Saltar al contenido
Merck
  • Novel analogs of antitumor agent calixarene 0118: Synthesis, cytotoxicity, click labeling with 2-[(18)F]fluoroethylazide, and in vivo evaluation.

Novel analogs of antitumor agent calixarene 0118: Synthesis, cytotoxicity, click labeling with 2-[(18)F]fluoroethylazide, and in vivo evaluation.

European journal of medicinal chemistry (2014-12-03)
Tilman Läppchen, Ruud P M Dings, Raffaella Rossin, Justine F Simon, Ton J Visser, Martine Bakker, Priya Walhe, Tiemen van Mourik, Katia Donato, Judy R van Beijnum, Arjan W Griffioen, Johan Lub, Marc S Robillard, Kevin H Mayo, Holger Grüll
RESUMEN

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.

MATERIALES
Referencia del producto
Marca
Descripción del producto

Sigma-Aldrich
Acetonitrilo, suitable for HPLC, gradient grade, ≥99.9%
Sigma-Aldrich
Dimetilsulfóxido, Hybri-Max, sterile-filtered, BioReagent, suitable for hybridoma, ≥99.7%
Sigma-Aldrich
Dimetilsulfóxido, ACS reagent, ≥99.9%
Sigma-Aldrich
Dimetilsulfóxido, for molecular biology
Sigma-Aldrich
Dimetilsulfóxido, suitable for HPLC, ≥99.7%
Sigma-Aldrich
Acetonitrilo, HPLC Plus, ≥99.9%
Sigma-Aldrich
Dimetilsulfóxido, sterile-filtered, BioPerformance Certified, meets EP, USP testing specifications, suitable for hybridoma
Sigma-Aldrich
Dimetilsulfóxido, ReagentPlus®, ≥99.5%
Sigma-Aldrich
Acetonitrilo, ACS reagent, ≥99.5%
Sigma-Aldrich
Dimetilsulfóxido, ≥99.5% (GC), suitable for plant cell culture
Sigma-Aldrich
Acetonitrilo, anhydrous, 99.8%
Sigma-Aldrich
Acetonitrilo, for HPLC, for UV, ≥99.9% (GC)
Sigma-Aldrich
Dimetilsulfóxido, puriss. p.a., ACS reagent, ≥99.9% (GC)
Sigma-Aldrich
Acetonitrilo, suitable for HPLC, gradient grade, ≥99.9%
Sigma-Aldrich
Dimetilsulfóxido, anhydrous, ≥99.9%
Sigma-Aldrich
Dimetilsulfóxido, BioUltra, for molecular biology, ≥99.5% (GC)
Sigma-Aldrich
Acetonitrilo, suitable for HPLC-GC, ≥99.8% (GC)
Sigma-Aldrich
Acetonitrilo, biotech. grade, ≥99.93%
Sigma-Aldrich
Dimetilsulfóxido, puriss. p.a., dried, ≤0.02% water
Sigma-Aldrich
Dimetilsulfóxido, PCR Reagent
Sigma-Aldrich
Tris[(1-benzyl-1H-1, 2, 3-triazol-4-yl)methyl]amine, 97%
Sigma-Aldrich
Tantalum(V) ethoxide, 99.98% trace metals basis
Sigma-Aldrich
Dimetilsulfóxido, meets EP testing specifications, meets USP testing specifications
Sigma-Aldrich
Acetonitrilo, HPLC Plus, ≥99.9%, poly-coated bottles
Sigma-Aldrich
Acetonitrilo, ReagentPlus®, 99%
Sigma-Aldrich
Acetonitrilo solution, contains 0.1 % (v/v) formic acid, suitable for HPLC
Sigma-Aldrich
Acetonitrilo solution, contains 0.1 % (v/v) trifluoroacetic acid, suitable for HPLC
Sigma-Aldrich
Acetonitrilo, suitable for DNA synthesis, ≥99.9% (GC)
Sigma-Aldrich
Acetonitrilo, electronic grade, 99.999% trace metals basis
Supelco
Acetonitrilo, Pharmaceutical Secondary Standard; Certified Reference Material