Cyclam Derivatives Research Articles

Extending the Scope of the C-Functionalization of Cyclam via Copper(I)-Catalyzed Alkyne-Azide Cycloaddition to Bifunctional Chelators of Interest.

Cyclam, known for its potent chelation properties, is explored for diverse applications through selective N-functionalization, offering versatile ligands for catalysis, medical research, and materials science. The challenges arising from N-alkylation, which could decrease the coordination properties, are addressed by introducing a robust C-functionalization method. The facile two-step synthesis proposed here involves the click chemistry-based C-functionalization of a hydroxyethyl cyclam derivative using Cu(I)-catalyzed alkyne-azide cycloaddition (CuAAC). Boc-protecting groups prevent undesired copper coordination, resulting in compounds with a wide range of functionalities. The optimized synthesis conditions enable C-functional cyclams to be obtained easily and advantageously, with high application potential in the previously cited fields. The methodology has been extended to trehalose-based Siamese twin amphiphiles, enabling efficient gene delivery applications.

Reusable HNO Sensors Derived from Cu Cyclam: A DFT Study on the Mechanistic Origin of High Reactivity and Favorable Conformation Changes and Potential Improvements.

Nitroxyl (HNO) exhibits unique favorable properties in regulating biological and pharmacological activities. However, currently, there is only one Cu-based HNO sensor that can be recycled for reusable detection, which is a Cu cyclam derivative with a mixed thia/aza ligand. To elucidate the missing mechanistic origin of its high HNO reactivity and subsequent favorable conformation change toward a stable CuI product that is critical to be oxidized back by the physiological O2 level for HNO detection again, a density functional theory (DFT) computational study was performed. It not only reproduced experimental structural and reaction properties but also, more importantly, revealed an unknown role of the coordination atom in high reactivity. Its conformation change mechanism was found to not follow the previously proposed one but involve a novel favorable rotation pathway. Several newly designed complexes incorporating beneficial effects of coordination atoms and substituents to further enhance HNO reactivity while maintaining or even improving favorable conformation changes for reusable HNO detection were computationally validated. These novel results will facilitate the future development of reusable HNO sensors for true spatiotemporal resolution and repeated detection.

Cross-bridged cyclam derivatives with bis(phosphinate) and phosphinate-phosphonate pendant arms (cb-BPC) as chelators for copper radioisotopes.

Copper radioisotopes can be used for imaging as well as for therapy and, thus, can form ideal theranostic pairs. The Cu(II) complexes of cross-bridged cyclam (cb-cyclam) derivatives are considered to be highly stable in vivo. However, the complexes are mostly formed under harsh conditions not compatible with sensitive biomolecules. Here, a new class of cb-cyclam derivatives, cross-bridged bis(phosphinate)cyclams ("cb-BPC"), were investigated. Ligands with one or two methylene-bis(phosphinate) -CH2-PO2H-CH2-PO2H(R) (R = H, OH, substituted alkyl) pendant arms were synthesized. Bifunctionalization on the distant phosphorus atom was carried out by employing P-nitrobenzyl (R = CH2-Ph-4-NO2) precursors and/or, for cb-BPC with two bis(phosphinate) pendant arms, by reactions of silyl-phosphites obtained by silylation of their P(O)-H fragments. The reactive bifunctional groups include amine, carboxylate, azide, isothiocyanate, maleimide and/or tetrazine, and also their orthogonally reactive combination in a single molecule of chelator. The cb-BPCs with one bis(phosphinate) arm were not efficiently radiolabelled with 64Cu. The cb-BPCs with two pendant arms were radiolabelled even at room temperature and with only a small excess of chelator, leading to a high specific activity. Radiolabelling was fully comparable with that of analogous bis(phosphinate) derivatives of cyclam and identical radiolabelling of cyclam and cb-cyclam derivatives was observed for the first time. The cb-BPCs with two bis(phosphinate) pendant arms represent a new class of rigid chelators for copper radioisotopes that are easily synthetically modifiable, highly hydrophilic and radiolabelled under mild conditions.

Trans-IV restriction: a new configuration for metal bis-cyclam complexes as potent CXCR4 inhibitors.

The chemokine receptor CXCR4 is implicated in multiple diseases including inflammatory disorders, cancer growth and metastasis, and HIV/AIDS. CXCR4 targeting has been evaluated in treating cancer metastasis and therapy resistance. Cyclam derivatives, most notably AMD3100 (Plerixafor™), are a common motif in small molecule CXCR4 antagonists. However, AMD3100 has not been shown to be effective in cancer treatment as an individual agent. Configurational restriction and transition metal complex formation increases receptor binding affinity and residence time. In the present study, we have synthesized novel trans-IV locked cyclam-based CXCR4 inhibitors, a previously unexploited configuration, and demonstrated their higher affinity for CXCR4 binding and CXCL12-mediated signaling inhibition compared to AMD3100. These results pave the way for even more potent CXCR4 inhibitors that may provide significant efficacy in cancer therapy.

