Search

Site specific introduction of the polar hydrophobic trifluoromethyl-λ6-tetrafluorosulfanyl (CF3SF4) group can effectively control the secondary structure of a heptapeptide, the minimum repeat unit of an α-helix. The structural influence of CF3SF4-containing amino acid on the heptapeptide was established using NMR methods.

Pyrazinamide (PZA), an essential constituent of short-course tuberculosis chemotherapy, binds weakly but selectively to Sirtuin 6 (SIRT6). Despite the structural similarities between nicotinamide (NAM), PZA, and pyrazinoic acid (POA), these inhibitors modulate SIRT6 by different mechanisms and through different binding sites, as suggested by saturation transfer difference (STD) NMR. Available experimental evidence, such as that derived from crystal structures and kinetic experiments, has been of only limited utility in elucidation of the mechanistic details of sirtuin inhibition by NAM or other inhibitors. For instance, crystallographic structural analysis of sirtuin binding sites does not help us understand important differences in binding affinities among sirtuins or capture details of such dynamic process. Hence, STD NMR was utilized throughout this study. Our results not only agreed with the binding kinetics experiments but also gave a qualitative insight into the binding process. The data presented herein suggested some details about the geometry of the binding epitopes of the ligands in solution with the apo- and holoenzyme. Recognition that SIRT6 is affected selectively by PZA, an established clinical agent, suggests that the rational development of more potent and selective NAM surrogates might be possible. These derivatives might be accessible by employing the malleability of this scaffold to assist in the identification by STD NMR of the motifs that interact with the apo- and holoenzymes in solution.

Combining the advantage of higher efficacy due to local pulmonary administration of pyrazinoic acid (POA) and potent effect of pyrazinoic acid ester (PAE) delivered as an aerosol would aid in tuberculosis therapy. A combination spray dried dry powder, composed of POA, PAE (n-propyl POA), maltodextrin and leucine, was prepared for aerosol delivery to animals. Solid-state characteristics of morphology (scanning electron microscopy) crystallinity (X-ray powder diffraction), thermal properties (thermogravimetric analysis and differential scanning calorimetry) and moisture content (Karl Fisher) were evaluated. Particle size distributions, by volume (laser diffraction) for the dispersed powder and by mass (inertial impaction) were determined. Efficient delivery of the powder to a nose only animal exposure chamber employed a novel rotating brush/micro-fan apparatus. Spherical, crystalline particles were prepared. The volume median diameter, ~1.5 μm, was smaller than the mass median aerodynamic diameter, ~3.0 μm, indicating modest aggregation. Drug content variations were observed across the particle size distribution and may be explained by PAE evaporative losses. Delivery to the nose-only exposure chamber indicated that boluses could be administered at approximately 3 min intervals to avoid aerosol accumulation and effect uniform dose delivery with successive doses suitable for future pharmacokinetic and pharmacodynamic studies.

Analog development of existing drugs and direct drug delivery to the lungs by inhalation as treatments for multiple and extensively drug resistant (MDR and XDR) tuberculosis (TB) represent new therapeutic strategies. Pyrazinamide (PZA) is critical to drug sensitive TB therapy and is included in regimens for MDR TB. However, PZA-resistant Mycobacterium tuberculosis (Mtb) strains threaten its use. Pyrazinoic acid esters (PAEs) are PZA analogs effective against Mtb in vitro, including against the most common PZA resistant strains. However, PAEs require testing for TB efficacy in animal models. PAEs were delivered daily as aqueous dispersions from a vibrating mesh nebulizer to Mtb infected guinea pigs for 4 weeks in a regimen including orally administered first-line TB drugs. PAEs tested as a supplement to oral therapy significantly reduced the organ bacterial burden in comparison to infected, untreated control animals. Thus, PAE aerosol therapy is a potentially significant addition to the regimen for PZA resistant MDR-TB and XDR-TB treatment. Interestingly, low dose oral PZA treatment combined with standard therapy also reduced bacterial burden. This observation may be important for PZA susceptible disease treatment. The present study justifies further evaluation of PZA analogs and their lung delivery to treat TB.

