
authors.affiliation: Department Minimally Invasive Healthcare, Philips Research, High Tech Campus 11, 5656 AE Eindhoven, The Netherlands.
authors.forename: Raffaella
authors.initials: R
authors.lastname: Rossin
authors.affiliation: Department Minimally Invasive Healthcare, Philips Research, High Tech Campus 11, 5656 AE Eindhoven, The Netherlands.
authors.forename: Justine F
authors.initials: JF
authors.lastname: Simon
authors.affiliation: Syncom BV, Kadijk 3, 9747 AT Groningen, The Netherlands.
authors.forename: Ton J
authors.initials: TJ
authors.lastname: Visser
authors.affiliation: Department Minimally Invasive Healthcare, Philips Research, High Tech Campus 11, 5656 AE Eindhoven, The Netherlands.
authors.forename: Martine
authors.initials: M
authors.lastname: Bakker
authors.affiliation: Department Minimally Invasive Healthcare, Philips Research, High Tech Campus 11, 5656 AE Eindhoven, The Netherlands.
authors.forename: Priya
authors.initials: P
authors.lastname: Walhe
authors.affiliation: Department Minimally Invasive Healthcare, Philips Research, High Tech Campus 11, 5656 AE Eindhoven, The Netherlands.
authors.forename: Tiemen
authors.initials: T
authors.lastname: van Mourik
authors.affiliation: Department Minimally Invasive Healthcare, Philips Research, High Tech Campus 11, 5656 AE Eindhoven, The Netherlands.
authors.forename: Katia
authors.initials: K
authors.lastname: Donato
authors.affiliation: Angiogenesis Laboratory, Department of Medical Oncology, VU University Medical Center, De Boelelaan 1118, 1081 HV Amsterdam, The Netherlands.
authors.forename: Judy R
authors.initials: JR
authors.lastname: van Beijnum
authors.affiliation: Angiogenesis Laboratory, Department of Medical Oncology, VU University Medical Center, De Boelelaan 1118, 1081 HV Amsterdam, The Netherlands.
authors.forename: Arjan W
authors.initials: AW
authors.lastname: Griffioen
authors.affiliation: Department Minimally Invasive Healthcare, Philips Research, High Tech Campus 11, 5656 AE Eindhoven, The Netherlands. Electronic address: johan.lub@philips.com.
authors.forename: Johan
authors.initials: J
authors.lastname: Lub
authors.affiliation: Department Minimally Invasive Healthcare, Philips Research, High Tech Campus 11, 5656 AE Eindhoven, The Netherlands.
authors.forename: Marc S
authors.initials: MS
authors.lastname: Robillard
authors.affiliation: Department of Biochemistry, Molecular Biology & Biophysics, University of Minnesota Health Sciences Center, 6-155 Jackson Hall, 321 Church Street, Minneapolis, MN 55455, USA.
authors.forename: Kevin H
authors.initials: KH
authors.lastname: Mayo
authors.affiliation: Department Minimally Invasive Healthcare, Philips Research, High Tech Campus 11, 5656 AE Eindhoven, The Netherlands.
authors.forename: Holger
authors.initials: H
authors.lastname: Grüll
mesh_terms: D020533:Angiogenesis Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D001386:Azides / Q000737:chemistry*; D047250:Calixarenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D057930:Click Chemistry; D061565:Cycloaddition Reaction; D015195:Drug Design; D005260:Female; D005462:Fluorine Radioisotopes / Q000737:chemistry*; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D015394:Molecular Structure; D011854:Radiochemistry; D016896:Treatment Outcome; D023041:Xenograft Model Antitumor Assays
chemical_list: C522266:2-fluoroethylazide; D020533:Angiogenesis Inhibitors; D001386:Azides; D005462:Fluorine Radioisotopes; C530377:compound 0118; D047250:Calixarenes
keywords: Anti-angiogenic therapy; Calixarene; Click chemistry; Compound 0118; Fluorine-18; PET imaging