Bis-tropolonate complexes of tungsten: scaffolds for selective side-on binding of nitriles, imines and ketones.

The chiral bis-tropolonate tungsten(ii) tricarbonyl compound, (trop)2W(CO)3 (1), has been synthesized and structurally characterized. This seven-coordinate compound readily loses two carbonyl ligands to preferentially bind a series of π-bonding substrates to form six-coordinate complexes of the type (trop)2W(CO)(L). Alkynes coordinate strongly to form (trop)2W(CO)(η(2)-RCCR) (2) in which spectroscopic data is consistent with the alkyne serving as a 4-electron donor. Compound 1 will also preferentially coordinate organic nitriles in a side-on fashion through the CN triple bond. A dramatic shift in the nitrile carbon signals to greater than 210 ppm in the (13)C NMR confirms the nitriles are coordinated in an η(2) 4-electron donating capacity. Aldehydes, ketones, and imines also react with 1 to form 4-electron donor η(2) adducts. The imine adduct (trop)2W(CO)(η(2)-MeN=C(H)(tol)) (5) was characterized crystallographically and the short 1.91 A W-N bond distance supports the postulation of 4-electron donation from the imine through C=N π-bonding and N lone pair donation. Side-on coordination of ligands of this type is rare and may provide a means towards asymmetric functionalization of these substrates. All of the tropolonate compounds are prone to oxidation in air and the alkyne compounds will oxidize to stable W(IV) oxo alkyne species, (trop)2W(O)(η(2)-RCCR) (6). This causes a 90° rotation of the alkyne ligand and a reduction in alkyne donation to approximately 3 electrons, to maintain an optimal 18 electron configuration.

64Cu-NO2A-RGD-Glu-6-Ahx-BBN(7-14)NH2: a heterodimeric targeting vector for positron emission tomography imaging of prostate cancer.

INTRODUCTION: The present study describes the design and development of a new heterodimeric RGD-bombesin (BBN) agonist peptide ligand for dual receptor targeting of the form (64)Cu-NO2A-RGD-Glu-6-Ahx-BBN(7-14)NH(2) in which Cu-64=a positron emitting radiometal; NO2A=1,4,7-triazacyclononane-1,4-diacetic acid; Glu=glutamic acid; 6-Ahx=6-aminohexanoic acid; RGD=the amino acid sequence [Arg-Gly-Asp], a nonregulatory peptide that has been used extensively to target α(v)ß(3) receptors up-regulated on tumor cells and neovasculature; and BBN(7-14)NH(2)=Gln-Trp-Ala-Val-Gly-His-Leu-Met-NH(2), an agonist analogue of bombesin peptide for specific targeting of the gastrin-releasing peptide receptor (GRPr). METHODS: RGD-Glu-6-Ahx-BBN(7-14)NH(2) was manually coupled with NOTA (1,4,7-triazacyclononane-1,4,7-triacetic acid), and the resulting conjugate was labeled with (64)Cu to yield (64)Cu-NO2A-RGD-Glu-6-Ahx-BBN(7-14)NH(2). Purification was achieved via reversed-phase high-performance liquid chromatography and characterization confirmed by electrospray ionization-mass spectrometry. RESULTS: Competitive displacement binding assays displayed single-digit nanomolar IC(50) values showing very high binding affinities toward the GRPr for the new heterodimeric peptide analogues. In vivo biodistribution studies showed high uptake and retention of tumor-associated radioactivity in PC-3 tumor-bearing rodent models with little accumulation and retention in nontarget tissues. The radiolabeled conjugate also exhibited rapid urinary excretion and high tumor-to-background ratios. Micro-positron emission tomography (microPET) molecular imaging investigations produced high-quality, high-contrast images in PC-3 tumor-bearing mice 15 h postinjection. CONCLUSIONS: Based on microPET imaging experiments that show high-quality, high-contrast images with virtually no residual gastrointestinal radioactivity, this new heterodimeric RGD-BBN conjugate can be considered as a promising PET tracer candidate for the diagnosis of GRPr-positive tumors in human patients.

Reduction of an eta2-iminoacyl ligand to eta2-iminium enabled by adjacent carbon monoxide ligand replacement with a variable electron donor alkyne ligand in a cationic Tungsten(II) bis(acetylacetonate) complex.