The fluorescence intensity of a C-terminal acceptor chromophore, N-(7-dimethylamino-4-methyl coumarin (DACM), increased proportionally with 280 nm irradiation of an increasing number of donor tryptophan residues located on a β-sheet forming polypeptide. The fluorescence intensity of the acceptor chromophore increased even as the length of the β-sheet edge approached 256 A, well beyond the Forster radius for the tryptophan-acceptor chromophore pair. The folding of the peptides under investigation was verified by circular dichroism (CD) and deep UV resonance Raman experiments. Control experiments showed that the enhancement of DACM fluorescence occurred concomitantly with peptide folding. In other control experiments, the DACM fluorescence intensity of the solutions of tryptophan and DACM did not show any enhancement of DACM fluorescence with increasing tryptophan concentrations. Formation of fibrillar aggregates of the substrate peptides prepared for the fluorescence studies was undetectable by thioflavin T (ThT) fluorescence.

Fatty acid synthase 1 (FAS I) from Mycobacterium. tuberculosis (Mtb) is an essential protein and a promising drug target. FAS I is a multi-functional, multi-domain protein that is organized as a large (1.9 MDa) homohexameric complex. Acyl intermediates produced during fatty acid elongation are attached covalently to an acyl carrier protein (ACP) domain. This domain is activated by the transfer of a 4’-Phosphopantetheine (4’-PP, also termed P-pant) group from CoA to ACP catalyzed by a 4’-PP transferase, termed acyl carrier protein synthase (AcpS). In order to obtain an activated FAS I in E. coli, we transformed E. coli with tagged Mtb fas1 and acpS genes encoded by a separate plasmid.We induced the expression of Mtb FAS I following induction of AcpS expression. FAS I was purified by Strep-Tactin affinity chromatography. Activation of Mtb FAS I was confirmed by the identification of a bound P-pant group on serine at position 1808 by mass spectrometry. The purified FAS I displayed biochemical activity shown by spectrophotometric analysis of NADPH oxidation and by CoA production, using the Ellman reaction. The purified Mtb FAS I forms a hexameric complex shown by negative staining and cryo-EM. Purified hexameric and active Mtb FAS I is required for binding and drug inhibition studies and for structurefunction analysis of this enzyme. This relatively simple and short procedure for Mtb FAS I production should facilitate studies of this enzyme.

The design of biomimetic materials through molecular self-assembly is a growing area of modern nanotechnology. With problems of protein folding, self-assembly, and sequence–structure relationships as essential in nanotechnology as in biology, the effect of the nucleation of β-hairpin formation by proline on the folding process has been investigated in model studies. Previously such studies were limited to investigations of the influence of proline on the formation of turns in short peptide sequences. The effect of proline-based triads on the folding of an 11-kDa amyloidogenic peptide GH6[(GA)3GY(GA)3GE]8GAH6 (YE8) was investigated by selective substitution of the proline-substituted triads at the γ-turn sites. The folding and fibrillation of the singly proline-substituted polypeptides, e.g., GH6[(GA)3GY(GA)3GE]7(GA)3GY(GA)3PDGAH6 (8PD), and doubly proline-substituted polypeptides, e.g., GH6[(GA)3GY(GA)3GE]3(GA)3GY(GA)3PD[(GA)3GY(GA)3GE]3(GA)3GY(GA)3PDGAH6 (4,8PD), were directly monitored by circular dichroism and deep UV resonance Raman and fluorescence spectroscopies. These findings were used to identify the essential folding domains, i.e., the minimum number of β-strands necessary for stable folding. These experimental findings may be especially useful in the design and construction of peptidic materials for a wide range of applications as well as in understanding the mechanisms of folding critical to fibril formation. © 2015 Wiley Periodicals, Inc. Biopolymers 103: 339–350, 2015.

The preparation of aliphatic aryl tetrafluoro-λ6-sulfanes was achieved by direct addition of readily available chlorotetrafluorosulfanyl arenes to alkenes and alkynes. Systematic substitution of the ligands bound to the tetrafluoro-λ6-sulfanyl group enabled investigations of the substituent effects on the reactivity of aryl tetrafluoro-λ6-sulfanyl-substituted products. The modulation of reactivity was effected by variation of electron-withdrawing or electron-donating effects. All isolable products were fully characterized. In addition structural characterization of these compounds suggested insights into the influence of the substituents on the nature of bonding at the tetrafluoro-λ6-sulfanyl group.

The discoveries that non-native proteins have a role in amyloidosis and that multiple protein misfolding diseases can occur concurrently suggest that cross-seeding of amyloidogenic proteins may be central to misfolding. To study this process, a synthetic chimeric amyloidogenic protein (YEHK21-YE8) composed of two components, one that readily folds to form fibrils (YEHK21) and one that does not (YE8), was designed. Secondary structural conformational changes during YEHK21-YE8 aggregation demonstrate that, under the appropriate conditions, YEHK21 is able to induce fibril formation of YE8. The unambiguous demonstration of the induction of folding and fibrillation within a single molecule illuminates the factors controlling this process and hence suggests the importance of those factors in amyloidogenic diseases.

