Monofunctionalization of Calix[4]arene Tetracarboxylic Acid at the Upper Rim with Isothiocyanate Group: First Bifunctional Chelating Agent for Alpha-Emitter Ac-225

Abstract

A procedure is reported for synthesizing a novel, water-soluble bifunctional chelating agent derived from calix [4]arene. This chelate features tetracarboxylic acid groups at the lower rim as an actinium-225 ionophore, and an isothiocyanate functional group at the upper rim for labeling of the N-terminus of monoclonal antibodies through thiourea linkage.Keywords actinium-225; bifunctional chelating agents; calixarenes; isothiocyanate For radioimmunotherapy of cancer, it is well established that alpha (α) particles from radionuclide labels are more effective cytotoxic agents than beta (β) particles. This is because α particles dissipate a larger amount of energy over a shorter range (few cell diameters), and thus are more effective in cell killing than are β particles. 1,2 Among the α-emitting radionuclides considered suitable for radioimmunotherapy of cancer is actinium-225 (t 1/2 = 10 d), which decays through a rapid chain of daughter products to a stable product and emits four α particles, two β particles, and several gamma-ray (γ) photons with a combined energy of about 28 MeV. 3 Applications in radioimmunotherapy require Ac-225 to be bound to a protein that specifically targets cancer cells. This application also requires a bifunctional complexing agent that tightly binds Ac-225 on one side and can be linked to protein on the other side. This bifunctional complexing agent must be stable under physiological conditions. We have recently reported 4 that t-butylcalix [4] (2) reported in the literature. 6,7 Conversion of triacid to triester derivative was accomplished by refluxing in EtOH with catalytic amount of p-toluenesulfonic acid. Nitration was conducted with the treatment of 70% HNO 3 in the presence of HOAc at 0°C. Under these conditions, only one nitro group was introduced at the para position of the phenol ring of calix[4]arene without ester group. Further esterification of the remaining phenol group of 3 kept the tetraester in conic conformation. Hydrolysis of the mononitro-tetraester derivative, using NaOH or KOH as base, gave a mixture of free acid 4 and Na + or K + complexes. Only a bulky base, such as tetramethylammonium hydroxide (Me 4 NOH), gave a satisfactory NMR spectrum with exclusion of cation complexation. Reduction of 4 using the standard pressurized hydrogenation with Pd-C or Raney-Ni as a catalyst, gave virtually no reduction product; however, in the presence of palladized charcoal, hydrazine hydrate 8,9 reduced 4 to amine 5 in nearly-quantitative yield within 2 hours. Reaction of the amino compound with thiophosgene 10 gave the title compound, 5-isothiocyanato-25,26,27,28-tetrakis-[(hydroxycarbonyl)methoxy]-calix[4]arene (6).1 H NMR 11 of the monofunctionalized calixarene 4 clearly showed cone conformation. Because of its asymmetric structure, four pairs of doublets for the ArCH 2 Ar methylene protons (two AX systems) and 3 singlets in the ratio of 2:1:1 for OCH 2 COOH groups were found in the spectrum. Amino-and isothiocyanato-derivatives showed simplified pattern for OCH 2 COO...

Synthesis of a Calix[4]arene‐Monodiazonium Salt for Surface Modification

“…The precipitate was washed with methanol (5 mL), CH 2 Cl 2 (3 × 5 mL) and dried under vacuum to yield product 8 as white solid (0.393 g, 73 % yield). The 1 H NMR spectrum of 8 is in accordance with the one reported in the literature …”

“…Hydrolysis of the ester groups of 6 yielded the tetra‐acid 7 in high yield and a Staudinger reduction of the azido group gave the corresponding amino derivative 8 . It is noteworthy that compound 8 was already described in the literature but it was obtained in a lower 28 % overall yield from tris‐ester 3 (42 % in our case) through a different synthesis that involved the sensitive nitration of 3 . Finally, target mono‐diazonium salt 1 was obtained in high yield by treating 8 with nitrosonium tetrafluoroborate at low temperature in acetonitrile.…”

“…Compound 3 was thus prepared through the iteroselective alkylation of calix[4]arene 2 with ethylbromoacetate in the presence of CaH 2 (Scheme ). Selective mono‐nitration of 3 at the para ‐position of the phenolic ring was already described in a moderate 56 % yield . Our attempts to reproduce this protocol using a mixture of HNO 3 (70 %) and glacial acetic acid in dichloromethane were however unsuccessful.…”

Actinium-225 for Targeted α Therapy: Coordination Chemistry and Current Chelation Approaches

“…Based on these promising studies, a derivative of this calix [4]arene tetracarboxylic acid bearing an amine-reactive isothiocyanate was prepared. 101 The further exploration of the utility of this ligand as a bifunctional chelator for 225 Ac, however, was not investigated. The synthesis of two other bifunctional calix [4]arene tetracarboxylic acid-based ligands have also been reported.…”

Barium-selective Chromoionophoric Properties of Nitro Derivative of Calix[4]arene-crown Ethers

“…Dinitro derivatives 2a and 2b were prepared by the selective nitration 7 . 9 We have utilized the nitrophenol groups 10 for the signaling unit which can be prepared easily by selective nitration of phenols and can also be used as electroactive functions.…”