Synthesis, in vitro and in silico assessment of organometallic Rhenium(I) and Technetium(I) thymidine complexes

Thymidine kinases have been identified as suitable targets for non-invasive imaging of gene therapy and cancer. Thus, there is a high interest in new, reliable and inexpensive radiolabeled thymidine analogues for these applications. In this study we present the synthesis and in vitro evaluation of M(CO)3-complexes of thymidine (M = 99mTc, Re) for potential use in SPECT tumor imaging. 5'-amino-5'-deoxythymidine was derivatized at position C5' with spacers of various lengths (not, vert, similar0–30 Å) carrying tridentate metal chelating entities such as iminodiacetic acid and picolylamine-N-monoacetic acid. The nucleoside derivatives were reacted with the precursors [ReBr3(CO)3]2− and [99mTc(OH2)3(CO)3]+, respectively. The organometallic thymidine complexes have been fully characterized by means of IR, NMR and mass spectrometry. Enzyme kinetic studies revealed mixed inhibition of the human cytosolic thymidine kinase with Ki values ranging from 4.4 to 334 μM for all thymidine complexes. Competitive inhibition of herpes simplex virus type 1 thymidine kinase was only achieved when thymidine and the metal core were separated by a spacer of approximately 30 Å length. These findings were supported by in silico molecular docking and molecular dynamic experiments

New Monodentate Amidine Superbasic Ligands with a Single Configuration in fac

Treatment of two precursors, fac-[Re(CO)(3)(L)(CH(3)CN)]BF(4) [L = 5,5′-dimethyl-2,2′-bipyridine (5,5′-Me(2)bipy) (1) and 6,6′-dimethyl-2,2′-bipyridine (6,6′-Me(2)bipy) (2)], with five C(2)-symmetrical saturated heterocyclic amines yielded ten new amidine complexes, fac-[Re(CO)(3)(L)(HNC(CH(3))N(CH(2)CH(2))(2)Y)]BF(4) [Y = CH(2), (CH(2))(2), (CH(2))(3), NH or O]. All ten complexes possess the novel feature of having only one isomer (amidine E configuration), as established by crystallographic and (1)H NMR spectroscopic methods. We are confident that NMR signals of the other possible isomer (amidine Z configuration) would have been detected, if it were present. Isomers are readily detected in closely related amidine complexes because the double-bond character of the amidine C–N3 bond (N3 is bound to Re) leads to slow E to Z isomer interchange. The new fac-[Re(CO)(3)(L)(HNC(CH(3))N(CH(2)CH(2))(2)Y)]BF(4) complexes have C–N3 bonds with essentially identical double-bond character. However, the reason that the Z isomer is so unstable as to be undetectable in the new complexes is undoubtedly because of unfavorable clashes between the equatorial ligands and the bulky N(CH(2)CH(2))(2)Y ring moiety of the axial amidine ligand. The amidine formation reactions in acetonitrile (25 °C) proceeded more easily with 2 than with 1, indicating that the distortion in 6,6′-Me(2)bipy resulting from the proximity of the methyl substituents to the inner coordination sphere enhanced the reactivity of the coordinated CH(3)CN. Reaction times for 1 and 2 exhibited a similar dependence on the basicity and ring size of the heterocyclic amine reactants. Moreover, when the product of the reaction of 1 with piperidine, fac-[Re(CO)(3)(5,5′-Me(2)bipy)(HNC(CH(3))N(CH(2)CH(2))(2)CH(2))]BF(4), was challenged in acetonitrile-d(3) or CDCl(3) with a fivefold excess of the strong 4-dimethylaminopyridine ligand, there was no evidence for replacement of the amidine ligand after two months, thus establishing that the piperidinylamidine ligand is a robust ligand. This chemistry offers promise as a suitable means for preparing isomerically pure conjugated fac-[(99m)Tc(CO)(3)L](n+/−) imaging agents, including conjugates with known bioactive heterocyclic amines

Formation of a Metal-to-Nitrogen Bond of Normal Length by a Neutral Sufonamide Group within a Tridentate Ligand. A New Approach to Radiopharmaceutical Bioconjugation