Substituted alkenyl aryl tetrafluoro-λ(6) -sulfanes have been prepared by the direct addition of readily accessible chlorotetrafluorosulfanyl arenes to primary alkynes. Substitution of an apical fluorine of the pentafluorosulfanyl group enables modulation of the reactivity of this little explored functional group while at the same time facilitating the direct investigation of aryl substituent effects on the aryl tetrafluorosulfanyl-substituted products.

β-Lactams were diastereoselectively formed by the reaction of SF5-containing aldimines, or an SF5-containing ketimine, with benzyloxyketene in a conrotatory ring closure process. Imine formation and cyclization were possible in spite of the acidification of protons on the carbon bound to SF5. The reactions of the aldimines demonstrated very good 1,2-lk diastereoselectivity, however lack of stereochemical control of the C–N ketimine geometry was reflected in the stereochemistry of the product β-lactam. Cyclization of imines with a stereogenic center bearing SF5 was reflected in the 1,2-lk,lk selectivity of the β-lactam.

A new difluoroalkene with a triethylsilyl group, 4,4-difluoro-3-(triethylsilyl)- but-3-en-1-ol ( 1 ), was synthesized as a new building block for 1,1-difluoro-1-alkenes. Treatment of 1 with sodium hydride in the presence of a catalytic amount of p -methoxyphenol induced Si C sp 2 bond dissociation. Subsequent addition of an aldehyde to the reactive intermediate afforded 3,3-difluoroallyl alcohol ( 9 ). The reaction was accelerated by added p -methoxyphenol.

The diastereotopic nature of geminal protons γ to the pentafluorosulfanyl (SF 5 ) group was investigated by computational modeling and experimental methods. 1D and 2D NMR techniques were employed to determine the vicinal coupling constants used in the estimation of H C C H dihedral angles required for the approximation of the average solution conformation of SF 5 -substituted alkyl chains. Rotational energy barriers were calculated at the B3LYP/6-31++G (d,p) level in an effort to assess the relative steric demand of the SF 5 group relative to a trifluoromethyl or tert -butyl group. The observed diastereotopicity is likely a result of hindered molecular rotation where one of the γ protons is trapped between two equatorial fluorines of the SF 5 group.

A facile preparation of aliphatic 2-pentafluorosulfanyl aldehydes is described. To investigate the utility of the aldehydes as synthetic building blocks, various transformations of the aldehydes were explored. The pentafluorosulfanyl group was stable under a variety of reaction conditions, and the pentafluorosulfanylated products were obtained in moderate to good yields in most cases.

The design and synthesis of pentafluorosulfanyl-containing heptad amino acid sequence was described. The three-dimensional conformation of the peptide was investigated by using CYANA (combined assignment and dynamics algorithm for NMR applications) and the integrated autoassignment. This study shows that the one of the diastereomers assumed a very tight coiled conformation in [D6]DMSO where both pentafluorosulfanyl groups assumed a synclinal relationship. The propensity of the protected heptapeptide to form such a tight coil and of the pentafluorosulfanyl groups to align so uniformly is suggestive of the utility of pentafluorosulfanylated amino acids in promoting conformational control.

Understanding of numerous biological functions of intrinsically disordered proteins (IDPs) is of significant interest to modern life science research. A large variety of serious debilitating diseases are associated with the malfunction of IDPs including neurodegenerative disorders and systemic amyloidosis. Here we report on the molecular mechanism of amyloid fibrillation of a model IDP (YE8) using 2D correlation deep UV resonance Raman spectroscopy. YE8 is a genetically engineered polypeptide, which is completely unordered at neutral pH yet exhibits all properties of a fibrillogenic protein at low pH. The very first step of the fibrillation process involves structural rearrangements of YE8 at the global structure level without the detectable appearance of secondary structural elements. The formation of β-sheet species follows the global structural changes and proceeds via the simultaneous formation of turns and β-strands. The kinetic mechanism revealed is an important new contribution to understanding of the general fibrillation mechanism proposed for IDP.

