Synthesis of novel C-2 substituted pyrimidine nucleoside analogs

A series of 2-(2-oxoalkylidene)-4(1H)-pyrimidinone nucleoside analogs were synthesized by the addition of the lithium enolates of methylketones to 2,5′- and 2,2′-anhydrouridines and to 2,5′-anhydrothymidines. Alternatively, 2-thiouridine was alkylated with bromomethyl ketones to yield 2-(2-oxoalkyl)thio-4(1H)-pyrimidinone ribofuranosides in good yields. These intermediates were subsequently transformed into the title compounds via an Eschenmoser sulfur extrusion reaction. The 2-(2-oxoalkylidene)-4-(1H)-pyrimidinone nucleoside analogs exhibit enol proton signals in their ¹H nmr spectra indicative of hydrogen bonding between N-3 and keto oxygen. These structures offer functional groups with potential for Watson-Crick hydrogen bonding.     

Fragment-asperity interaction model for earthquakes

A model for earthquake dynamics consisting of two rough profiles interacting via fragments filling the gap is introduced, the fragments being produced by the local breakage due to the interaction of the local plates. The irregularities of the fault planes can interact with the fragments between them to develop a mechanism for triggering earthquakes. The fragment size distribution function comes from a nonextensive formulation, starting from first principles. An energy distribution function, which gives the Gutenberg-Richter law as a particular case, is analytically deduced.     

Boryl‐Functionalized σ‐Alkynyl and Vinylidene Rhodium Complexes: Synthesis and Electronic Properties

The synthesis, reactivity, and properties of boryl‐functionalized σ‐alkynyl and vinylidene rhodium complexes such as trans‐[RhCl(?C?CHBMes₂)(PiPr₃)₂] and trans‐[Rh(C?CBMes₂)(IMe)(PiPr₃)₂] are reported. An equilibrium was found to exist between rhodium vinylidene complexes and the corresponding hydrido σ‐alkynyl complexes in solution. The complex trans‐[Rh(C?CBMes₂)(IMe)(PiPr₃)₂] (IMe=1,3‐dimethylimidazol‐2‐ylidene) was found to exhibit solvatochromism and can be quasireversibly oxidized and reduced electrochemically. Density functional calculations were performed to determine the reaction mechanism and to help rationalize the photophysical properties of trans‐[Rh(C?CBMes₂)(IMe)(PiPr₃)₂].     

Using biased randomization for solving the two-dimensional loading vehicle routing problem with heterogeneous fleet

This paper discusses the two-dimensional loading capacitated vehicle routing problem (2L-CVRP) with heterogeneous fleet (2L-HFVRP). The 2L-CVRP can be found in many real-life situations related to the transportation of voluminous items where two-dimensional packing restrictions have to be considered, e.g.: transportation of heavy machinery, forklifts, professional cleaning equipment, etc. Here, we also consider a heterogeneous fleet of vehicles, comprising units of different capacities, sizes and fixed/variable costs. Despite the fact that heterogeneous fleets are quite ubiquitous in real-life scenarios, there is a lack of publications in the literature discussing the 2L-HFVRP. In particular, to the best of our knowledge no previous work discusses the non-oriented 2L-HFVRP, in which items are allowed to be rotated during the truck-loading process. After describing and motivating the problem, a literature review on related work is performed. Then, a multi-start algorithm based on biased randomization of routing and packing heuristics is proposed. A set of computational experiments contribute to illustrate the scope of our approach, as well as to show its efficiency.     

