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This article reports the design, synthesis, and evaluation of a novel class of molecules of intermediate size (approximately 7000 Da), which possess both the targeting and effector functions of antibodies. These compounds—called synthetic antibody mimics targeting prostate cancer (SyAM-Ps)—bind simultaneously to prostate-specific membrane antigen and Fc gamma receptor I, thus eliciting highly selective cancer cell phagocytosis. SyAMs have the potential to combine the advantages of both small-molecule and biologic therapies, and may address many drawbacks associated with available treatments for cancer and other diseases.

Three-component systems are often more complex than their two-component counterparts. Although the reversible association of three components in solution is critical for a vast array of chemical and biological processes, no general physical picture of such systems has emerged. Here we have developed a general, comprehensive framework for understanding ternary complex equilibria, which relates directly to familiar concepts such as “EC50” and “IC50” from simpler (binary complex) equilibria. Importantly, application of our model to data from the published literature has enabled us to achieve new insights into complex systems ranging from coagulation to therapeutic dosing regimens for monoclonal antibodies. We also provide an Excel spreadsheet to assist readers in both conceptualizing and applying our models. Overall, our analysis has the potential to render complex three-component systems – which have previously been characterized as “analytically intractable” – readily comprehensible to theoreticians and experimentalists alike.

For over a quarter of a century the hydrogen-terminated Si(111) single-crystalline surface has been the gold standard as a starting point for silicon surface modification chemistry. However, creating a well-defined and stable interface based on Si-N bonds has remained elusive. Despite the fact that azides, nitro compounds, and amines do lead to the formation of surface Si-N, each of these modification schemes produces additional carbon- or oxygen-containing functional groups that in turn react with the surface itself, leaving contaminants that affect the interface properties for any further modification protocols. We describe the preparation of a Si(111) surface functionalized predominantly with Si-NH-Si species based on chlorination followed by the room temperature ammonia treatment utilizing NH(3)-saturated tetrahydrofuran (THF). The obtained surface has been characterized by infrared spectroscopy and X-ray photoelectron spectroscopy. This analysis was supplemented with DFT calculations. This newly characterized surface will join the previously established H-Si(111) and Cl-Si(111) surfaces as a general starting point for the preparation of oxygen- and carbon-free interfaces, with numerous potential applications.

Structurally complex and physiologically active natural products often include bicyclic and polycyclic ring systems having defined relative and absolute configuration. Approaches that allow the construction of more than one carbocyclic ring at a time have proven valuable, in particular those that allow at the same time the control of an array of new stereogenic centers. One of the most general and most widely used protocols has been the intramolecular Diels-Alder [4 + 2] cycloaddition, in which a single stereogenic center between the diene and the dienophile can control the relative and absolute configuration of the product. We report a two-step [1 + 4 + 1] procedure for bicyclic and polycyclic construction, based on the cyclization of an omega-dienyl ketone. This is complementary to, and will likely be as useful as, the intramolecular Diels-Alder cycloaddition.

The protein CD1d binds self and foreign glycolipids for presentation to CD1-restricted T cells by means of TCR recognition and activates T(H)1 and T(H)2 chemokine release. In this study, a variety of glycolipid ligands were attached to a microarray surface and their binding with dimeric CD1d was investigated. An alpha-galactosyl ceramide (alpha-GalCer) bearing a carbamate group at the 6'-OH position was tethered to the surface, and the dissociation constant on surface with CD1d was determined to reflect the multivalent interaction. Competition assays were then used to determine the dissociation constants (Ki) of new and intact glycolipids in solution. The 4-fluorophenyloctanoyl-modified alpha-GalCer (18) was found to bind most strongly with CD1d (Ki 0.21 microM), 2 orders of magnitude stronger than alpha-GalCer and more than three times more selective than alpha-GalCer for IFN-gamma release from NKT cells. Various alpha-GalCer analogues were analyzed, and the results showed that the binding affinity of glycolipids to CD1d correlates well with IFN-gamma production but poorly with IL-4 secretion by NKT cells, suggesting that tighter binding ligands could bias cytokine release through the T(H)1 pathway.