Recently, well-ordered biological materials have been exploited to pattern inorganic nanoparticles into linear arrays that are of particular interest for nanoelectronic applications. In this work, a de novo designed E. coli-expressed polypeptide (previously shown to form highly rectilinear, β-sheet-containing structures) operates as a template for divalent metal cations. EDX and TEM analysis verify the attachment of platinum ions to the histidine-rich fibril surface, which was designed specifically to facilitate attachment of chemical moieties. Following chemical reduction, TEM further confirms the formation of localized zero-valent metal aggregates with sub-nanometer interparticle spacing.

The pyrazinamide (PZA) analog 5-chloropyrazinamide (5-Cl PZA) is active against mycobacterial species, including PZA-resistant strains of Mycobacterium tuberculosis . In M. smegmatis , overexpression of the type 1 fatty acid synthase (FAS I) confers resistance to 5-Cl PZA, a potent FAS I inhibitor. Since M. tuberculosis and M. bovis cannot tolerate FAS I overexpression, 5-Cl PZA resistance mutations have yet to be described for tubercle bacilli. In an attempt to identify other factors that govern the activity of 5-Cl PZA, we selected for 5-Cl PZA-resistant isolates from a library of transposon-mutagenized M. smegmatis isolates. Here, we report that increased expression of the M. smegmatis pyrazinamidase PzaA confers resistance to 5-Cl PZA and susceptibility to PZA in M. smegmatis , M. tuberculosis , and M. bovis . In contrast, while ectopic overexpression of the M. tuberculosis pyrazinamidase PncA increases PZA susceptibility, this amidase does not mediate resistance to 5-Cl PZA. We conclude that PncA-independent turnover of 5-Cl PZA represents a potential mechanism of resistance to this compound for M. tuberculosis , which will likely translate into enhanced PZA susceptibility. Thus, countersusceptibility can be manipulated as a resistance-proofing strategy for PZA-based compounds when these agents are used simultaneously.

New therapeutic strategies are needed to treat drug resistant tuberculosis (TB) and to improve treatment for drug sensitive TB. Pyrazinamide (PZA) is a critical component of current first-line TB therapy. However, the rise in PZA-resistant TB cases jeopardizes the future utility of PZA. To address this problem, we used the guinea pig model of TB and tested the efficacy of an inhaled dry powder combination, referred to as Pyrazinoic acid/ester Dry Powder (PDP), which is comprised of pyrazinoic acid (POA), the active moiety of PZA, and pyrazinoic acid ester (PAE), which is a PZA analog. Both POA and PAE have the advantage of being able to act on PZA-resistant Mycobacterium tuberculosis. When used in combination with oral rifampicin (R), inhaled PDP had striking effects on tissue pathology. Effects were observed in lungs, the site of delivery, but also in the spleen and liver indicating both local and systemic effects of inhaled PDP. Tissue granulomas that harbor M. tuberculosis in a persistent state are a hallmark of TB and they pose a challenge for therapy. Compared to other treatments, which preferentially cleared non-necrotic granulomas, R+PDP reduced necrotic granulomas more effectively. The increased ability of R+PDP to act on more recalcitrant necrotic granulomas suggests a novel mechanism of action. The results presented in this report reveal the potential for developing therapies involving POA that are optimized to target necrotic as well as non-necrotic granulomas as a means of achieving more complete sterilization of M. tuberculosis bacilli and preventing disease relapse when therapy ends.

Aldimines were selectively α-monochlorinated without any interference of α,α-dichlorinated derivatives, by a sequence of reactions involving α-trimethylsilylation of preformed 1-azaenolates, α-chlorination using N-chlorosuccinimide and desilylation in methanol. Upon acidic hydrolysis, these α-monochloroimines provide an easy access to α-monochloroaldehydes.

The influence of electrostatic interactions on protein amyloidogenesis has been investigated using de novo designed repetitive polypeptides YEHK21 [GH6[(GA)3GY(GA)3GE(GA)3GY(GA)3GE]21GAH6] and YE8 [GH6[(GA)3GY(GA)3GE]8GAH6]. The beta-sheet forming polypeptides were designed with identical beta-strands but with variable substitution at the turns that enable precise location of charged residues (Topilina et al. Biopolymers 2007, 86 (4), 261-264; Topilina et al. Biopolymers 2010, submitted for publication; Topilina et al. Biomacromolecules 2006, 7 (4), 1104-11). Solubility, folding, and aggregation of YEHK21 and YE8 were shown to be controlled by charge distribution. Under those conditions favoring the development of charge, YEHK21 and YE8 have significant propensities to form intermolecular beta-sheet assemblies illustrating the potential of charged polypeptide chains to form ordered amyloid aggregates even in the absence of additional environmental factors such as the presence of polyelectrolytes, salts, and so on.