We demonstrate that a tertiary sulfonamide group, N(SO(2)R)R′(2), can re-hybridize to form a M–N bond of normal length even when the group is in a linear tridentate ligand, such as in the new tridentate N(SO(2)R)dpa ligands derived from di-(2-picolyl)amine (N(H)dpa). N(SO(2)R)dpa ligands were used to prepare fac-[Re(CO)(3)(N(SO(2)R)dpa)](PF(6) or BF(4)) complexes. Structural characterization of the new complexes established that the tertiary sulfonamide nitrogen atom binds to Re with concomitant sp(2)-to-sp(3) re-hybridization, facilitating facial coordination. The new fac-[Re(CO)(3)(N(SO(2)R)dpa)]X structures provide the only examples for any metal with the sulfonamide as part of a noncyclic linear tridentate ligand and with a normal metal-to-nitrogen(tertiary sulfonamide) bond length. Rare previous examples of such normal M–N bonds have been found only in more constrained situations, such as with tripodal tetradentate ligands. Our long-term objectives for the new tridentate N(SO(2)R)dpa ligands are to develop the fundamental chemistry relevant to the eventual use of the fac-[M(I)(CO)(3)](+) core (M = (99m)Tc, (186/188)Re) in imaging and therapy. The sulfonamide group uniquely contributes to two of our goals: expanding ways to conjugate the fac-[M(I)(CO)(3)](+) core to biological molecules and also developing new symmetrical tridentate ligands that can coordinate facially to this core. Tests of our conjugation method, conducted by linking the fac-[Re(I)(CO)(3)](+) core to a new tetraarylporphyrin (T(N(SO(2)C(6)H(4))dpa)P) as well as to a dansyl (5-(dimethylamino)naphthalene-1-sulfonyl) group, demonstrate that large molecular fragments can be tethered via a coordinated tertiary sulfonamide linkage to this core

Complexes Possessing Rare “Tertiary” Sulfonamide Nitrogen-to-Metal Bonds of Normal Length: fac

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(SO(2)R)(CH(2)Z)(2))](n) complexes (Z = 2-pyridyl) with N(SO(2)R)dpa ligands derived from di-(2-picolyl)amine (N(H)dpa). fac-[M(CO)(3)(N(SO(2)R)(CH(2)Z)(2))](n) agents (M = (186/188)Re, (99m)Tc) could find use as radiopharmaceutical bioconjugates when R is a targeting moiety. However, the planar, electron-withdrawing 2-pyridyl groups of N(SO(2)R)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(CH(2)Z)(2) chelate framework. New C(2)-symmetric ligands, N(SO(2)R)(CH(2)Z)(2) with (Z = CH(2)NH(2); R = Me, dmb, or tol), were prepared by treating N(H)dien(Boc)(2), a protected diethylenetriamine (N(H)dien) derivative, with methanesulfonyl chloride (MeSO(2)Cl), 3,5-dimethylbenzenesulfonyl chloride (dmbSO(2)Cl), and 4-methylbenzenesulfonyl chloride (tolSO(2)Cl). Treatment of fac-[Re(CO)(3)(H(2)O)(3)](+) with these ligands, designated as N(SO(2)R)dien, afforded new fac-[Re(CO)(3)(N(SO(2)R)dien)]PF(6) complexes. Comparing the fac-[Re(CO)(3)(N(SO(2)Me)dien)]PF(6) and fac-[Re(CO)(3)(N(SO(2)Me)dpa)]PF(6) complexes, we find that the Re(I)–N(sulfonamide) bonds are normal in length and statistically identical and that the methyl (13)C 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 sp(2)-to-sp(3) rehybridization upon coordination to Re(I) in both complexes. Thus, the sulfonamide N of N(SO(2)R)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(SO(2)tol)dien)]PF(6) complex, even after several weeks. This complex is also stable to heat in aqueous solution. These results indicate that N(SO(2)R)dien ligands form fac-[Re(CO)(3)(N(SO(2)R)dien)]PF(6) complexes sufficiently robust to be utilized for radiopharmaceutical development