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New cyclen (1,4,7,10-teraazacyclododecane) cored dendrimers up to the second generation, functionalized with 4, 8 and 16 pyrene units, respectively, were synthesized following a convergent procedure. All new compounds were characterized by NMR spectroscopies and ESI or MALDI TOF mass spectrometry. The optical and photophysical properties of the new dendrimers were studied in THF solution. Absorption spectra showed the typical absorption bands of pyrene moieties. In the fluorescence spectra, monomer as well as excimer emission were observed for all compounds. An increased proportion of excimer emission was observed in the dendrimer of the highest generation.

In this study, a competitive assay based on a colorimetric sensing system for thymidine triphosphate (TTP) was developed using 11-mercaptoundecylphosphoric acid functionalized gold nanoparticles (Phos-AuNPs) and a p -xylyl-bis(metal 2+ -cyclen) complex as reporter and receptor units, respectively. A detection limit of 372 nM was achieved with high selectivity for TTP over other nucleotides, including thymidine diphosphate and thymidine monophosphate. The improvement in selectivity was achieved by metal ion tuning in p -xylyl-bis(metal 2+ -cyclen).

A novel Hg2+-selective colorimetric sensor based on a cyclen–nitrobenzoxadiazole (NBD) conjugate was investigated. A cyclen derivative with three ester ligands was used as the binding site and the NBD moiety acted as the reporting chromogenic subunit. Interaction of 1 with Hg2+ ions resulted in a pronounced color change from pink to yellow, and fluorescence signaling was also possible. Selective colorimetric signaling of Hg2+ ions by NBD-functionalized cyclen with a detection limit of 1.5 × 10−6 M in aqueous environments was successfully achieved.

Peptides containing the chelator DOTA have gained importance for molecular imaging and therapy with radionuclides. However, all synthons described for the convergent solid phase synthesis of DOTA–peptide conjugates show windows of stability that are too narrow to allow a clean and convergent deprotection process. The synthesis of the new prochelator DOTA-tris(OPp ester) starting from cyclen is reported. Using this prochelator for the synthesis of several DOTA peptide conjugates revealed that its cleavage—in contrast to the cleavage of DOTA-tris(tBu ester) conjugates—does not require an extended deprotection time, and therefore results in clean and homogenous products.

Three approaches to three types of cyclen-based macrotricycles have been elaborated starting from trans-bis(3-bromobenzyl)cyclen. The macrotricycles were synthesized via Pd-catalyzed amination. The first approach employed consecutive macrocyclization and benzylation steps giving a cage-like tricycle. In the second, cyclen amino groups were Boc-protected prior to formation of the second and the third rings. In the third method, macrotricycles were synthesized according to a one-step procedure using diazacrown ethers.

The design, synthesis and photophysical evaluation of 1.Tb.Na, a Tb(III)-cyclen-based sensor, possessing a phenyl iminodiacetate-based receptor, for the selective detection of Cu(II) and Hg(II) ions in water is demonstrated. Sensitisation of the Tb(III) 5D4 excited state was achieved by excitation of the phenyl receptor, which in water gave rise to a characteristic time-delayed and line-like Tb(III) emission. The Tb(III) emission was shown to be pH independent over the physiological pH window. The changes in the Tb(III) emission were monitored by carrying out metal titrations using various groups I, II and transition metal ions. Of these, only the titrations of Cu(II) and Hg(II) gave rise to modulations in the Tb(III) emission; resulting in quenching in the Tb(III) emission by ca. 65% and 40%, respectively.

A high yielding N-trans diprotection procedure for cyclen has been developed by using succinimide carbamate derivates of Boc and Cbz and chloroformate protecting groups.

The synthesis of tris-allyl-DOTA starting from cyclen and its application in the preparation of DOTA–peptide conjugates is reported. Clinically important conjugates such as DOTA–Tyr3-octreotide (DOTA–TOC), DOTA–Tyr3-octreotate (DOTA–TATE) as well as a DOTA–RGD peptide were synthesized in high yields with Fmoc solid phase peptide synthesis. The final, extremely reliable de-allylation was achieved on solid phase by different methods identifying morpholine/Pd(0) as the most suitable one obtaining all DOTA peptide conjugates in high yields. All DOTA–peptides were purified by reversed phase HPLC and structural identity was proved using MALDI-TOF mass spectrometry.

Phosphonic acid appended tetraazacyclododecane (cyclen)-based macrocycles are attractive metal-ion chelators for diagnostic imaging and therapeutic delivery. Here, we report a novel P-protected methodology that facilitates the rapid synthesis and purification of targeted phosphonic acid bearing macrocycles. Purification of these intermediates is facile, and deprotection using neat TFA is rapid, yet mild enough to preserve the integrity of delicate peptides and/or targeting moieties.

The cyclen based pyridine complexes 1Ln – 3Ln (Ln = La(III) and Eu(III)) were synthesised as metallo-ribonuclease mimics and their ability to hydrolytically cleave the phosphodiester of HPNP at 37 °C was investigated using UV–vis spectroscopy, whereas the binding of the substrate was evaluated using 31 P NMR and Eu(III)-luminescent measurements. In contrast 2La gave rise to fast pH dependent hydrolysis of HPNP, with maximum efficiency at ca. pH 8.2, and with a half-lifetime of ∼1 h, the 1Ln and 3Ln complexes were found to be inactive, emphasizing the importance of the nature of the pyridine isomer as a cofactor in the hydrolytic process.