Novel cyclam multicomponent crystal forms: synthesis, characterization and antimicrobial activity

Novel multicomponent crystal forms were obtained from reactions of trans-disubstituted cyclam derivatives with flufenamic and salicylic acids.

On the dissociation pathways of copper complexes relevant as PET imaging agents

Several bifunctional chelators have been synthesized in the last years for the development of new 64Cu-based PET agents for in vivo imaging. When designing a metal-based PET probe, it is important to achieve high stability and kinetic inertness once the radioisotope is coordinated. Different competitive assays are commonly used to evaluate the possible dissociation mechanisms that may induce Cu(II) release in the body. Among them, acid-assisted dissociation tests or transchelation challenges employing EDTA or SOD are frequently used to evaluate both solution thermodynamics and the kinetic behavior of potential metal-based systems. Despite of this, the Cu(II)/Cu(I) bioreduction pathway that could be promoted by the presence of bioreductants still remains little explored. To fill this gap we present here a detailed spectroscopic study of the kinetic behavior of different macrocyclic Cu(II) complexes. The complexes investigated include the cross-bridge cyclam derivative [Cu(CB-TE1A)]+, whose structure was determined using single-crystal X-ray diffraction. The acid-assisted dissociation mechanism was investigated using HClO4 and HCl to analyse the effect of the counterion on the rate constants. The complexes were selected so that the effects of complex charge and coordination polyhedron could be assessed. Cyclic voltammetry experiments were conducted to investigate whether the reduction to Cu(I) falls within the window of common bioreducing agents. The most striking behavior concerns the [Cu(NO2Th)]2+ complex, a 1,4,7-triazacyclononane derivative containing two methylthiazolyl pendant arms. This complex is extremely inert with respect to dissociation following the acid-catalyzed mechanism, but dissociates rather quickly in the presence of a bioreductant like ascorbic acid.

Concurrent base and silver(I) catalysis pulsed by fuel acid.

Treatment of a crown-ether receptor and a silver(I)-loaded cyclam derivative (NetState-I) with a fuel acid reversibly afforded the protonated cyclam and the silver(I)-loaded crown ether (NetState-II). While NetState-I was catalytically OFF, a base-catalysed Michael addition and a silver(I)-catalysed oxime cyclisation reaction was pulsed under dissipative conditions in NetState-II.

Carborane clusters increase the potency of bis-substituted cyclam derivatives against Mycobacterium tuberculosis.

Bis-substituted cyclam derivatives have recently emerged as a promising new class of antibacterial agents, displaying excellent activity against drug-resistant Mycobacterium tuberculosis (Mtb) and in vivo efficacy in a zebrafish assay. Herein we report the synthesis and biological activity of new carborane derivatives within this class of antitubercular compounds. The resulting carborane-cyclam conjugates incorporating either hydrophobic closo-1,2-carborane or anionic, hydrophilic nido-7,8-carborane clusters display promising activity in an antibacterial assay employing the virulent Mtb strain H37Rv. The most active of these carborane derivatives exhibit MIC50 values of <1 μM, making them the most active compounds in this unique class of antibacterial cyclams reported to date.

Cyclam with a phosphinate-bis(phosphonate) pendant arm is a bone-targeting carrier of copper radionuclides.