Straightforward synthesis of thiodisaccharides by ring-opening of sugar epoxides

3,4-Anhydro hexopyranosides have been prepared by diastereoselective epoxidation of derivatives of 2-propyl 3,4-dideoxy-alpha-D-erythro-hex-3-enopyranoside (5), selectively protected at HO-2 and HO-6. The allylic group at C-2, in 5 and derivatives, plays a critical role in the facial selectivity of the epoxidation reaction. Thus, the free HO-2 in 3 (the 6-O-acetyl derivative of 5) directs the attack of m-chloroperbenzoic acid from the more hindered alpha face of the molecule to give 2-propyl 6-O-acetyl-3,4-anhydro-alpha-D-allopyranoside (7) accompanied by the beta epoxide 6 as a very minor product. Reverse diastereoselectivity has been obtained when the HO-2 in 3 was substituted by a bulky tert-butyldimethylsilyl (TBS) group. In this case, the major isomer was the 2-O-TBS derivative of 6 (alpha-D-galacto configuration). The ring-opening of sugar epoxides by nucleophilic per-O-acetyl-1-thio-beta-D-glucopyranose (11) was employed as a convenient approach to the synthesis of (1-->3)- and (1-->4)-thiodisaccharides. For example, ring-opening of the oxirane 7 by 11 led to the expected regioisomeric per-O-acetyl thiodisaccharides beta-D-Glc-S-(1-->3)-4-thio-alpha-D-Glc-O-iPr (12) and beta-D-Glc-S-(1-->4)-4-thio-alpha-D-Gul-O-iPr (13). Regioselectivity in the construction of the (1-->4)-thioglycosidic linkage could be achieved by hindering C-3 of the 3,4-anhydro sugar with a bulky silyloxy group at the vicinal C-2. For instance, coupling of the 2-O-TBS derivative of 7 with 11 led regioselectively to the protected thiodisaccharide beta-D-Glc-S-(1-->4)-4-thio-alpha-D-Glc-O-iPr (27). The utility of the approach was demonstrated through the synthesis of sulfur-linked analogues of naturally occurring (laminarabiose and cellobiose) and non-natural disaccharides (i.e., beta-D-Glc-(1-->4)-alpha-D-Gul).     

A pyrazine bis‐adduct of a binuclear rhodium(II) carboxylate containing 3,4,5‐triethoxybenzoate as the ­equatorial ligand

The title compound, tetrakis(μ‐3,4,5‐triethoxy­benzoato‐κ²O:O′)­bis­[(pyrazine‐κN)­rhodium(II)](Rh—Rh), [Rh₂(C₁₃H₁₇O₅)₄(C₄H₄N₂)₂], crystallizes on an inversion centre in the triclinic space group . The equatorial carboxyl­ate ligands bridge the two Rh^II atoms, giving a binuclear lantern‐like structure. The pyrazine mol­ecules occupy the two axial coordination sites. The phenyl rings are tilted by ca 10° with respect to the attached carboxyl­ate groups. The pyrazine planes have a torsion angle of ca 19° around the Rh—N bond with respect to the plane of the nearer carboxyl­ate group and are not coplanar with the Rh—Rh bond.     

Conformational and electronic study of dopamine interacting with the D2 dopamine receptor

We report an exhaustive conformational and electronic study on dopamine (DA) interacting with the D₂ dopamine receptor (D₂DR). For the first time, the complete surface of the conformational potential energy of the complex DA/D₂DR is reported. Such a surface was obtained through the use of QM/MM calculations. A detailed study of the molecular interactions that stabilize and destabilize the different molecular complexes was carried out using two techniques: Quantum Theory of Atoms in Molecules computations and nuclear magnetic shielding constants calculations. A comparative study of the behavior of DA in the gas phase, aqueous solution, and in the active site of D₂DR has allowed us to evaluate the degree of deformation suffered by the ligand and, therefore, analyze how rustic are the lock-key model and the induced fit theory in this case. Our results allow us to propose one of the conformations obtained as the “biologically relevant” conformation of DA when it is interacting with the D₂DR.     

Cloning, Sequencing, and Identification Using Proteomic Tools of a Protease from Bromelia hieronymi Mez

Fruits of Bromelia hieronymi, a tropical South American plant, possess a high content of peptidases with potential biotechnological uses. Total RNA was extracted from unripe fruits and peptidase cDNA was obtained by 3'RACE-PCR. The consensus sequence of the cysteine peptidase cDNA contained 875 bp, the 690 first ones codifying for a hypothetical polypeptide chain of the mature peptidase, named Bh-CP1 (molecular mass 24.773 kDa, pI 8.6, extinction molar coefficient 58,705 M(-1) cm(-1)). Bh-CP1 sequence shows a high percentage of identity with those of other cysteine plant proteases. The presence of highly preserved residues is observed, like those forming the catalytic site (Gln19, Cys25, His159, and Asn175, papain numbering), as well as other six Cys residues, involved in the formation of disulfide bounds. Molecular modeling results suggest the enzyme belongs to the α?+?β class of proteins, with two disulfide bridges (Cys23-Cys63 and Cys57-Cys96) in the α domain, while the β domain is stabilized by another disulfide bridge (Cys153-Cys203). Additionally, peptide mass fingerprints (PMFs) of the three peptidases previously isolated from B. hieronymi fruits (namely hieronymain I, II, and III) were performed and compared with the theoretical fingerprint of PMF of Bh-CP1, showing a partial matching between the in silico-translated protein and hieronymain II.