Syntheses of the four enantiomerically pure diastereomers of 5-F2t-isoprostane (5−8) are described. The key step is the lipase-catalyzed chemo-enzymatic resolution of the racemic diol 40 to give the mono-acetates 41 and 42. The enantiomerically pure diastereomers of 5-F2t-isoprostane (5) may be human hormones.

The first enantioselective synthesis of (−)-isonitrin B (2), the parent of a small family of isonitrile antibiotics having compact but highly functionalized (and highly reactive) cyclopentane rings, is described. They key in this synthesis is the cyclization of 5b to 4b, by way of the intermediate alkylidene carbene.

Diastereoselective and enantioselective hydrogenation of the racemic β-keto ester 5 to give the enantiomerically pure (96% ee) ester 8 is reported. The conversion of the derived vinylstannane 11 to the antibiotic marine alkaloid (−)-haliclonadiamine (1) is described.

Rhodium-mediated cyclization of the α-diazo ester 1 proceeds with high diastereoselectivity, to give the trisubstituted cyclopentane 5. A computational model (ZINDO and Molecular Mechanics) based on our current mechanistic understanding of the reaction is presented. This model correctly predicts the dominant diastereomer from the cyclization of 1 and the eight (Table 2) other α-diazo esters studied thus far.

The preparation and solid-state characterization of the 1,3-phenylene-bridged bis(dithiadiazolyl) and bis(diselenadiazolyl) diradicals 1,3-[(E2N2C)C6H4(CN2E2)] (E = S, Se) are reported. The isomorphous crystals of 1,3-[(E2N2C)C6H4(CN2E2)] so obtained are tetragonal, space group I41/a. Stacks of diradical molecules, linked vertically in a zigzag fashion through alternaie ends by long E- - -E contacts (mean 3.140/3.284 Å, for E = S/Se), are arranged in pinwheellike clusters about the 41 and ¯4 axes, producing complex patterns of interstack E- - -E contacts. Both compounds show the presence of spin defects in the lattice, and there is a very large enhancement in the paramagnetism of the sulfur compound at high temperatures. The selenium compound is a semiconductor, with a room temperature conductivity of 2 × 10-4 S cm-1. Solid-state NMR experiments find enhanced relaxation times, which have their origin in the presence of a mobile paramagnetic defect. Extended Hückel band structure calculations show the materials to be semiconductors, with band gaps of about 1.0/0.8 eV for E = S/Se. Although the compounds adopt a columnar structure, the calculations indicate significant interactions between the stacks and the materials exhibit well-developed three dimensionality. The enhanced paramagnetism in the sulfur compound is attributed to the presence of thermally generated phase kinks in the lattice, whereas the selenium compound is classified as an intrinsic semiconductor.

Introduction of an aromatic group into the fatty acyl chain of alpha-GalCer modulates the activity and selectivity of IFN-gamma/IL-4 secretion through CD1d-mediated activation of NKT cells. Compound 14-16 are more potent than alpha-Galcer and biased for IFN-gamma than for IL-4. These new glycolipids may find use as adjuvants or as antimetastatic agents.

Two complementary procedures have been developed for the conversion of the oximes of alpha-aryl ketones to azirines. On heating, the azirines rearrange smoothly to the corresponding indoles. The overall transformation offers a versatile route to indoles, complementary to the Fischer indole synthesis.

The anthrax lethal factor (LF), a Zn-dependent endopeptidase, is considered the dominant virulence factor of anthrax. Because pharmacological inhibition of the catalytic activity of LF is considered a plausible mechanism for preventing the lethality of anthrax, a high-throughput screening experiment based on LF-catalyzed cleavage of a fluorescent substrate was performed to identify novel inhibitors of LF. The RNA-targeting antibiotics, neomycin B and some synthetic dimeric aminoglycosides, were found to be nanomolar active-site inhibitors of LF.