Pyrazinamide is unusual among anti-tuberculous agents in its ability to promote a durable cure and shorten the duration of therapy. Yet the basis for this effect is not well understood. A particularly effective strategy for the development of new drugs can be to synthetically manipulate the well-established structures to improve either the spectrum of activity or some pharmacological properties. Similar to previously described aminomethylene amides such as morphazinamide, it was found that novel aminomethylene amides can have in vitro activity at higher than the very acidic pH conditions where pyrazinamide is inactive as well as retaining activity against pyrazinamide-resistant M. tuberculosis. These new compounds have shown an improved anti-tuberculous activity in infected human macrophages relative to pyrazinamide. Compound 1, in combination with rifamycin, was especially effective in both infected human macrophages and in a murine model of infection. The activity of these analogs against pyrazinamide-resistant strains suggests that the development of second generation pyrazinamide analogs may be especially fruitful.

The synthesis of 2,6-dinitro-4-pentafluorosulfanyl-N,N-dipropylaniline, 2, was achieved in a straightforward manner from commercially available 1-nitro-4-pentafluorosulfanylbenzene. In post-emergence screening 2 was found to be approximately twice as potent as trifluralin with the same general spectrum of activity. In contrast, in pre-emergence tests, 2 was nearly 5 fold more potent against quackgrass and crabgrass. Given the existing structure–activity-relationship for adverse properties of the dinitroaniline herbicides, 2 is proposed to have properties quite comparable to the commercial agent trifluralin.

The three complexes, Pd(tmhd) 2 ( 1 ), Pd( S -tmhd) 2 ( 2 ), and Pd( S , S -tmhd) 2 ( 3 ) (where tmhd, S -tmhd, and S , S -tmhd are the anions of 2,2,6,6-tetramethyl-3,5-heptanedione, 2,2,6,6-tetramethyl-5-thioxo-3-heptanone, and 2,2,6,6-tetramethyl-3,5-heptanedithione, respectively) were prepared and characterized by thermogravimetric analysis in order to assess their relative volatilities as a function of sulfur substitution. Complexes 1 and 2 volatilized with little residue, while 3 experienced significant decomposition during volatilization. The solid-state structure of 3 was determined in order to complete a structural trans -influence series with 1 and 2 and to assess possible reasons for its lower thermal stability. A large trans -influence was observed for the bond lengths in the coordination sphere across the series of complexes 1 , 2 , and 3 . The longer Pd–S bond distances found in 3 may be a contributing factor to its unsuitability as a CVD precursor.

A variety of mono- and difluoroacetylsilanes and the corresponding silyl enol ethers were prepared from trifluoroethanol and chlorotrialkylsilanes in the presence of LDA through retro-Brook rearrangement. Sterically demanding silyl groups, especially those bound to oxygen, resulted in higher yields of difluoroacetylsilanes. The yields of difluoroacetylsilanes were also dramatically affected by the method of the termination of the reaction. Difluorohaloacetylsilanes were prepared from the corresponding difluoroethenyl silyl ethers with electrophilic halogenating reagents in good yields. A gamma-fluorinated beta-diketone 9a was prepared from monofluoroacetyltriisopropylsilane by nucleophilic acylation with methyl trifluoroacetate.

Trifluoroacetyltrialkyl(aryl)silanes, synthetic equivalents of trifluoroacetaldehyde, were prepared in good to moderate yields by reaction of 1,1-difluoro-2-trialkyl(aryl)silyl-2-trimethylsilyloxyethenes with Selectfluor ® . Sakurai reaction of fluorinated acylsilanes formed either the α-silylated ketones by means of Brook- and retro-Brook isomerization or, in the absence of Brook isomerization, homoallylic alcohols.

The sila-β-diketone, 2,2,6,6-tetramethyl-2-silaheptane-3,5-dione (tmshdH), was synthesized by the condensation of the anion of 2-trimethylsilyl-1,3-dithiane with 1-bromo-3,3-dimethylbutan-2-one, followed by unmasking of the latent carbonyl moiety with HgO/HgCl 2 . A monoclinic polymorph of the known copper(II) complex, Cu(tmshd) 2 , was crystallized and studied by X-ray diffraction methods and found to be disordered like the orthorhombic one. Attempts to synthesize the disilylated β-diketone, 2,2,6,6-tetramethyl-2,6-disilaheptane-3,5-dione and monosilylated 4,4-dimethyl-4-sila-3-oxo-pentanal using the dithiane method were not successful. However, the 1,3-dithianyl precursors, along with the impurity 2,2 ′ -bis(trimethylsilyl)-2,2 ′ -bi-1,3-dithiane, were studied crystallographically. Large stereoelectronic and steric effects on the solid-state bonding parameters were observed for these molecules.