Ligands combining a bis(phosphonate) group with a macrocycle function as metal isotope carriers for radionuclide-based imaging and for treating bone metastases associated with several cancers. However, bis(phosphonate) pendant arms often slow down complex formation and decrease radiochemical yields. Nevertheless, their negative effect on complexation rates may be mitigated by using a suitable spacer between bis(phosphonate) and the macrocycle. To demonstrate the potential of bis(phosphonate) bearing macrocyclic ligands as a copper radioisotope carrier, we report the synthesis of a new cyclam derivative bearing a phosphinate-bis(phosphonate) pendant (H5te1PBP). The ligand showed a high selectivity to CuII over ZnII and NiII ions, and the bis(phosphonate) group was not coordinated in the CuII complex, strongly interacting with other metal ions in solution. The CuII complex formed quickly, in 1 s, at pH 5 and at a millimolar scale. The complexation rates significantly differed under a ligand or metal ion excess due to the formation of reaction intermediates differing in their metal-to-ligand ratio and protonation state, respectively. The CuII-te1PBP complex also showed a high resistance to acid-assisted hydrolysis (t1/2 2.7 h; 1 M HClO4, 25 °C) and was effectively adsorbed on the hydroxyapatite surface. H5te1PBP radiolabeling with [64Cu]CuCl2 was fast and efficient, with specific activities of approximately 30 GBq 64Cu per 1 μmol of ligand (pH 5.5, room temperature, 30 min). In a pilot experiment, we further demonstrated the excellent suitability of [64Cu]CuII-te1PBP for imaging active bone compartments by dedicated small animal PET/CT in healthy mice and subsequently in a rat femoral defect model, in direct comparison with [18F]fluoride. Moreover, [64Cu]CuII-te1PBP showed a higher uptake in critical bone defect regions. Therefore, our study highlights the potential of [64Cu]CuII-te1PBP as a PET radiotracer for evaluating bone healing in preclinical and clinical settings with a diagnostic value similar to that of [18F]fluoride, albeit with a longer half-life (12.7 h) than 18F (1.8 h), thereby enabling extended observation times.

New heterobimetallic Cu(II)/Mn(II) complexes with trans-1,8-cyclam derivatives: Synthesis, characterization, magnetic properties and crystal structures of (µ2-Chloro)-(dpc)-copper(II)-trichloro-manganese(II) and two polymorphs of (µ2-Chloro)-(dac)-copper(II)-trichloro-manganese(II)

Two derivatives of cyclam (cyclam = 1,4,8,11-tetraazacyclotetradecane) with propyl- or allyl- (prop-2-en-1-yl) substituents on nitrogen atoms in trans positions, namely 1,8-dipropyl-1,4,8,11-tetraazacyclotetradecane (dpc) and 1,8-diallyl-1,4,8,11-tetraazacyclotetradecane (dac) were prepared and characterized by IR, 1H NMR and 13C NMR spectroscopy. Reaction of dpc and dac with copper(II) chloride gives compounds [Cu(dpc)(H2O)2]Cl2 (1) and [Cu(dac)(H2O)2]Cl2 (3) with similar crystal structures. Compounds 1 and 3 were used as precursors in the synthesis of Cu(II)/Mn(II) complexes 2, 4a and 4b. Prepared complexes were characterized by IR spectroscopy, elemental analysis and their crystal structures were determined using single crystal X-ray analysis. Compounds 4a and 4b are polymorphs, both crystallize in the monoclinic crystal system and the main difference in their crystal structures is in steric arrangement of metal centres within a chain. Moreover, measurements of magnetic susceptibility and Broken Symmetry DFT calculations (BS DFT calculations) carried out for bimetallic complexes 2 and 4a showed that a ferromagnetic exchange interaction J/kB = 2.28 K and J/kB = 2.34 K, respectively, exists within the dinuclear units.

Au(III) complexes with tetradentate-cyclam-based ligands.

Chiral cyclam (1,4,8,11-tetraazacyclotetradecane) derivatives were synthesized stepwise from chiral mono-Boc-1,2-diamines and (dialkyl)malonyl dichloride via open diamide-bis(N-Boc-amino) intermediates (65–91%). Deprotection and ring closure with a second malonyl unit afforded the cyclam tetraamide precursors (80–95%). The new protocol allowed the preparation of the target cyclam derivatives (53–59%) by a final optimized hydride reduction. Both the open tetraamine intermediates and the cyclam derivatives successfully coordinated with AuCl3 to give moderate to excellent yields (50–96%) of the corresponding novel tetra-coordinated N,N,N,N-Au(III) complexes with alternating five- and six-membered chelate rings. The testing of the catalytic ability of the cyclam-based N,N,N,N-Au(III) complexes demonstrated high catalytic activity of some complexes in selected test reactions (full conversion in 1–24 h, 62–97% product yields).

Synthesis and structural analysis of two cyclam derivatives

Two macrocycle derivatives (1 and 2) from the modification of 1,4,8,11-tetraazacyclotetradecane (cyclam) have been synthesized and structurally characterized. The synthesis was straightforward and led to the production of the final products at high yields and purity. Central rings of both compounds at solid state display a chair conformation with the substituents dangling around the cyclam ring. The binding cavity radii from the crystal structures are 1.349 Å in the unsubstituted precursor cyclam, 1.926 Å in 1, and 2.140 Å in 2. A computational study provided similar bond matrices but slightly larger cavity sizes, likely as a result of the spacious environment and elasticity of the molecules at gas phase. This research provided an intensive look into the modification of polyamine, which further implicates how the molecule could be manipulated to adjust its properties and functions.

