Dioxygenase-catalysed sulfoxidation of bicyclic alkylaryl sulfides and chemoenzymatic synthesis of acyclic disulfoxides

Toluene- and naphthalene-dioxygenase-catalysed oxidation of six bicyclic disulfide substrates, using whole cells of Pseudomonas putida, gave the corresponding monosulfoxides with high ee values and enantiocomplementarity, in most cases. Two alcohol-sulfoxide diastereoisomers, formed from the reaction of the (R)-1,3-benzodithiole-1-oxide metabolite with n-butyllithium and benzaldehyde, were separated and stereochemically assigned. Treatment, of enantiopure (1R,3R)-benzo-1,3-dithiole-1,3-dioxide, obtained by chemoenzymatic synthesis, with alkyllithium reagents, resulted in a novel ring-opening reaction which proceeded with inversion of configuration to yield a series of acyclic disulfoxides. (C) 2003 Elsevier Ltd. All rights reserved.

Novel macrocyclic and acyclic cationic lipids for gene transfer: Synthesis and in vitro evaluation

The synthesis and in vitro evaluation of four cationic lipid gene delivery vectors, characterized by acyclic or macrocyclic, and saturated or unsaturated hydrophobic regions, is described. The synthesis employed standard protocols, including ring-closing metathesis for macrocyclic lipid construction. All lipoplexes studied, formulated from plasmid DNA and a liposome composed of a synthesized lipid, 1,2-dimyristoyl-sn-glycero-3-ethylphosphocholine (EPC), and either 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE) or cholesterol as co-lipid, exhibited plasmid DNA binding and protection from DNase I degradation, and concentration dependent cytotoxicity using Chinese hamster ovary-K1 cells. The transfection efficiency of formulations with cholesterol outperformed those with DOPE, and in many cases the EPC/cholesterol control, and formulations with a macrocyclic lipid (+/- 10:1) outperformed their acyclic counterparts (+/- 3:1).

Effects of KCl concentration on accumulation of acyclic sugar alcohols and trehalose in conidia of three entomopathogenic fungi

Beauveria bassiana, Metarhizium anisopliae and Paecilomyces farinosus were grown on Sabouraud Dextrose Agar (SDA) modified with KCl to give a range of water activity (a(w)) from 0.938 to 0.998. Growth of all three species was optimal at 0.983 a(w) and growth occurred over the a(w) range tested. Acyclic sugar alcohol (polyol) and trehalose content of conidia was determined by HPLC and found to vary with species and a(w). Conidia of B. bassiana and P. farinosus were found to contain totals of 1.5% and 2.3% polyols respectively at 0.998 a(w), and double these amounts at <0.950 a(w). Conidia of M. anisopliae contained from 5.7% to 6.8% polyols at each a(w) tested. In conidia of all three species the predominant polyol was mannitol. The lower molecular weight polyols, arabitol and erythritol, were found to accumulate at reduced a(w). Small amounts of glycerol were present in conidia of each species; <15% total polyols. Conidia of B. bassiana and M. anisopliae contained about 0.5% trehalose from 0.970 to 0.998 a(w), but only trace amounts below 0.950 a(w). Conidia of P. farinosus contained 2.1% trehalose at 0.998 a(w) and this decreased to <0.1% below 0.950 a(w). Potential to manipulate the endogenous reserves of conidia of these biological control agents to enhance viability and desiccation tolerance is discussed.

Selectivity studies of the benzene cis-dihydrodiol dehydrogenase enzyme from Pseudomonas putida ML2 with Vicinal diol substrates

The enantiopure (1S, 2S)-cis-dihydrodiol metabolites 2B-5B have been obtained in low yield from the corresponding monosubstituted halobenzene substrates 2A-5A, using a wild-type strain of Pseudomonas putida (ML2) containing benzene dioxygenase (BDO). Benzene cis-dihydrodiol dehydrogenase (BCD) from P. putida ML2 and naphthalene cis-dihydrodiol dehydrogenase (NCD) from P. putida 8859 were purified and used in a comparative study of the stereoselective biotransformation of cis-dihydrodiol enantiomers 2B-5B. The BCD and NCD enzymes were found to accept cis-dihydrodiol enantiomers of monosubstituted benzene cis-dihydrodiol substrates 2B-5B of opposite absolute configuration. The acyclic alkene 1,2-diols 10-17 were also found to be acceptable substrates for BCD.

