Complexes Possessing Rare “Tertiary” Sulfonamide Nitrogen-to-Metal Bonds of Normal Length: fac-[Re(CO)₃(N(SO₂R)dien)]PF₆ Complexes with Hydrophilic Sulfonamide Ligands

Abstract

Tertiary sulfonamide nitrogen-to-metal bonds of normal length are very rare. We recently discovered such a bond in one class of fac-[Re(CO)3(N(SO2R)(CH2Z)2)]n complexes (Z = 2-pyridyl) with N(SO2R)dpa ligands derived from di-(2-picolyl)amine (N(H)dpa). fac-[M(CO)3(N(SO2R)(CH2Z)2)]n agents (M = 186/188Re, 99mTc) could find use as radiopharmaceutical bioconjugates when R is a targeting moiety. However, the planar, electron-withdrawing 2-pyridyl groups of N(SO2R)dpa destabilize the ligand to base and create relatively rigid chelate rings, raising the possibility that the rare M– N(sulfonamide) bond is an artifact of a restricted geometry. Also, the hydrophobic 2-pyridyl groups could cause undesirable accumulation in the liver, limiting future use in radiopharmaceuticals. Our goal is to identify a robust, hydrophilic, and flexible N(CH2Z)2 chelate framework. New C2-symmetric ligands, N(SO2R)(CH2Z)2 with (Z = CH2NH2; R = Me, dmb, or tol), were prepared by treating N(H)dien(Boc)2, a protected diethylenetriamine (N(H)dien) derivative, with methanesulfonyl chloride (MeSO2Cl), 3,5-dimethylbenzenesulfonyl chloride (dmbSO2Cl), and 4-methylbenzenesulfonyl chloride (tolSO2Cl). Treatment of fac-[Re(CO)3(H2O)3]+ with these ligands, designated as N(SO2R)dien, afforded new fac-[Re(CO)3(N(SO2R)dien)]PF6 complexes. Comparing the fac-[Re(CO)3(N(SO2Me)dien)]PF6 and fac-[Re(CO)3(N(SO2Me)dpa)]PF6 complexes, we find that the ReI–N(sulfonamide) bonds are normal in length and statistically identical and that the methyl 13C NMR signal has an unusually upfield shift compared to that in the free ligand. We attribute this unusual upfield shift to the fact that the sulfonamide N undergoes an sp2-to-sp3 rehybridization upon coordination to ReI in both complexes. Thus, the sulfonamide N of N(SO2R)dien ligands is a good donor, even though the chelate rings are conformationally flexible. Addition of the strongly basic and potentially monodentate ligand, 4-dimethylaminopyridine, did not affect the fac-[Re(CO)3(N(SO2tol)dien)]PF6 complex, even after several weeks. This complex is also stable to heat in aqueous solution. These results indicate that N(SO2R)dien ligands form fac-[Re(CO)3(N(SO2R)dien)]PF6 complexes sufficiently robust to be utilized for radiopharmaceutical development.

Synthesis, characterization and biological evaluation of dipicolylamine sulfonamide derivatized platinum complexes as potential anticancer agents

“… 30 Sulfonamide appended rhenium complexes, for example fac -[Re(CO) 3 (NSO 2 Rdien)]PF 6 (R = dmb, tol) have also been proposed as model systems for radiopharmaceuticals. 31 Symmetrically complexed radiopharmaceuticals derived from dipicolylamine, such as glucosamine-dpa 32 have been synthesized and evaluated. Previous studies revealed that the replacement of the amine proton of N(SO 2 R)dpa by various substituents facilitates the formation of metal to nitrogen bonds within the normal range of bond lengths arising exceptional biochemical properties.…”

Message in a molecule

“…The boronic acid and dipicolylamine (DPA) groups, for example, provide m-SMS with an affinity towards different saccharides45 and metal ions46, respectively. The thiourea and sulfonamide functionalities serve as additional metal ion-binding sites474849, as well as anion50 receptors and hydrogen-bonding motifs5152. Additional binding interactions may involve hydrogen bonding with the amides and carboxylic acid of m-SMS, in addition to hydrophobic interactions and π-stacking with the various aromatic groups.…”

Synthesis of Radiolabeled Technetium- and Rhenium-Luteinizing Hormone-Releasing Hormone (99mTc/Re-Acdien-LHRH) Conjugates for Targeted Detection of Breast Cancer Cells Overexpressing the LHRH Receptor

“…Symmetrical tridentate ligands such as those utilized for conjugation of these complexes have been shown to be suitable linkers because they are less likely to form racemic or diastereoisomeric mixtures, thereby increasing stability. 46 , 47 …”