In many common protein secondary structures, such as alpha-, 3(10), and polyproline II helices, an n --> pi* interaction places the adjacent backbone amide carbonyl groups in close proximity to each other. This interaction, which is reminiscent of the Burgi-Dunitz trajectory, involves delocalization of the lone pairs (n) of the oxygen (O(i-1)) of a peptide bond over the antibonding orbital (pi*) of C(i)=O(i) of the subsequent peptide bond. Such a proximal arrangement of the amide carbonyl groups should be opposed by the Pauli repulsion between the lone pairs (n) of O(i-1) and the bonding orbital (pi) of C(i)=O(i). We explored the conformational effects of this Pauli repulsion by employing common peptidomimetics, wherein the n --> pi* interaction is attenuated while the Pauli repulsion is retained. Our results indicate that this Pauli repulsion prevents the attainment of such proximal arrangement of the carbonyl groups in the absence of the n --> pi* interaction. This finding indicates that the poor mimicry of the amide bond by many peptidomimetics stems from their inability to partake in the n --> pi* interaction and emphasizes the quantum-mechanical nature of the interaction between adjacent amide carbonyl groups in proteins.

Asymmetric epoxidation reactions comprise a venerable method in organic synthesis, and just as storied a testing ground for new concepts in asymmetric catalysis. 1 Among many highlights of this history are potent metal-catalyzed methods, 2 powerful ketone-catalysts, 3,4 sulfidecatalyzed processes 5 and also the Juliá-Colonna reaction of chalcones catalyzed by oligoamides such as poly(ala) n . 6 Our own interest in this area stemmed from the hypothesis that tunable, peptide-based catalysts could be developed that could provide either enantioselectivity or regioselectivity for a range of alkenes or polyenes. In contrast to the classical nucleophilic epoxidation of enones as exemplified in the Julia-Colonna epoxidation, we sought to develop a system involving well-defined peptide-based catalysts that could operate by an alternative, potentially generalizable electrophilic mechanism.The key issue to be established initially was the nature of the catalytic moiety to reside within the peptide. As we wished to use only readily available amino acids as the catalytic residue, we were drawn to the carboxylic acid functionality of aspartic acid (Asp) and glutamic acid (Glu). The plan then emerged to develop a catalytic cycle based on Asp-derived peracids, as illustrated by the shuttle between 1 and 2 (Scheme 1). Our plan was to capitalize on concepts developed for carboxyl activation in peptide synthesis to generate and regenerate the aspartic per-acid 2. 7 As such, we found that carbodiimide activation of 1, in the presence of 30% aqueous H 2 O 2 or, less efficiently, urea-hydrogen peroxide (UHP), led to oxygen transfer to olefin 3 (Table 1, entries 2 and 3). The presence of an acyl transfer co-catalyst such as DMAP accelerates the entire process, so that catalytic epoxidation occurs to deliver epoxide rac-4, with up to nearly 15 catalytic turnovers (5 mol % 1 leading to 74% yield of epoxide rac-4 within 3.5 h; Table 1, entry 5). To our knowledge, these results constitute the first demonstration of catalytic epoxidation employing acid-peracid shuttles that exhibit turnover. 8Several additional experiments suggest a number of competing pathways that may operate alongside the productive catalytic cycle shown in Scheme 1. For example, control experiments aimed at establishing the role of each component of the reaction mixture show that, as expected from literature precedent, 9 the known 9b Asp-derived diacyl peroxide 5 is formed under the reaction conditions (Scheme 2); this event has been shown to occur by reaction of peracid with O-acyl urea or with carbodiimide. 9a The formation of 5 retards the oxygen transfer process, as 5 only slowly undergoes perhydrolysis (i.e. 5 to 2 in Scheme 2). 10 Fortunately, the addition of DMAP accelerates the oxygen transfer event (Table 1, entries 1 and 2), presumably by making the formation of 5 a reversible process and promoting the productive catalytic cycle. Although DMAP may undergo fast in situ oxidation to the DMAP-N-oxide 6 ,11 either DMAP or DMAP-N-oxide may function as a nucleophil...