Lewis acid platinum complexes of conformationally flexible NUPHOS diphosphines: Highly efficient catalysts for the carbonyl-ene reaction

Enantiopure Lewis acid complexes of conformationally flexible acyclic and monocyclic NUPHOS diphosphines, delta- and lambda-[(NUPHOS)Pt(OTf)(2)], are efficient catalysts for the carbonyl-ene reaction between various unsymmetrical 1,1'-disubstituted alkenes and phenylglyoxal or ethyl glyoxylate. While catalyst performance was substrate dependent, ee values as high as 95% and yields up to 90% have been obtained. In a number of cases catalysts generated from delta- and lambda-[(NUPHOS)Pt{(S)-BINOL}] showed marked enhancements in enantioselectivity in ionic liquids compared with organic media. Although an enhancement in enantioselectivity was not obtained for all substrate combinations in such cases, the enantioselectivities were comparable to those obtained in dichloromethane. Furthermore, although the ee's are initially comparable in both the ionic liquid and dichloromethane, a gradual erosion of ee with time was found in the organic solvent, whereas the ee remained constant in the ionic liquid. Preliminary kinetic investigations suggest that the decrease in ee may be due to a faster racemization of the catalyst in dichloromethane compared with the ionic liquid.

Unprecedented regio and stereocontrol in Povarov reaction of benzylidene-(3-nitrophenyl) amine

Typically, Povarov reactions of imines derived from aromatic amines and aromatic aldehydes show poor exo/endo-stereoselectivity and to date no data is available on the regioselectivity of the cyclisation when 3-substituted imines are employed. We have demonstrated that reaction using acyclic enamides as the alkene component with 3-nitro substituted imines is completely regioselective and gave only the 5-nitro substituted tetrahydroquinoline. As a bonus the reaction also became completely exo-selective with the stereochemistry of the E-alkene preserved in the tetrahydroquinoline product.

Transamidation reactions of  -lactams: a synthesis of ( )-dihydroperiphylline.

Ammonolysis of N-(halogenoalkyl)azetidin-2-ones affords medium ring azalactams via transamidation but large or strained rings are not isolated, acyclic ?-amino-amides being produced; two successive transamidative ring expansions from 4-phenylazetidin-2-one give a synthesis of (?)-dihydroperiphylline (I).

Study of the transamidative ring expansion of N--halogenoalkyl--lactams of alkyl chain lengths 2–12 in liquid ammonia and other liquid amines: syntheses of 7-, 8- and 9-membered 1,5-diaza cyclic ketones, including routes to (±)-dihydroperiphylline and (±)-celabenzine

N-(3-Halogenopropyl)-4-phenylazetidin-2-ones undergo amination in liquid ammonia followed by transamidative ring expansion to give the eight-membered 4-phenyl -1,5-diazacyclooctan-2-one in excellent yield. Ring expansion of the amines in liquid ammonia is found to be much more effective than in hydrocarbon solvents. Formation of 7-, 8-, and 9-membered azalactams from the requisite -halogenoalkyl--lactams is an excellent synthetic process, though it is not applicable to 10membered rings. In the cases of rings of 13-, 15- and 17-members, although amination and apparent expansion takes place, the large rings appear not to be stable to ammonia and the final products are acyclic amides. N-[4-Halogenobut-2(Z)-enyl]-4-phenylazetidin-2-one satisfactorily forms a 9-membered (Z)-olefinic azalactam, but the (E)-isomer gives an acyclic amino amide. By using alkyl-substituted -lactam side-chains, C-substituted medium rings can be obtained; the relative instability of N-acyl -lactams to ammonia, however, leads to acylamino amides rather than expanded rings.Employing ethylamine in place of ammonia, it is shown that N-ethylated azalactams are formed satisfactorily, and using allylamine, N-allyl medium rings capable of further elaboration are obtained. The chemistry of these systems is discussed. Using transamidation in liquid ammonia, a short synthesis of the 9-membered spermidine alkaloid (±)-dihydroperiphylline is reported. Synthesis of key intermediates, whose transformation into the 13-membered alkaloids of the celabenzine group has already been effected, has been carried out.X-Ray single-crystal structure determinations for 4-phenyl-1,5-diazacyclononan-2-one, trans-4-phenyl-8-methyl-1,5-diazacyclooctan-2-one and (Z)-4-phenyl-1,5-diazacyclonon-7-en-2-one are reported, and comment is made on certain conformational features.

A splitting result for the algebraic K-theory of projective toric schemes

Suppose X is a projective toric scheme defined over a ring R and equipped with an ample line bundle L . We prove that its K-theory has a direct summand of the form K(R)(k+1) where k = 0 is minimal such that L?(-k-1) is not acyclic. Using a combinatorial description of quasi-coherent sheaves we interpret and prove this result for a ring R which is either commutative, or else left noetherian.