Paramagnetic Cobalt(II) Complexes with Cyclam Derivatives: Toward 19F MRI Contrast Agents.

In order to develop novel, more efficient, and/or selective contrast agents for magnetic resonance imaging (MRI), different modi operandi are explored as alternatives to water-relaxation enhancement. In this work, cobalt(II/III) complexes of bis(N-trifluoroethyl)cyclam derivatives with two acetate or two phosphonate pendant arms, H2te2f2a and H4te2f2p, were prepared and investigated. X-ray diffraction structures confirmed octahedral coordination with a very stable trans-III cyclam conformation and with fluorine atoms located about 5.3 Å from the metal center. The Co(II) complexes are kinetically inert, decomposing slowly even in 1 M aqueous HCl at 80 °C. The Co(II) complexes exhibited well-resolved paramagnetically shifted NMR spectra. These were interpreted with the help of quantum chemistry calculations. The 13C NMR shifts of the trans-[CoII(te2f2p)]2- complex were successfully assigned based on spin density delocalization within the ligand molecule. The obtained spin density also helps to describe d-metal-induced NMR relaxation properties of 19F nuclei, including the contribution of a Fermi contact relaxation mechanism. The paramagnetic complexes show convenient relaxation properties to be used as 19F MRI contrast agents.

Cross-Bridged Cyclam with Phosphonate and Phosphinate Pendant Arms: Chelators for Copper Radioisotopes with Fast Complexation.

Cross-bridged cyclam derivatives bearing two phosphonate (H4L1), bis(phosphinate) (H4L2), or phosphinate (H2L3) pendant arms were synthesized and studied with respect to their application as copper radioisotope carriers in nuclear medicine. The ligands show high macrocycle basicity (pK1 > 14) and high Cu(II) complex stability (log K = 20-24). The complexation and dissociation kinetics of the Cu(II) complexes were studied by ultraviolet-visible spectroscopy. Phosphonate Cu(II)-H4L1 and bis(phosphinate) Cu(II)-H4L2 complexes form very quickly, reaching quantitative formation within 1 s at pH ∼6 and millimolar concentrations. Conversely, the formation of the phosphinate complex Cu(II)-H2L3 is much slower (9 min at pH ∼6) due to the low stability of the out-of-cage reaction intermediate. All studied complexes are highly kinetically inert, showing half-lives of 120, 11, and 111 h for Cu(II)-H4L1, Cu(II)-H4L2, and Cu(II)-H2L3 complexes, respectively, in 1 M HClO4 at 90 °C. The high thermodynamic stability, fast formation, and extreme kinetic inertness of Cu(II) complexes indicate that phosphonate and bis(phosphinate) derivatives are promising ligands for nuclear medicine.

Imaging CXCR4 Expression with Iodinated and Brominated Cyclam Derivatives

PurposeCXCR4 is one of several “chemokine” receptors expressed on malignant tumors (including GBM and PCNSL) and hematopoietic stem cells. Although 68Ga-pentixafor and 68Ga-NOTA-NFB have been shown to effectively image CXCR4 expression in myeloma and other systemic malignancies, imaging CXCR4 expression in brain tumors has been more limited due to the blood-brain barrier (BBB) and a considerable fraction of CXCR4 staining is intracellular.MethodsWe synthesized 6 iodinated and brominated cyclam derivatives with high affinity (low nM range) for CXCR4, since structure-based estimates of lipophilicity suggested rapid transfer across the BBB and tumor cell membranes.ResultsWe tested 3 iodinated and 3 brominated cyclam derivatives in several CXCR4(+) and CXCR4(−) cell lines, with and without cold ligand blocking. To validate these novel radiolabeled cyclam derivatives for diagnostic CXCR4 imaging efficacy in brain tumors, we established appropriated murine models of intracranial GBM and PCNSL. Based on initial studies, 131I-HZ262 and 76Br-HZ270-1 were shown to be the most avidly accumulated radioligands. 76Br-HZ270-1 was selected for further study in the U87-CXCR4 and PCNSL #15 intracranial tumor models, because of its high uptake (9.5 ± 1.3 %ID/g, SD) and low non-specific uptake (1.6 ± 0.7 %ID/g, SD) in the s.c. U87-CXCR4 tumor models. However, imaging CXCR4 expression in intracranial U87-CXCR4 and PCNSL #15 tumors with 76Br-HZ270-1 was unsuccessful, following either i.v. or spinal-CSF injection.ConclusionsImaging CXCR4 expression with halogenated cyclam derivatives was successful in s.c. located tumors, but not in CNS located tumors. This was largely due to the following: (i) the hydrophilicity of the radiolabeled analogues—as reflected in the “measured” radiotracer distribution (LogD) in octanol/PBS—which stands in contrast to the structure-based estimate of LogP, which was the rationale for initiating the study and (ii) the presence of a modest BTB in intracranial U87-CXCR4 gliomas and an intact BBB/BTB in the intracranial PCNSL animal model.