The ability to profile the prevalence and functional activity of endogenous antibodies is of vast clinical and diagnostic importance. Serum antibodies are an important class of biomarkers and are also crucial elements of immune responses elicited by natural disease causing-agents as well as vaccines. In particular, materials for manipulating and/or enhancing immune responses toward disease-causing cells or viruses have exhibited significant promise for therapeutic applications. Antibody-recruiting molecules (ARMs) – bifunctional organic molecules that re-direct endogenous antibodies to pathological targets, thereby increasing their recognition and clearance by the immune system – have proven particularly interesting. Notably, although ARMs capable of hijacking antibodies against oligosaccharides and electron-poor aromatics have proven efficacious, systematic comparisons of the prevalence and effectiveness of natural anti-hapten antibody populations have not appeared in the literature. Herein we report head-to-head comparisons of three chemically-simple antigens, which are known ligands for endogenous antibodies. Thus, we have chemically synthesized bifunctional molecules containing 2,4-dinitrophenyl (DNP), phosphorylcholine (PC) and rhamnose. We then used a combination of ELISA, flow cytometry, and cell-viability assays to compare these antigens in terms of their abilities both to recruit natural antibody from human serum and also to direct serum-dependent cytotoxicity against target cells. These studies have revealed rhamnose to be the most efficacious of the synthetic antigens examined. Furthermore, analysis of 122 individual serum samples has afforded comprehensive insights into population-wide prevalence and isotype distributions of distinct anti-hapten antibody populations. In addition to providing a general platform for comparing and studying anti-hapten antibodies, these studies serve as a useful starting point for the optimization of antibody-recruiting molecules and other synthetic strategies for modulating human immunity.

Keywordsepoxidation; peptide; asymmetric catalysis; olefin isostere; fluorine; peptidomimetic The biosynthesis of natural products that contain epoxides represents a powerful stimulus for the study of "epoxidase" enzymes. [i] Likewise, these processes have inspired a generation of science focused on small molecule catalysts that mediate selective epoxidations through a variety of mechanisms. [ii] With respect to the naturally occurring epoxidases, the mechanistic basis of O-atom transfer is often associated with the chemistry of either flavinoid cofactors, P450 enzymes containing a heme group, or chloroperoxidases that lead to stepwise ring formation. [iii] In thinking about the known biosynthetic apparatus for epoxide formation, we became curious about an alternative mode for O-atom transferone based on functional groups available in proteins, but perhaps not well-documented in the biosynthesis of epoxides. In particular, we speculated and recently showed that asparticacid-containing peptides (e.g., 1; Figure 1a) might shuttle between the side-chain carboxylic acid and the corresponding peracid (e.g., 2) creating a catalytic cycle competent for asymmetric epoxidation with turnover of the aspartate-derived catalyst. Such an approach is orthogonal to the Julia-Colonna epoxidation, a complementary peptide-based epoxidation based on a nucleophilic mechanism. [iv] Indeed, as shown in Figure 1b, this new electrophilic epoxidation catalytic cycle mediates the asymmetric epoxidation of substrates like 3 to give products like 4 with up to 92% ee. [v] Mechanistic questions abound in this catalytic system. To date, we have identified a number of relevant aspects. For example, we observed off-catalytic cycle intermediates, including catalytically inactive diacyl peroxides (6). [vi] We also showed that these off-cycle intermediates could be reinserted into the productive pathway through the action of nucleophiles such as DMAP or DMAP-N-oxide (7). On the other hand, the basis of stereochemical information transfer was not immediately clear. Indeed, the high precision delineation of the stereochemical mode of action of chiral catalysts is a critical frontier in the discipline of asymmetric catalysis, whether the catalysts are enzymes or small molecules. With this back-drop, we began a detailed study of the mode of action for catalyst 5.The conversion of 3 to 4 was originally undertaken with the hypothesis that substratecatalyst hydrogen bonding might contribute to transition state organization. [vii] Indeed, a substrate lacking obvious H-bonding capability (phenylcyclohexene) was found to undergo epoxidation with catalyst 5 with low enantioselectivity (~10% ee). Thus, we envisioned several potential loci for contacts between 3 and 5 (Figure 2a). Shown in blue is the site that

