Bifunctional reagents are important synthons for the organic chemist. Many of these reagents (3) have as their

SiMe2 (6 H, a) 6.01 6.58 7.33 7.63 7.73 7.27 7.08 8.55 7.47 2.71bond stretching of azomethines. It is noteworthy that the stretching frequency of the unreacted C=N group of 25 (2080 cm-l) was significantly lower than that of t h e free ligand (2150 cm-I). This decrease in frequency might be attributable to the internal coordination of the cyano group on the coordinatively unsaturated uranium atom.6 'H N M R spectra of compounds 2 (Table 11) were remarkably simple. (NSiMe& and SiMe3 protons exhibit very sharp singlets at high fields whereas CH2 protons appear as broad, dramatically deshielded signals.' Each set of protons on the inserted azomethines showed very good resolved signals that were easily assigned t o the corresponding hydrogens.8 Experimental SectionAll operations on the air-and moisture-sensitive metallacycle 1 were performed under argon atmosphere in W e d -t y p e vessels.The solvents were distilled from sodium benzophenone ketyl under argon just prior to use. 'H NMFt spectra were recorded on Bruker 400W spectrometer in c&. Chemical shifts are reported in ppm from external TMS. Gas chromatographic analof ketones were performed on XE60,5% on Chromosorb NAW 100-120. Metallacycle 1 was easily synthetized from UC14 and Na N(SiMe3), in nearly quantitative yields according to a published procedure! It was stored in the crystalline state or as standardized solutions in toluene or pentane (1-2 mol L-*).General Procedure for the Synthesis of the Metallacycles 2. To a stirred solution of 1 (1.8 "01) in 10 mL of toluene was added slowly (2 min) at rwm temperature 1.8 "01 of nitrile in 10 mL of toluene. After 5 min, the solvent was removed under vacuum and the brown residue was extracted twice with 10 mL of pentane. The solution was filtered and evaporated to give satisfactorily pure 2 (more than 95%) as a brown microcrystalline powder. Yields on isolated product were reported in Table I.General Procedure for Direct Synthesis of the Methyl Ketones. To a stirred solution of 1 (1.2 "01) in 2 mL of pentane was added 1.2 mmol of nitrile within 5 min. After 5 min, the mixture was quenched with 2 mL of HCl(1 M). The organic layer was separated, washed with 1 mL of water, dried over sodium sulfate, diluted to 10 mL with pentane, and analyzed by VPC.(6) The lack of reactivity observed for the second cyano group, even if an excess of uranium reagent was added, is in good accordance with the internal coordination of this group on the uranium atom. (7) The methylene singlet of 1 was strongly shielded (-118 ppm, CJ&, 25 "C) whereas the deehielding of the same protons in the metallacycles obtained after insertion of polar molecules into the U-C bond was a general feature (see ref 2, 3, 9 and also: Dormond, A.; Elbouadili, A,; Moise, C. J. Less. Com. Met. 1986, 122, 159).(8) T h e considerable splitting and the good resolution of signals in lH NMR spectra of the metallacyclee obtained after insertion in the uranium-methylene bond of 1 is a general feature for a wide range of organic molecules. Therefore, the utilization of t...

No abstract

Osteoclasts are actively motile on bone surfaces and undergo alternating cycles of migration and resorption. Osteoclast interaction with the extracellular matrix plays a key role in the osteoclast resorptive process and a substantial body of evidence suggests that integrin receptors are important in osteoclast function. These integrin receptors bind to the Arg-Gly-Asp (RGD) sequence found in a variety of extracellular matrix proteins and it is well established that the interaction of osteoclast v 3 integrin with the RGD motif within bone matrix proteins is important in osteoclast-mediated bone resorption. In this study, we characterized the effects of two synthetic peptidomimetic antagonists of v 3, SC-56631 and SC-65811, on rabbit osteoclast adhesion to purified matrix proteins and bone, and on bone resorption in vitro. SC-56631 and SC-65811 are potent inhibitors of vitronectin binding to purified v 3. Both SC-56631 and SC-65811 inhibited osteoclast adhesion to osteopontinand vitronectin-coated surfaces and time-lapse video microscopy showed that osteoclasts rapidly retract from osteopontin-coated surfaces when exposed to SC-56631 and SC-65811. SC-56631 and SC-65811 blocked osteoclast-mediated bone resorption in a dose-responsive manner. Further analysis showed that SC-65811 and SC-56631 reduced the number of resorption pits produced per osteoclast and the average pit size. SC-65811 was a more potent inhibitor of bone resorption and the combination of reduced pit number and size led to a 90% inhibition of bone resorption. Surprisingly, however, osteoclasts treated with SC-65811, SC-56631 or the disintegrin echistatin, at concentrations that inhibit bone resorption did not inhibit osteoclast adhesion to bone. These results suggest that v 3 antagonists inhibited bone resorption by decreasing osteoclast bone resorptive activity or efficiency but not by inhibiting osteoclast adhesion to bone per se.

No abstract