Magnetic Properties of Fe(II) Complexes of Cyclam Derivative with One p-Aminobenzyl Pendant Arm

In order to prepare an Fe(II) spin crossover (SCO) complex that could be consequently modified to a bimetallic coordination compound that possesses another magnetic property of interest, a specially designed ligand L-NH2 (1-(4-aminobenzyl)-4,11-bis(pyridine-2-ylmethyl)- 1,4,8,11-tetraazacyclotetradecane) was prepared. This ligand consists of a macrocyclic cyclam part containing two 2-pyridylmethyl pendant arms (expecting SCO upon Fe(II) complexation) and one p-aminobenzyl pendant arm with an NH2 group. The presence of this group enables the consequent transformation to various functional groups for the selective complexation of other transition metals or lanthanides (providing the second property of interest). Furthermore, the performed theoretical calculations (TPSSh/def2-TZVP) predicted SCO behavior for the Fe(II) complex of L-NH2. Thus, Fe(II) complexes [Fe(L-NH2)](ClO4)2 (1) and [Fe(L-NH2)]Cl2·6H2O (2) were synthesized and thoroughly characterized. Based on the crystal structure of an isostructural analogous Ni(II) complex [Ni(L-NH2)]Cl2·6H2O (3), the coordination number six was confirmed with an octahedral coordination sphere and a cis-arrangement of the pyridine pendant arms. The measured magnetic data confirmed the high-spin behavior of both compounds with large magnetic anisotropy (D = 17.8 for 1 and 20.9 cm−1 for 2 complemented in both cases also with large rhombicity), though unfortunately without any indication of the SCO behavior with decreasing temperature. The lack of SCO can be ascribed to the crystal packing and/or the non-covalent intermolecular interactions stabilizing the high-spin state in the solid state.

Reactivities of cyclam derivatives with metal–amyloid-β

New examples of azamacrocyclic metal chelators that modulate the interactions between metal ions and Aβ and the reactivities of metal–Aβ were developed under criteria based on structural and functional variations on the backbone of Cyclam.

New heterobimetallic complexes of CuII and MnII with cyclam derivatives

New heterobimetallic complexes of Cu^II and Mn^II with cyclam derivatives

PP#105 - Bifunctional cyclam derivatives with a bis(phosphinate) pendant arm as efficient chelators for copper radionuclides

PP#105 - Bifunctional cyclam derivatives with a bis(phosphinate) pendant arm as efficient chelators for copper radionuclides

Synthesis, structural characterization, EPR spectroscopy and Hirshfeld surface analysis of a novel Cu2+-doped 3,14-diethyl-2,13-diaza-6,17-diazoniatricyclo[16.4.0.07,12]docosane bis(perchlorate).

Cyclam derivatives and their metal complexes have been found to exhibit an anti-HIV effect and stimulate the activity of stem cells from bone marrow. The strength of their binding to the CXCR4 receptor correlates with anti-HIV and stem-cell activities. Knowledge of the conformation and crystal packing of various macrocyclic metal complexes has become important in developing new effective anti-HIV drugs. The synthesis and preparation of single crystals of a new Cu2+-doped macrocyclic compound, (3,14-diethyl-2,6,13,17-tetraazatricyclo[16.4.0.07,12]docosane)copper(II) bis(perchlorate)-3,14-diethyl-2,13-diaza-6,17-diazoniatricyclo[16.4.0.07,12]docosane bis(perchlorate) (0.69/0.31), {[Cu(C22H44N4)](ClO4)2}0.69·(C22H46N42+·2ClO4-)0.31, is reported. Characterization by X-ray diffraction analysis shows that the asymmetric unit contains half of a centrosymmetric molecule. The macrocyclic ligand in the compound adopts the most stable trans-III conformation. The Cu-N distances of 2.015 (3) and 2.047 (3) Å are normal, but the long axial Cu-O bond of 2.795 (3) Å may be due to a combination of the Jahn-Teller effect and the strong in-plane ligand field. The crystal structure is stabilized by hydrogen bonding between secondary N-H groups, the N atoms of the macrocycle and the O atoms of the perchlorate anions. Hirshfeld surface analysis with 2D (two-dimensional) fingerprint plots indicates that the main contributions to the crystal packing are from H...H (58.0%) and H...O/O...H (41.9%) interactions. Electron paramagnetic resonance (EPR) properties are also described.