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Dithiazolyl (DTA)-based radicals have furnished many examples of organic spin-transition materials, some of them occurring with hysteresis and some others without. Herein, we present a combined computational and experimental study aimed at deciphering the factors controlling the existence or absence of hysteresis by comparing the phase transitions of 4-cyanobenzo-1,3,2-dithiazolyl and 1,3,5-trithia-2,4,6-triazapentalenyl radicals, which are prototypical examples of non-bistable and bistable spin transitions, respectively. Both materials present low-temperature diamagnetic and high-temperature paramagnetic structures, characterized by dimerized (⋅⋅⋅A-A⋅⋅⋅A-A⋅⋅⋅) and regular (⋅⋅⋅A⋅⋅⋅A⋅⋅⋅A⋅⋅⋅A⋅⋅⋅) π-stacks of radicals, respectively. We show that the regular π-stacks are not potential energy minima but average structures arising from a dynamic inter-conversion between two degenerate dimerized configurations: (⋅⋅⋅A-A⋅⋅⋅A-A⋅⋅⋅) ↔(-A⋅⋅⋅A-A⋅⋅⋅A-) . The emergence of this intra-stack dynamics upon heating gives rise to a second-order phase transition that is responsible for the change in the dominant magnetic interactions of the system. This suggests that the promotion of a (⋅⋅⋅A-A⋅⋅⋅A-A⋅⋅⋅) ↔(-A⋅⋅⋅A-A⋅⋅⋅A-) dynamics is a general mechanism for triggering spin transitions in DTA-based materials. Yet, this intra-stack dynamics does not suffice to generate bistability, which also requires a rearrangement of the intermolecular bonds between the π-stacks via a first-order phase transition.

Synthetic compounds for controlling or creating human immunity have the potential to revolutionize disease treatment. Motivated by challenges in this arena, we report herein a strategy to target metastatic cancer cells for immune-mediated destruction by targeting the urokinase-type plasminogen activator receptor (uPAR). Urokinase-type plasminogen activator (uPA) and uPAR are overexpressed on the surfaces of a wide range of invasive cancer cells and are believed to contribute substantially to the migratory propensities of these cells. The key component of our approach is an antibody-recruiting molecule that targets the urokinase receptor (ARM-U). This bifunctional construct is formed by selectively, covalently attaching an antibody-binding small molecule to the active site of the urokinase enzyme. We demonstrate that ARM-U is capable of directing antibodies to the surfaces of target cancer cells and mediating both antibody-dependent cellular phagocytosis (ADCP) and antibody-dependent cellular cytotoxicity (ADCC) against multiple human cancer cell lines. We believe that the reported strategy has the potential to inform novel treatment options for a variety of deadly, invasive cancers.

Lysyl oxidase has emerged as an important enzyme in cancer metastasis. Its activity has been reported to become upregulated in several types of cancer, and blocking its activity has been shown to limit the metastatic potential of various cancers. The small-molecules phenylhydrazine and β-aminopropionitrile are known to inhibit lysyl oxidase; however, issues of stability, toxicity, and poorly defined mechanisms limit their potential use in medical applications. The experiments presented herein evaluate three other families of hydrazine-derived compounds – hydrazides, alkyl hydrazines, and semicarbazides – as irreversible inhibitors of lysyl oxidase including determining the kinetic parameters and comparing the inhibition selectivities for lysyl oxidase against the topaquinone-containing diamine oxidase from lentil seedlings. The results suggest that the hydrazide group may be a useful core functionality that can be developed into potent and selective inhibitors of lysyl oxidase and eventually find application in cancer metastasis research.