Treatment of (EBI)ZrMe2 with B(C6F5)3 and 100 equiv of 1-hexene in toluene-d8 at -40 degrees C for 1 h, followed by addition of5 equiv of propene, generates a living polypropene catalyst (3) with a polyhexene "tail". Upon further addition of propene, speciation of the catalyst and propagation kinetics are measured directly by NMR, yielding a propagation rate law that is first order in [propene] and [living catalyst] with a rate constant of 2.6 M-1 s-1 at -40 degrees C and the activation parameters DeltaH = 3.4(0.2) kcal/mol and DeltaS = -42(2) cal/(mol K). In the absence of propene, elimination of vinylidene-terminated polymer is observed with a first-order rate constant of 3.3 (0.5) x 10-5 s-1 at -40 degrees C and DeltaH = 12.9(1.4) kcal/mol and DeltaS = -23(5) cal/(mol K). Use of 1-13C-propene and 1,1-2H-2,3-13C-propene and 1H, 19F, and 13C NMR spectroscopy provide rigorous characterization of the living catalyst and enable the first direct observation of both 1,3-isomerization and chain-end epimerization processes at a metallocene catalyst. Isomerization and epimerization occur with rates that are similar to that of vinylidene termination and are consistent with previous mechanistic hypotheses featuring isomerization via a tertiary alkyl intermediate and switching between enantiofaces of the coordinated alkene.

Syntheses of the eight enantiomerically pure diastereomers of the 12-F(2)-isoprostanes (4-11) are described. The key steps included rhodium-mediated intramolecular cyclopropanation and enzymatic resolution of the racemic diol 12.

The preparation of the diastereomerically pure beta-tetralone ketal 4 is reported. Intramolecular alkylidene C-H insertion followed by hydrolysis of 4 proceeded to give the enantiomerically pure cyclopentene 15. The key step in this synthesis was the bis-intramolecular cyclization of keto aldehyde 2 to give the tetracyclic intermediate 20. Enone 20 was converted over several steps to (-)-morphine 1.

Organolanthanide complexes of the general type Cp'(2)LnE(TMS)(2) (Cp' = eta(5)-Me(5)C(5); Ln = La, Sm, Y, Lu; E = CH, N; TMS = SiMe(3)) serve as effective precatalysts for the rapid intramolecular hydrophosphination/cyclization of the phosphinoalkenes and phosphinoalkynes RHP(CH(2))(n)()CH=CH(2) (R = Ph, H; n = 3, 4) and H(2)P(CH(2))(n)C triple bond C-Ph (n = 3, 4) to afford the corresponding heterocycles and respectively. Kinetic and mechanistic data for these processes exhibit parallels to, as well as distinct differences from, organolanthanide-mediated intramolecular hydroamination/cyclizations. The turnover-limiting step of the present catalytic cycle is insertion of the carbon-carbon unsaturation into the Ln-P bond, followed by rapid protonolysis of the resulting Ln-C linkage. The rate law is first-order in [catalyst] and zero-order in [substrate] over approximately one half-life, with inhibition by heterocyclic product intruding at higher conversions. The catalyst resting state is likely a lanthanocene phosphine-phosphido complex, and dimeric [Cp'(2)YP(H)Ph](2) was isolated and cystallographically characterized. Lanthanide identity and ancillary ligand structure effects on rate and selectivity vary with substrate unsaturation: larger metal ions and more open ligand systems lead to higher turnover frequencies for phosphinoalkynes, and intermediate-sized metal ions with Cp'(2) ligands lead to maximum turnover frequencies for phosphinoalkenes. Diastereoselectivity patterns also vary with substrate, lanthanide ion, and ancillary ligands. Similarities and differences in hydrophosphination vis-à-vis analogous organolanthanide-mediated hydroamination are enumerated.

The reactivity of [rac-(C2H4(1-indenyl)2)Zr(n-butyl)][MeB(C6F5)3] (4), [rac-(C2H4(1-indenyl)2)Zr(sec-butyl)][MeB(C6F5)3] (5), and [rac-(C2H4(1-indenyl)2)Zr(polypropenyl)][MeB(C6F5)3] with propene, ethene, and hydrogen was studied by low-temperature (

The propagating species for 1-hexene, propene, and ethene polymerization as catalyzed by [rac-(C2H4(1-indenyl)2)Zr(CH3)][CH3B(C6F5)3] has been intercepted at T-40 degrees C and characterized by NMR methods. Observation of the propagating species permits direct monitoring of initiation, propagation, and termination processes by NMR. Detailed examination of alkene incorporation into Zr-polymeryl species using 13C-labeled 1-alkenes supports a continuous insertion mechanism whereby the anion re-coordinates after each alkene insertion.