Finite domination and Novikov rings. Iterative approach

Suppose C is a bounded chain complex of finitely generated free modules over the Laurent polynomial ring L = R[x,x -1]. Then C is R-finitely dominated, i.e. homotopy equivalent over R to a bounded chain complex of finitely generated projective R-modules if and only if the two chain complexes C ? L R((x)) and C ? L R((x -1)) are acyclic, as has been proved by Ranicki (A. Ranicki, Finite domination and Novikov rings, Topology 34(3) (1995), 619–632). Here R((x)) = R[[x]][x -1] and R((x -1)) = R[[x -1]][x] are rings of the formal Laurent series, also known as Novikov rings. In this paper, we prove a generalisation of this criterion which allows us to detect finite domination of bounded below chain complexes of projective modules over Laurent rings in several indeterminates.

The Computational Complexity of Dominance and Consistency in CP-Nets

We investigate the computational complexity of testing dominance and consistency in CP-nets. Previously, the complexity of dominance has been determined for restricted classes in which the dependency graph of the CP-net is acyclic. However, there are preferences of interest that define cyclic dependency graphs; these are modeled with general CP-nets. In our main results, we show here that both dominance and consistency for general CP-nets are PSPACE-complete. We then consider the concept of strong dominance, dominance equivalence and dominance incomparability, and several notions of optimality, and identify the complexity of the corresponding decision problems. The reductions used in the proofs are from STRIPS planning, and thus reinforce the earlier established connections between both areas.

Semiring induced valuation algebras: Exact and approximate local computation algorithms

Local computation in join trees or acyclic hypertrees has been shown to be linked to a particular algebraic structure, called valuation algebra.There are many models of this algebraic structure ranging from probability theory to numerical analysis, relational databases and various classical and non-classical logics. It turns out that many interesting models of valuation algebras may be derived from semiring valued mappings. In this paper we study how valuation algebras are induced by semirings and how the structure of the valuation algebra is related to the algebraic structure of the semiring. In particular, c-semirings with idempotent multiplication induce idempotent valuation algebras and therefore permit particularly efficient architectures for local computation. Also important are semirings whose multiplicative semigroup is embedded in a union of groups. They induce valuation algebras with a partially defined division. For these valuation algebras, the well-known architectures for Bayesian networks apply. We also extend the general computational framework to allow derivation of bounds and approximations, for when exact computation is not feasible.

Optimization of an ether series of mGluR5 positive allosteric modulators: Molecular determinants of MPEP site interaction crossover

We report the optimization of a series of non-MPEP site metabotropic glutamate receptor 5 (mGlu5) pos. allosteric modulators (PAMs) based on a simple acyclic ether series. Modifications led to a gain of MPEP site interaction through incorporation of a chiral amide in conjunction with a nicotinamide core. A highly potent PAM, 8v (VU0404251), was shown to be efficacious in a rodent model of psychosis. These studies suggest that potent PAMs within topol. similar chemotypes can be developed to preferentially interact or not interact with the MPEP allosteric binding site.

Finite domination and Novikov rings: Laurent polynomial rings in two variables

Let C be a bounded cochain complex of finitely generatedfree modules over the Laurent polynomial ring L = R[x, x−1, y, y−1].The complex C is called R-finitely dominated if it is homotopy equivalentover R to a bounded complex of finitely generated projective Rmodules.Our main result characterises R-finitely dominated complexesin terms of Novikov cohomology: C is R-finitely dominated if andonly if eight complexes derived from C are acyclic; these complexes areC ⊗L R[[x, y]][(xy)−1] and C ⊗L R[x, x−1][[y]][y−1], and their variants obtainedby swapping x and y, and replacing either indeterminate by its inverse.

Min-BDeu and Max-BDeu Scores for Learning Bayesian Networks

This work presents two new score functions based on the Bayesian Dirichlet equivalent uniform (BDeu) score for learning Bayesian network structures. They consider the sensitivity of BDeu to varying parameters of the Dirichlet prior. The scores take on the most adversary and the most beneficial priors among those within a contamination set around the symmetric one. We build these scores in such way that they are decomposable and can be computed efficiently. Because of that, they can be integrated into any state-of-the-art structure learning method that explores the space of directed acyclic graphs and allows decomposable scores. Empirical results suggest that our scores outperform the standard BDeu score in terms of the likelihood of unseen data and in terms of edge discovery with respect to the true network, at least when the training sample size is small. We discuss the relation between these new scores and the accuracy of inferred models. Moreover, our new criteria can be used to identify the amount of data after which learning is saturated, that is, additional data are of little help to improve the resulting model.