TNAs [(L)-alpha-threofuranosyl oligonucleotides] containing vicinally connected (3'-->2') phosphodiester bridges undergo informational base pairing in antiparallel strand orientation and are capable of cross-pairing with RNA and DNA. Being derived from a sugar containing only four carbons, TNA is structurally the simplest of all potentially natural oligonucleotide-type nucleic acid alternatives studied thus far. This, along with the base-pairing properties of TNA, warrants close scrutiny of the system in the context of the problem of RNA's origin.

The synthesis of potentially natural nucleic acid alternatives and comparison of some of their chemical properties with those of RNA and DNA have led to findings that we consider to be relevant in the context of a chemical etiology of nucleic acid structure.Chemical etiology of nucleic acid structure refers to systematic experimental studies aimed at narrowing the diversity of possible answers to the question of why nature chose the structure type of ribofuranosyl nucleic acids, rather than some other family of molecular structures, as the molecular basis of life's genetic system. The experimental strategy is to conceive potentially natural alternatives to the nucleic acid structure, to synthesize such alternatives by chemical methods, and to compare them with the natural nucleic acids with respect to those chemical properties that are fundamental to the biological function of RNA and DNA ( Fig. 1).In the course of these studies it was found that all four members of the family of pentopyranosyl-(4'AE2')-oligonucleotide systems that contain b-ribo, b-xylo-, a-lyxo-or a-arabinopyranosyl units as repeating sugar building blocks are found to be much stronger Watson-Crick base-pairing systems than RNA [1][2][3]. The a-arabinopyranosyl system is the strongest of all, in fact, it belongs to the strongest oligonucleotide base-pairing systems known. We conclude that, whatever the chemical determinants by which nature selected RNA as a genetic system, maximization of base-pairing strengths within the domain of pentose-derived oligonucleotide systems was not the critical selection criterion [4] (Fig. 2).The so far experimentally most comprehensively studied system among the potentially natural sugar-based nucleic acid alternatives is the pyranosyl isomer of RNA. One of the chemical properties of this system provides a transparent illustration of the intrinsic potential of an informational oligomer system to break molecular mirror symmetry. Hemi-self-complementary p-RNA tetramer-2',3'-cyclophosphates were shown to undergo efficient self-templating ligation to higher oligomers with high sequence-, regio-, and chiro-selectivity. Tetramers with differing, but fitting, hemi-complementary base sequences can undergo stochastic co-oligomerization to give rise to large libraries of p-RNA sequences. The high chiroselectivity of the ligation process leads one to think of a scenario in which a comprehensively stochastic co-oligomerization process starting from the heterochiral and strictly racemic library of all eight possible diastereomers of all possible tetramer-2',3'-cyclophosphates (256 = 4 4 ) would necessarily break molecular mirror symmetry of higher oligomers in the sense that the resulting (equal amounts of) homochiral D-and L-libraries of a given (high) oligomer would not constitute a racemic mixture since the two libraries would have to have different sequence compositions by statistical reasons (Fig. 3).A thought-experiment in which this kind of capacity of an informational oligomer system is combined with a cap...

Here, we report evidence for the production of ozone in human disease. Signature products unique to cholesterol ozonolysis are present within atherosclerotic tissue at the time of carotid endarterectomy, suggesting that ozone production occurred during lesion development. Furthermore, advanced atherosclerotic plaques generate ozone when the leukocytes within the diseased arteries are activated in vitro. The steroids produced by cholesterol ozonolysis cause effects that are thought to be critical to the pathogenesis of atherosclerosis, including cytotoxicity, lipid-loading in macrophages, and deformation of the apolipoprotein B-100 secondary structure. We propose the trivial designation "atheronals" for this previously unrecognized class of steroids.

Recently we reported that antibodies can generate hydrogen peroxide (H2O2) from singlet molecular oxygen (1O2*). We now show that this process is catalytic, and we identify the electron source for a quasi-unlimited generation of H2O2. Antibodies produce up to 500 mole equivalents of H2O2 from 1O2*, without a reduction in rate, and we have excluded metals or Cl- as the electron source. On the basis of isotope incorporation experiments and kinetic data, we propose that antibodies use H2O as an electron source, facilitating its addition to 1O2* to form H2O3 as the first intermediate in a reaction cascade that eventually leads to H2O2. X-ray crystallographic studies with xenon point to putative conserved oxygen binding sites within the antibody fold where this chemistry could be initiated. Our findings suggest a protective function of immunoglobulins against 1O2* and raise the question of whether the need to detoxify 1O2* has played a decisive role in the evolution of the immunoglobulin fold.

Recently, we showed that antibodies catalyze the generation of hydrogen peroxide (H2O2) from singlet molecular oxygen (1O2*) and water. Here, we show that this process can lead to efficient killing of bacteria, regardless of the antigen specificity of the antibody. H2O2 production by antibodies alone was found to be not sufficient for bacterial killing. Our studies suggested that the antibody-catalyzed water-oxidation pathway produced an additional molecular species with a chemical signature similar to that of ozone. This species is also generated during the oxidative burst of activated human neutrophils and during inflammation. These observations suggest that alternative pathways may exist for biological killing of bacteria that are mediated by potent oxidants previously unknown to biology.