Cationic iminoacyl-carbonyl tungsten complexes of the type [W(CO) (eta (2)-MeNCR)(acac) 2] (+) (acac = acetylacetonate; R = Ph ( 1a), Me ( 1b)) easily undergo thermal substitution of CO with two-electron donors to yield [W(L)(eta (2)-MeNCR)(acac) 2] (+) (L = tert-butylisonitrile [R = Ph ( 2a), Me ( 2b)], 2,6-dimethylphenylisonitrile [R = Me ( 2c)], triphenylphosphine [R = Ph ( 3a), Me ( 3c)], and tricyclohexylphosphine [R = Ph ( 3b)]). Tricyclohexylphosphine complex 3b exhibits rapid, reversible phosphine ligand exchange at room temperature on the NMR time scale. Photolytic replacement of carbon monoxide with either phenylacetylene or 2-butyne occurs efficiently to form [W(eta (2)-alkyne)(eta (2)-MeNCR)(acac) 2] (+) complexes ( 5a- d) with a variable electron donor eta (2)-alkyne paired with the eta (2)-iminoacyl ligand in the W(II) coordination sphere. PMe 3 adds to 1a or 5b to form [W(L)(eta (2)-MeNC(PMe 3)Ph)(acac) 2] (+) [L = CO ( 4), MeCCMe ( 6)] via nucleophilic attack at the iminoacyl carbon. Addition of Na[HB(OMe) 3] to 5b yields W(eta (2)-MeCCMe)(eta (2)-MeNCHPh)(acac) 2, 8, which exhibits alkyne rotation on the NMR time scale. Addition of MeOTf to 8 places a second methyl group on the nitrogen atom to form an unusual cationic eta (2)-iminium complex [W(eta (2)-MeCCMe)(eta (2)-Me 2NCHPh)(acac) 2][OTf] ( 9[OTf], OTf = SO 3CF 3). X-ray structures of 2,6-dimethylphenylisonitrile complex 2c[BAr' 4 ], tricyclohexylphosphine complex 3b[BAr' 4 ], and phenylacetylene complex 5a[BAr' 4 ] confirm replacement of CO by these ligands in the [W(L)(eta (2)-MeNCR)(acac) 2] (+) products. X-ray structures of alkyne-imine complexes 6[BAr' 4 ] and 8 show products resulting from nucleophilic addition at the iminoacyl carbon, and the X-ray structure of 9[BAr' 4 ] reflects methylation at the imine nitrogen to form a rare eta (2)-iminium ligand.

Bis(acetylacetonato)tricarbonyl tungsten(II): a convenient precursor to chiral bis(acac) tungsten(II) complexes.

Two equivalents of acetylacetonate (acac) have been successfully introduced into a monomeric tungsten(II) coordination sphere. With the tetracarbonyltriiodotungsten(II) anion as a precursor, the formation of a tungsten(II) bis(acac) tricarbonyl complex, W(CO)3(acac)2, 1, has been accomplished. The addition of PMe3 or PMe2Ph to tricarbonyl complex 1 formed tungsten(II)bis(acac)dicarbonylphosphine complexes 2a and 2b, respectively. Single-crystal X-ray diffraction studies of the parent tricarbonyl complex, 1, and dicarbonyl trimethylphosphine complex 2a confirmed seven-coordinate geometries for both complexes. Variable-temperature 1H and 13C{1H} NMR spectroscopy revealed fluxional behavior for these seven-coordinate molecules: rapid exchange of the three carbon monoxide ligands in 1 was observed, and movement of the phosphine ligand through a mirror plane in a C(S) intermediate species was observed for both 2a and 2b. Tricarbonyl complex 1 reacted readily with alkyne reagents to form bis(acac)monocarbonylmonoalkynetungsten(II) complexes 3a (PhC(triple bond)CH) and 3b (MeC(triple bond)CMe). Variable-temperature 1H NMR spectroscopy was used to probe rotation of the alkyne ligand in 3a and 3b. The introduction of two alkyne ligands was accomplished thermally using excess PhC(triple bond)CPh to form bis(alkyne) complex 4 which was characterized crystallographically, as well as by 1H and 13C NMR spectroscopy. The availability of W(CO)3(acac)2 as a source of the W(acac)2 d4 moiety lies at the heart of the chemistry reported here.