This chapter demonstrates the successful preparation and analytical and spectroscopic characterization of three new EDTA-N, N'' Bis(amides) ligands functionalized by luminophores (4-(aminomethyl)pyridine (L1) and 2-aminoanthraquinone (L2) and sulphonate (aminomethanesulfonic acid (L3)) on the amide side-arms (L1-L3) and their transition metal complexes (Mn (II), Cu (II) (except for L3), Zn (II)). Harnessing the strengths of two or more imaging modalities in terms of spatial resolution (for MRI) and specificity (for PET/OI) in a small molecule could immensely facilitate multimodal theranostic. A theranostic agent as a hybrid small molecule comprising both diagnostic and therapeutic arms with enhanced stability could effectively deliver the promise of precision medicine. Also, this cannot be achieved by a mere combination of two imaging agents unless they have identical pharmacodynamic properties. On the other hand, toxicity issues also pose limitations. The potential of L1-L3 to act as a dual-modal contrast agent for magnetic resonance imaging (MRI CA) was evaluated by measuring physicochemical properties such as (a) thermodynamic stability by measuring macroscopic protonation constants and stability constants with potentiometric titrations (b) R1 relaxivities by NMR relaxivity studies (c) spectrophotometric investigations. The stability of the AURKB-L1 complex was evaluated by monitoring the root-mean-square deviation (RMSD) of the protein C\(\alpha\) atoms and the root-mean-square fluctuation (RMSF) of the amino acid residues as well as the inhibitor-protein hydrogen bonding interactions along the simulation trajectory. Comparative studies revealed Mn-L1 has a performance comparable to the commercially available gadolinium-based contrast agents and is relatively higher than TESLASCAN. The photophysical characterization confirmed the ability of L1 and L2 to act as on-off type, fluorescent-based chemosensors for Cu (II). Time-resolved fluorescence investigations (TCSPC) indicated the potentiality of L1 for live-cell imaging. A structure-based virtual screening followed by molecular dynamic simulation validated that the potential of L1 could act as a multi-target ligand to modulate the activity of two unrelated receptor proteins: Aurora kinase B and human serum albumin.

Three new EDTA-N, N’’ Bis(amides) ligands functionalized by luminophores (4-(aminomethyl)pyridine (L1) and 2-aminoanthraquinone (L2) and sulphonate (aminomethanesulfonic acid (L3)) on the amide side-arms (L1-L3) and their transition metal complexes (Mn (II), Cu (II) (except for L3), Zn (II)) were synthesized and characterized by analytical and spectroscopic techniques. The potential of L1-L3 to act as a dual-modal contrast agent for magnetic resonance imaging (MRI CA) was evaluated by measuring physicochemical properties such as (a) thermodynamic stability by measuring macroscopic protonation constants and stability constants with potentiometric titrations (b) R1 relaxivities by NMR relaxivity studies (c) spectrophotometric investigations. Comparative studies revealed Mn-L1 has performance comparable to the commercially available gadolinium-based contrast agents Magnevist® and Dotarem®. It is also higher than Teslascan® (manganese-based contrast agent, previously clinically approved and withdrawn from the market). Specifically, Mn-L1 exhibited relaxivity of 3.52 mM-1S-1 (at 30 MHz, 37 °C) as opposed to Teslascan® of 1.88 mM-1s−1(at 20 MHz, 37 °C). L1 also exhibited high overall stability constant for its Zn (II) complex (16.03), slightly higher than Teslascan® (15.1). Furthermore, the sharp break exhibited in the NMRD titration profile of L1 with Mn (II) indicated a 1:1 complex formation and substantiates a higher association constant. The photophysical characterization confirmed the ability of L1 and L2 to act as on–off type, fluorescent-based chemosensors for Cu (II). Time-resolved fluorescence investigations (TCSPC) indicated the potentiality of L1 for live-cell imaging. Unfortunately, while relaxivity studies on L2 were prevented by solubility issues at physiological pH, L3 exhibited poor complexation with Mn (II) and prevented further investigation. We also demonstrate through a structure-based virtual screening that L1 could act as a multi-target ligand to modulate the activity of two unrelated receptor proteins; Human aurora B kinase and Human serum albumin. Moreover, L1 exhibited a strong binding affinity for blood plasma protein, human serum albumin and this was relatively higher than FODIPIR, the ligand for Teslascan®.

