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Relativity as a Synthesis Design Principle: A Comparative Study of [3 + 2] Cycloaddition of Technetium(VII) and Rhenium(VII) Trioxo Complexes with Olefins.

ABSTRACT: The difference in [3 + 2] cycloaddition reactivity between fac-[MO₃(tacn)]⁺ (M = Re, ⁹⁹Tc; tacn = 1,4,7-triazacyclononane) complexes has been reexamined with a selection of unsaturated substrates including sodium 4-vinylbenzenesulfonate, norbornene, 2-butyne, and 2-methyl-3-butyn-2-ol (2MByOH). None of the substrates was found to react with the Re cation in water at room temperature, whereas the ⁹⁹Tc reagent cleanly yielded the [3 + 2] cycloadducts. Interestingly, a bis-adduct was obtained as the sole product for 2MByOH, reflecting the high reactivity of a ⁹⁹TcO-enediolato monoadduct. On the basis of scalar relativistic and nonrelativistic density functional theory calculations of the reaction pathways, the dramatic difference in reactivity between the two metals has now been substantially attributed to differences in relativistic effects, which are much larger for the 5d metal. Furthermore, scalar-relativistic ΔG values were found to decrease along the series propene > norbornene > 2-butyne > dimethylketene, indicating major variations in the thermodynamic driving force as a function of the unsaturated substrate. The suggestion is made that scalar-relativistic effects, consisting of greater destabilization of the valence electrons of the 5d elements compared with those of the 4d elements, be viewed as a new design principle for novel ^99mTc/Re radiopharmaceuticals, as well as more generally in heavy-element coordination chemistry.

SUBMITTER: Braband H

PROVIDER: S-EPMC8388117 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:A pentapeptide macrocyclic ligand, KYCAR (lysyl-tyrosyl-cystyl-alanyl-arginine), has been designed as a potential chelating ligand for SPECT imaging and therapeutic in vivo agents. This study shows the synthesis and characterization of KYCAR complexes containing nonradioactive rhenium, 99mTc, or 188Re. The metal complexes were also biologically evaluated to determine in vivo distribution in healthy mice. The overall goals of this project were (1) to synthesize the Tc/Re pentapeptide complexes, (2) to identify spectroscopic methods for characterization of syn versus anti rhenium peptide complexes, (3) to analyze the ex vivo stability, and (4) to assess the biological properties of the [99mTc]TcO-KYCAR and [188Re]ReO-KYCAR complexes in vivo. Details on these efforts are provided below.MethodsNatRe/99mTc/188ReO-KYCAR complexes were synthesized, and macroscopic species were characterized via HPLC, IR, NMR, and CD. These characterization data were compared to the crystallographic data of ReO-KYC to assist in the assignment of diastereomers and to aid in the determination of the structure of the complex.ResultsThe radiometal complexes were synthesized with high purity (>95%). HPLC, IR, NMR and CD data on the macroscopic natReO-KYCAR complexes confirm the successful complexation as well as the presence of two diastereomers in syn and anticonformations. Tracer level complexes show favorable stabilities ex vivo for 2+ h.ConclusionMacroscopic metal complexes form diastereomers with the KYCAR ligand; however, this phenomenon is not readily observed on the tracer level due to the rapid interconversion. It was determined through pKa measurements that the macroscopic natReO-KYCAR complex is 0 at physiological pH. The [99mTc]TcO-KYCAR is stable in vitro while the [188Re]ReO-KYCAR shows 50% decomposition in PBS and serum. Biologically, the tracer level complexes clear through the hepatobiliary pathway. Some decomposition of both tracers is evident by uptake in the thyroid and stomach.

Project description:New Re(I) carbonyl complexes are proposed as candidates for photodynamic therapy after investigating the effects of the pyridocarbazole-type ligand conjugation, addition of substituents to this ligand, and replacement of one CO by phosphines in [Re(pyridocarbazole)(CO)3(pyridine)] complexes by means of the density functional theory (DFT) and time-dependent DFT. We have found, first, that increasing the conjugation in the bidentate ligand reduces the highest occupied molecular orbital (HOMO)-lowest unoccupied molecular orbital (LUMO) energy gap of the complex, so its absorption wavelength red-shifts. When the enlargement of this ligand is carried out by merging the electron-withdrawing 1H-pyrrole-2,5-dione heterocycle, it enhances even more the stabilization of the LUMO due to its electron-acceptor character. Second, the analysis of the shape and composition of the orbitals involved in the band of interest indicates which substituents of the bidentate ligand and which positions are optimal for reducing the HOMO-LUMO energy gap. The introduction of electron-withdrawing substituents into the pyridine ring of the pyridocarbazole ligand mainly stabilizes the LUMO, whereas the HOMO energy increases primarily when electron-donating substituents are introduced into its indole moiety. Each type of substituents results in a bathochromic shift of the lowest-lying absorption band, which is even larger if they are combined in the same complex. Finally, the removal of the π-backbonding interaction between Re and the CO trans to the monodentate pyridine when it is replaced by phosphines PMe3, 1,4-diacetyl-1,3,7-triaza-5-phosphabicyclo[3.3.1]nonane (DAPTA), and 1,4,7-triaza-9-phosphatricyclo[5.3.2.1]tridecane (CAP) causes another extra bathochromic shift due to the destabilization of the HOMO, which is low with DAPTA, moderate with PMe3, but especially large with CAP. Through the combination of the PMe3 or CAP ligands with adequate electron-withdrawing and/or electron-donating substituents at the pyridocarbazole ligand, we have found several complexes with significant absorption at the therapeutic window. In addition, according to our results on the singlet-triplet energy gap, all of them should be able to produce cytotoxic singlet oxygen.

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Relativity as a Synthesis Design Principle: A Comparative Study of [3 + 2] Cycloaddition of Technetium(VII) and Rhenium(VII) Trioxo Complexes with Olefins.

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