Metal-mediated allylations of difluoroacetyltriakylsilanes with various allyl bromides in aqueous media form homoallylic alcohols exclusively. The common Brook rearrangement, carbon to oxygen-silyl migration, is totally suppressed with no detectable formation of silyl enol ether. Influence of solvents on reaction is studied. Reactivity differences between indium and zinc are also described.

The crystal structures of the complexes Cu(txhd)2 and Cu(S-tmhd)2 (where txhd is the anion of 2,2,6-trimethylheptane-3,5-dione and S-tmhd is the anion of 5-mercapto-2,2,6,6-tetramethyl-4-hepten-3-one) were determined. In the solid state, both complexes are square planar. In each case, only one geometrical isomer (trans or cis) was observed in the crystals; arguments are presented that both isomers are present in bulk samples of Cu(txhd)2, while from electronic considerations, the monothio-β-diketonate ligands probably have cis geometry in Cu(S-tmhd)2. Calculations of molecular volumes for structurally similar Cu[t-BuC(O)CHC(O)R]2 complexes showed that there is a slight decrease in packing efficiency as the steric bulk of R increases. More importantly, strong ring-stacking interactions, such as those found for Cu(acac)2 are not observed, or are greatly attenuated, in complexes with bulkier peripheral substituents. [Cu(txhd)(μ3-OEt)]4, an impurity that co-sublimed with Cu(txhd)2, was isolated in low yield. ...

Fluorinated α-sila-β-diketones, synthesized in good yields via the Claisen condensation of the esters of fluorinated acids or fluorinated acid fluorides and the lithium enolates of acetyltrialkylsilanes, were employed in the preparation of volatile copper complexes for copper metallization. The thermal properties of the corresponding copper(II) complexes were determined by TGA and DSC to evaluate the potential of these materials as copper metal–organic chemical vapor deposition (MOCVD) precursors; the new copper compounds have greater volatility and stability than the corresponding copper complexes of non-fluorinated α-sila-β-diketonates.

The substitution of a carbon atom by silicon provides an attractive, novel approach to modification of the thermal stability and volatility of metal-organic chemical vapor deposition precursors supported by β-diketonate ancillary ligands. The low temperature reaction of the lithium enolates of acetyltrialkylsilanes with acyl chlorides affords the sila-β-diketones, R′C(O)CH2C(O)SiR3 (R′=Me, Et, n-Pr, i-Pr, n-Bu, i-Bu, s-Bu, t-Bu; SiR3=SiMe3, SiEt3, SiMe2(t-Bu), SiMe2(t-hexyl), Si(i-Pr)3), in good yields. Multinuclear NMR studies suggest that the sila-β-diketones exist as the enolic tautomer with a vinylsilane isomeric structure. Homoleptic Cu(II) sila-β-diketonate complexes were prepared in a first pass study to evaluate how precursor performance is affected by modulation of the peripheral substituents in the ligands. Thermal analyses, (TGA, DSC) show that the silylated Cu(II) precursors (SiR3=SiMe3; R′=t-Bu or i-Bu) have greater volatility than the corresponding carbon analogues. Some of the new Cu(II) complexes exist as liquids or low melting solids, which are preferred states for industrial deposition processes. X-ray diffraction studies of selected copper complexes showed them to have typical, square planar geometry; calculations of molecular volumes suggest that packing in the solid-state is less efficient for the silicon-containing complexes than for the non-silylated analogues.

Novel, potent inhibitors of dipeptidyl peptidase IV (DPP IV, EC 3.4.14.5, CD26), containing the fluoroolefin peptide isostere psi [CFz.dbnd6;C], have been prepared via the intermediacy of the Peterson fluoroolefination reaction. The nitrile containing inhibitors were found to inhibit dipeptidyl peptidase IV competitively with K(i) values for the l-3 and u-3 inhibitors of 7.69 and 6.03 microM, respectively. In contrast to earlier reported fluoroolefin containing inhibitors, the nitriles underwent no detectable degradation at pH 7.6 under buffered conditions.