The reactions of 1,5,9-triethyl-1,5,9-triphosphacyclododecane, [12]-ane-P3Et3, and 1,5,9-tri(2-propyl)-1,5,9-triphosphacyclododecane, [12]-ane-P3iPr3 with copper(i)halides produce either bimetallic species of the type [([12]-ane-P3R3)Cu(CuX2)] (X = halide) or monomeric [([12]-ane-P3R3)CuX] depending on the nature of the halide and, to a lesser extent, the macrocycle. With CuCl only bimetallic complexes are formed with one copper centre bound to the macrocycle and a second attached through a Cu-Cu bond with a mono bridging chloride. CuBr affords monomeric [([12]-ane-P3R3)CuBr] complexes when performed in a 1 : 1 M : L ratio whereas the bimetallic compound [([12]-ane-P3Et3)(CuBr)2], resulted when a 2 : 1 ratio of M : L was employed. With CuI in all ratios only monomeric complexes were obtained. The synthesised complexes have been fully characterised by spectroscopic and analytical techniques and by determination of the molecular structures by single-crystal X-ray diffractometry.

Two new DTPA analogues, centrally (L1) and terminally (L2) functionalised with a 1,8-naphthalimide chromophore, have been successfully prepared and fully characterized.

An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.

We report two tripodal frameworks, mono(2,2'-bipyrid-6-yl)bis(2-pyridyl)methanol () and bis(2,2'-bipyrid-6-yl)mono(2-pyridyl)methanol () which have one and two bipyridyl arms, respectively. Both ligands form complexes with the first row transition metals. Both ligands appear to overcome the steric strain involved in twisting the ligand to produce an octahedral complex and the solid state structures in general show more octahedral character than complexes of the related ligand, tris(2,2'-bipyrid-6-yl)methanol (). Continuous Shape Mapping (CShM) calculations based on crystallographic data reveal that is incapable of enforcing a trigonal prismatic (TP) co-ordination geometry in the solid state, surprisingly even upon co-ordination to metals with no stereochemical preference such as cadmium (S(TP) = 7.15 and S(Oh) = 3.95). However, ligand clearly maintains an ability to enforce a trigonal prismatic conformation which is demonstrated in the crystal structures of the Mn(II) and Cd(II) complexes (S(TP) = 0.75 and 1.09, respectively). While maintains near-TP configurations in the presence of metal ions with strong octahedral preferences, distorts towards predominantly octahedral co-ordination geometries, increasing in the order Co(II) < Ni(II) < Fe(II) and no trigonal prismatic structures.

An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.

The radiosynthesis and radiopharmacological evaluation including small animal PET imaging of a novel 64Cu-labelled cryptand molecule ([64Cu]CryptTM) possessing a tris-pyridyl/tris-amido set of donor atoms is described.