Selective and high yield synthesis of mono N-substituted derivatives of cyclam and cyclen can be achieved by using a direct and general synthetic method with very mild reaction conditions.

The Pd-catalyzed arylation of cyclam, cyclen, and azacrown ethers by aryl halides was studied. Cofacial biscyclam and bisazacrown were synthesized by direct bonding of the anthracenyl spacer to a nitrogen atom of macrocycles.

1,3-Alternate calix[4]-cyclen-benzo-crown-6 incorporating a cyclen subunit on one side and a benzo-crown-6 on the other side of the calix[4]arene framework has been synthesized. Preliminary complexation studies of this macropolycycle with cesium and zinc picrate salts have been carried out by means of proton nuclear magnetic resonance spectroscopy.

1-(Acetic acid)-4,7,10-tris( tert -butoxycarbonylmethyl)-1,4,7,10-tetraazacyclododecane (DOTA-Tris- t Bu ester or 1 ) is a precursor chelating agent for lanthanide ions and can be efficiently labeled with various functional moieties or macromolecules to improve the targeting specificity, intracellular delivery, bio-compatibility, and pharmacokinetics of resulting contrast media used in molecular imaging. This compound is commercially available but the extremely high cost seriously limits its wide utilization. Thus, we sought a convenient and inexpensive synthesis of DOTA-Tris- t Bu ester that is readily adapted for use in any laboratory. The synthetic approach described here is straightforward and has an overall yield of 92%. Significantly, the product can be purified conveniently without using of a time- and labor-intensive column chromatography. Other advantages of this method, such as operational convenience, starting material availability, and atom efficiency make it very attractive to prepare DOTA-Tris- t Bu ester in large quantity with a reduced cost.

A mixture of bis-aminal isomers was obtained from aqueous glyoxal-triethylenetetraamine condensation. The irreversible isomerization of the species was observed and a new synthesis of cyclen proposed.

Cyclen, cyclam and homocyclen have been synthesized from the corresponding butanedione-protected linear tetramines. The cyclization step is followed by a facile deprotection of the rigidifying moiety.

Geometric immobilization of polyamine ligands is expected to change their binding properties toward practical ion discrimination. Chemosensor 5 senses only two transition metal ions in water- Hg(II) (Kd≤1 μM) and Cu(II) (Kd 56 μM)- which can be compared with bindings of a non-immobilized reference compound (9-(trpnmethyl)-anthracene; 3) with Hg(II) (Kd 14 μM) and Cu(II) (Kd 39 μM). A related bridged cyclen derivative (7) showed no effect on fluorescence by any metal ion examined.

Reaction of metaltricarbonyl complexes of cyclen and cyclam with enolisable aldehydes or acid chlorides yields, after removal of the protecting M(CO) 3 moiety, selectively mono N-functionalized derivatives.

Cyclen derivatives, as coordinating ligands, have recovered considerable interest for the development of diagnostic and therapeutic drugs, mimicking the binding site of metalloproteins. We demonstrate that the on-resin reduction of head-to-tail cyclotetrapeptides, anchored to a solid support by the side-chain of a trifunctional amino acid, is an efficient synthetic strategy. The proposed approach leads to the cyclen scaffold still bound to the resin, ready for further decorations.

An exceptionally high yielding method for the tri-protection of cyclam and cyclen using ethyl trifluoroacetate is described. The selective reaction also applies to the di-protection of 1,4,7-triazacyclononane. The application of this method in the synthesis of AMD3100, a clinical candidate for stem cell mobilization is presented.

A three-step route was used to synthesize 1,7-bis(t-butoxycarbonylmethyl)-1,4,7,10-tetraazacyclododecane (DO2A-t-Bu ester) from 1,4,7,10-tetraazacyclododecane (cyclen). The overall time of reaction was reduced from a combined ~56 h to 2.3 h with an overall yield comparable to previously reported methods.

In an effort to produce strong fluorophores which are conjugated to biologically active substrates, we report a facile, high yielding synthesis of conjugable lanthanide chelates based on the cyclen (1,4,7,10-tetraazacyclododecane) macrocycle.

Resume Action of As (NMe 2 ) 3 on “cyclen” leads to conformationnaly labile species 1 (“atran” ⇌ “arsoranure”). With CDCl 3 a new reaction occurs giving an arsorane via dichlorocarben addition and prototropic As IV ⇌ As V equilibrium.

Cyclen-based macrocyclic ligands have an essential role in the development of contrast agents for magnetic resonance imaging (MRI). A prevailing need for preparation of multifunctional probes triggered a number of attempts to synthesize and derivatize ligands which efficiently chelate lanthanide ions and have advantageous MRI properties. This digest Letter summarizes the most common synthetic approaches for the preparation of macrocyclic ligands based on cyclen depending on the desired application.