Anfinsen showed that a protein's fold is specified by its sequence. Although it is clear why mutant proteins form amyloid, it is harder to rationalize why a wild-type protein adopts a native conformation in most individuals, but it misfolds in a minority of others, in what should be a common extracellular environment. This discrepancy suggests that another event likely triggers misfolding in sporadic amyloid disease. One possibility is that an abnormal metabolite, generated only in some individuals, covalently modifies the protein or peptide and causes it to misfold, but evidence for this is sparse. Candidate metabolites are suggested by the recently appreciated links between Alzheimer's disease (AD) and atherosclerosis, known chronic inflammatory metabolites, and the newly discovered generation of ozone during inflammation. Here we report detection of cholesterol ozonolysis products in human brains. These products and a related, lipid-derived aldehyde covalently modify A␤, dramatically accelerating its amyloidogenesis in vitro, providing a possible chemical link between hypercholesterolemia, inflammation, atherosclerosis, and sporadic AD. Anfinsen's classic experiments demonstrated that a protein's amino acid sequence specifies its conformation (1). These ideas were extended to explain the misfolding susceptibility of mutant proteins associated with a growing number of familial amyloid diseases (2-5). Although it is thus clear why mutant proteins might be more susceptible to misfolding, it is harder to understand why a wild-type protein or peptide adopts a native conformation in some individuals but it misfolds in others in what should be a common extracellular environment, leading to sporadic amyloid diseases. This discrepancy suggests that other events likely trigger misfolding in sporadic amyloid disease, but their nature remains elusive.The misfolding of secreted amyloid ␤ peptides (A␤) 39-43 residues in length is linked by a plethora of evidence to the pathology of Alzheimer's disease (AD) (6, 7). A␤ misfolding occurs when the soluble, monomeric, extracellular ensemble of extended conformations and low M r oligomers is transformed first into spherical assemblies, then into a number of intermediates, and lastly into fibrillar cross ␤-sheet quaternary structures known as amyloid (8)(9)(10)(11)(12). Amyloid fibrils and related structures recruit soluble A␤ to the aggregate by a seeded polymerization mechanism (10). The direct neurotoxicity of A␤ aggregates (8, 13) combined with their role in mediating chronic inflammation by microglia (14) and complement cascade activation (15) suggests that aggregation then mediates inflammation (16), which in turn promotes aggregation, in a vicious cycle of AD pathology.It is known that atherosclerosis and AD share many risk factors, including hypercholesterolemia and inflammation. The apoE-4 allele, which exacerbates hypercholesterolemia, has been linked to AD by data from both epidemiological and transgenic mouse studies (17)(18)(19)(20). It has also recently been shown t...

Dedicated to Professor Yoshito Kishi on the occasion of his 70th birthdayThe N,O-acetal and N,O-ketal derivatives (oxazolidinones) formed from proline, and aldehydes or ketones are well-known today, and they are detectable in reaction mixtures involving proline catalysis, where they have been considered parasitic dead ends . We disclose results of experiments performed in the early 1970 s, and we describe more recent findings about the isolation, characterization, and reactions of the oxazolidinone derived from proline and cyclohexanone. This oxazolidinone reacts (THF, room temperature) with the electrophiles b-nitrostyrene and chloral (¼ trichloroacetaldehyde), to give the Michael and aldol adduct, respectively, after aqueous workup (Scheme 5). The reactions occur even at À 758 when catalyzed with bases such as 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or EtN(i-Pr) 2 (DIPEA) (10%; Table 1). It is shown by NMR (Figs. 1 and 3) and IR analysis (Figs. 2 and 4) that the primarily detectable product (before hydrolysis) of the reaction with the nitro-olefin is again an oxazolidinone. When dissolved in hydroxylic solvents such as MeOH, hexafluoroisopropanol ((CF 3 ) 2 CHOH; HFIP), AcOH, CF 3 COOH, or in LiBr-saturated THF, the ring of the oxazolidinone from cyclohexanone and proline opens up to the corresponding iminium ion (Tables 2 -4), and when treated with strong bases such as DBU (in (D 8 )THF) the enamino-carboxylate derived from proline and cyclohexanone is formed (Scheme 8). Thus, the two hitherto putative participants (iminium ion and enamine) of the catalytic cycle (Scheme 9) have been characterized for the first time. The commonly accepted mechanism of the stereoselective C,C-or C,X-bond-forming step (i.e., A -D) of this cycle is discussed and challenged by thoughts about an alternative model with a pivotal role of oxazolidinones in the regio-and diastereoselective formation of the intermediate enamino acid (by elimination) and in the subsequent reaction with an electrophile (by trans-addition with lactonization; Schemes 11 -14). The stereochemical bias between endo-and exo-space of the bicyclo[3.3.0]octane-type oxazolidinone structure (Figs. 5 and 6) is considered to possibly be decisive for the stereochemical course of events.Helvetica Chimica Acta -Vol. 90 (2007) Finally, the remarkable consistency, with which the diastereotopic Re-face of the double bond of pyrrolidino-enamines (derived from proline) is attacked by electrophiles (Schemes 1 and 15), and the likewise consistent reversal to the Si-face with bulky (Aryl) 2 C-substituents on the pyrrolidine ring (Scheme 16) are discussed by invoking stereoelectronic assistance from the lone pair of pyramidalized enamine N-atoms.1. Introduction. -We would hardly have considered to become engaged in the timely research area of organocatalysis , had not, in the recent literature, the name of one of the present authors (D. S.) been implied in a statement on the mechanism of the stereoselection in proline catalysis (see title) such that this author was incited to ...

The biogenetic isoprene rule in its application to the triterpenes is discussed from a stereochemical standpoint. On the basis of a well defined system of arbitrary assumptions a scheme has been developed leading from squalene to the formulae of the basic representatives of all known cyclic triterpene groups ‐ i.e. euphol, tirucallol, lupeol, taraxasterol, germanicol, β‐amyrin, taraxerol, friedelin, α‐amyrin, lanosterol ‐ in their full structural and configurational detail. This result is considered to support the squalene hypothesis of the biogenesis of cyclic triterpenes.