The cationic complex (η4-1,2,3,4-tetramethylcyclobutadienyl)cobalt(trisacetonitrile), [(η4-C4Me4)Co(NCCH3)3]+ (1), allows the stepwise introduction of suitable phosphine precursors to the [(η4-C4Me4)Co]+ fragment by replacement of the labile acetonitrile ligands. These reactions give rise to the piano-stool complexes [(η4-C4Me4)Co(dppe)(NCCH3)]+ (2), [(η4-C4Me4)Co(dppe)(PH2Ph)]+ (3), [(η4-C4Me4)Co(dfppb)(NCCH3)]+ (4), and [(η4-C4Me4)Co(dfppb)(PH2Ph)]+ (5), where dfppb = 1,2-bis{di(2-fluorophenyl)phosphino}benzene and dppe = 1,2-bis(diphenylphosphino)ethane. Complex 5 is a template for the synthesis of the P3 macrocycle complex [(η4-C4Me4)Co{1,4-bis(2-fluorophenyl)-7-phenyl[b,e,h]tribenzo-1,4,7-triphosphacyclononane}]+ (6), through base-promoted intramolecular macrocyclization. The hydrogens of two of the ring methyls of the tetramethylcyclobutadienyl ligand in the macrocycle complex 6 are sufficiently acidic to undergo deprotonation by KOtBu, promoting nucleophilic attack at the fluorine-bearing ortho-carbons of the 2-fluoroaryl groups on two of the phosphorus donors in 6. The resultant hemi-incarcerand complex [{η4,κP,κP,κP-Me2C4-[1,4-bis(2-CH2C6H4)-7-C6H5-[b,e,h]tribenzo-1,4,7-triphosphacyclononane]-1,2}Co]+ (cis-7) contains a hybrid phosphorus/carbon donor ligand where the P3 macrocycle is connected to the cyclobutadienyl function through two cis-2-methylphenyl links. The new complexes have been characterized fully by spectroscopic and analytical techniques including single-crystal X-ray structure determinations of 2, 3, 4, 5, 6, and cis-7.

The tripodal bipyridine-based ligand tris(2,2’-bipyrid-6-yl) methanol (L 1 ) was shown in our previous work to have a strong steric preference for trigonal prismatic co - ordination environments with a series of transition metals. We now report the crystal structure of the ligand framework, isolated in its monoprotonated form with a perchlorate counterion. The structure was solved in a monoclinic space group C2/c with cell parameters, a = 21.5885(3), b = 11.7485(3), c = 24.6939(6) Å, α = 90°, β = 110.790(1) °, γ = 90°, volume = 5855.4(2) Å3 , Z = 8. The 1H NMR of the protonated ligand is similar to the parent ligand and showed the compound retained its 3-fold symmetry and all bipyridine groups were equivalent.

Nine-membered 1,4,7-triphosphamacrocycles with unsaturated benzo-backbones have been prepared using the [(CO)3Mn](+) unit as a template. Two synthetic methods have been employed for the macrocyclisation both of which involve the attack of a coordinated phosphide at an activated, electrophilic ortho-fluorophenyl substituent on a neighbouring pnictide donor. Addition of base to the precursor complex fac-[(CO)3Mn(dfppb)(PhPH2)](+), 1, where dfppb = 1,2-bis[di(2-fluorophenyl)phosphino]benzene, results in the direct formation of the macrocyclic compound fac-[Mn(CO)3(tribenzo-9aneP3-Ph,Ph(F)2)](+), 3. A second precursor, namely fac-[(CO)3Mn(1,2-bpb){P(Ph(F))3}](+), 5, where 1,2-bpb = 1,2-bis(phosphino)benzene, undergoes spontaneous partial macrocyclisation when dissolved in THF to give the intermediate complex fac-[(CO)3Mn{H2PC6H4P(H)C6H4P(Ph(F))2}](+), 6, which contains a linear tridentate phosphine with the unusual combination of a primary, secondary and tertiary phosphine donor. Addition of base to 6 gives the desired macrocyclic complex fac-[Mn(CO)3(tribenzo-9aneP3-H2,Ph(F))](+), 7, which is converted in situ to the more stable dimethylated fac-[Mn(CO)3(tribenzo-9aneP3-Me2,Ph(F))](+), 8. The new complexes have been fully characterised by spectroscopic and analytical methods including single crystal X-ray structure determinations for 1, 3, 5, 6 and 8.

An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.

An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.

Racemic trans-1,2-diphosphinocyclohexane (t-chxnP(2)) has been synthesised and its coordination chemistry to Cu(I), Ag(I), Mn(I) and Fe(II) investigated. Compounds of empirical formula [Cu(t-chxnP(2))(2)]BF4 and [Ag(t-chxnP(2))(2)]BF4 have been prepared as isomeric mixtures and the solid-state structure of both complexes determined by single-crystal techniques. The Cu(I) complex is a monomeric species which crystallises with one ligand bearing the R,R configuration and the other being the S,S isomer whereas the Ag(I) complex crystallises as a polymer containing both chelating and bridging t-chxnP(2) ligands with 3- and 4-coordinate Ag(I) centres and argentophilic bonds. The bidentate diprimary phosphine has been coordinated to Mn(I) and Fe(II) templates and used as a P-2 unit for the formation of chiral (albeit racemic) 1,4,7-triphosphamacrocycles (9aneP(3)). In addition 1R,2R- and 1R,2S-diaminocyclohexane (chxn) have been coordinated to Mn(I) and Fe(II) templates and similarly employed for the formation of new 1,4diamino-7-phosphamacrocycle (9anePN(2)) complexes.

Methods: Stability of [64Cu]Cu-CryptTM was assessed in vitro by challenging experiments using competitive chelators EDTA and NOTA. Radiopharmacological profile of [64Cu]Cu-CryptTM was evaluated by dynamic PET studies in EMT6-tumor bearing Balb/C mice. The current “gold standard” for kinetically inert 64Cu-cryptates [64Cu]Cu-DiAmSar was prepared and used as internal reference for in vitro and in vivo studies. Results: Radiochemical yields of > 95% were achieved by mixing CryptTM (0.25 nmol/μL) and [64Cu]Cu(OAc)2 (4.1 ± 0.5 MBq/μL) for 60 min at 37 °C. EDTA and NOTA clearly demonstrated kinetically- and thermodynamically-driven trans-chelation. Dynamic PET studies showed fast blood clearance for [64Cu]Cu-CryptTM and [64Cu]Cu-DiAmSar. [64Cu]Cu-CryptTM was predominantly eliminated hepatobiliary. Uptake of [64Cu]Cu-CryptTM in EMT6 tumors resulted in an SUV 0.40 ± 0.03 which was higher compared to muscle (SUV 0.16 ± 0.02 (n = 3) 60 min p.i.). Conclusion: Radiopharmacological evaluation of [64Cu]Cu-CryptTM revealed insufficient kinetic stability for in vivo applications. However, the facile synthetic access and its favorable 64Cu-labeling properties warrant further investigation of related derivatives possessing a tri-pyridyl/tri-amine donor group set to allow the formation of more kinetically inert 64Cu-cryptates.

The reaction of 1,2-o-xylyl dichloride with activated zinc in THF gives the organozinc compound [(μ-o-xyl)Zn2Cl2(THF)4], 1, where xyl = (2-methanidylphenyl)methanide. The compound is stable in the solid state but undergoes a slow decomposition in solution to generate the μ4-oxo cluster [(μ-o-xyl)2Zn4(μ-Cl)2(μ4-O)(THF)4], 3, which has been characterised in the solid state by single-crystal X-ray techniques. The organozinc complex 1 catalyses the ring-opening of THF in the presence of PCl3 to give a mixture of the two compounds [Cl(CH2)4O]PCl2 and [Cl(CH2)4O]2PCl.

The title compound has been obtained from the one-pot reaction of benzene-1,2-dicarbonitrile with NaH followed by addition of two equivalents of (BuPCl2)-Bu-t. The compound is obtained as an orange-red solid in good yield and has been characterized by spectroscopic and analytical methods including the determination of the molecular structure by single-crystal X-ray techniques.

The new tripodal ligand tris(picolyl-2-carboxyamido-6-pyridyl) methanol (L1) has been synthesised via a Pd-catalysed amidocarbonylation reaction in good yield (64%). The ligand has been shown to readily form mononuclear complexes with both Fe(II) and Zn(II). Continuous Shape Mapping calculations have also been performed which confirm the ligands ability to enforce near-perfect trigonal prismatic co-ordination environments upon each of these metal ions.