The synthesis of cypridina etioluciferamine and the proof of structure of cypridina luciferin

An unambiguous synthesis of Cypridina etioluciferamine was accomplished in order to prove the structure of this important bioluminescent natural product. Several 2-aminopyrazine 1-oxides were synthesized in order to establish a spectroscopic method for determining the placement of substituents on the pyrazine nucleus of Cypridina etioluciferamine. Titanium tetrachloride was used to improve the yields of these compounds; for example, the yield of 2-amino-3-methyl-5-phenylpyrazine 1-oxide (19) from reaction of phenylglyoxal 1-oxime and α-aminopropionitrile was raised from 3% to 51% by the use of titanium tetrachloride. The pyrazine ring proton is found at τ 1·37 (DMSO-d₆). The isomeric 2-amino-3-methyl-6-phenylpyrazine 1-oxide (22) was similarly prepared and its pyrazine ring proton is found at τ 2·18. This large difference (0·81 ppm) in chemical shift was used to determine whether a 2-aminopyrazine 1-oxide was 5- or 6- substituted. Prepared in an analogous fashion were 2-amino-5-(indol-3-yl)-3-methylpyrazine 1-oxide (23) and 2-amino-5-(indol-3-yl)-3-(3-phthalimidopropyl)pyrazine 1-oxide (16). The structures of these compounds were verified by NMR spectroscopy. By treatment with Raney nickel and hydrogen gas, then 100% hydrazine hydrate, 16 was converted to 2-amino-3-(3-aminopropyl)-5-indol-3-ylpyrazine (5), isolated as the dihydrochloride. This compound, with the indole moiety definitely placed at C-5, is identical with Cypridina etioluciferamine dihydrochloride (IR, UV, TLC). These results show that the structures of Cypridina etioluciferamine and luciferin are correct as published.     

The use of trans-2,3-divinyl epoxides as precursors to carbonyl ylides

trans-2,3-Divinyl epoxides have been found to be good substrates for the generation of carbonyl ylides in CCl₄ and 145 °C. These ylides, to a limited extent, undergo isomerization to cis-2,3-divinyl epoxides, leading to the isolation of 4,5-dihydrooxepins. Of greater potential usefulness is the finding that these ylides can be efficiently trapped in an intermolecular sense by a dipolarophile, leading to dihydrofurans.     

Cyclization of methyl 6,7-epoxycitronellate to methylcyclopentane derivatives : Alkoxide induced conversion of γ-lactones to γ,δ-unsaturated acids

The reaction of sodium hydride or potassium t-butoxide with methyl epoxycitronellate (1) in dimethylformamide affords a mixture of cis,cis-puleganolide (2) and cis,trans-puleganolide (3) in high yield. When the cyclization is conducted at 110°, the isomeric 2-isopropenyl-5-methylcyclopentanecarboxylic acids (8a–d) become the major products. It is demonstrated that γ-lactones undergo alkoxide-induced elimination to afford γ,δ-unsaturated acids.     

Stereoselective association of binuclear metallacycles in coordination polymers

A series of structurally related binuclear metallacycles [Cd(NO(3))(2)L](2), where L is an angular exo-bidentate ligand, have been synthesized. Each metallacycle contains two coordinatively unsaturated, chiral metal centers within a single molecule, and the assembly of these metallacycles into polymeric framework structures has been studied systematically for the first time. Stereoselective homochiral association of [Cd(NO(3))(2)L](2) leads to the formation of helical coordination polymers, whereas meso type association results in nonhelical chain structures. The type of stereoselective aggregation depends on the conditions of self-assembly as well as on ligand functionality. Both helical and nonhelical polymeric complexes have been isolated for the metallacycle [Cd(NO(3))(2)(2,4'-pyacph)](2) (2,4'-pyacph = 2,4'-(4-ethynylphenyl)bipyridyl). Homochiral association results in the formation of helical [Cd(NO(3))]( infinity ) chains which link the binuclear [Cd(NO(3))(2)(2,4'-pyacph)](2) metallacycles into racemic two-dimensional sheets which contain both P and M [Cd(NO(3))]( infinity ) helices. In contrast, meso-association leads to the formation of nonhelical one-dimensional chains. It is shown that the product of homochiral association is predominately formed at room temperature and that of meso-association is generated at elevated temperatures. Thus, it may be concluded that the homochiral association appears to be energetically less favorable than the meso-association, a conclusion that has been confirmed by theoretical calculations of the crystal lattice energy. Several high-yield syntheses of bipyridyl-type ligands used for metallacyclic assembly are also reported.     

Physically based molecular device model in a transient circuit simulator

Two efficient, physically based models for the real-time simulation of molecular device characteristics of single molecules are developed. These models assume that through-molecule tunnelling creates a steady-state Lorentzian distribution of excess electron density on the molecule and provides for smooth transitions for the electronic degrees of freedom between the tunnelling, molecular-excitation, and charge-hopping transport regimes. They are implemented in the fREEDA™ transient circuit simulator to allow for the full integration of nanoscopic molecular devices in standard packages that simulate entire devices including CMOS circuitry. Methods are presented to estimate the parameters used in the models via either direct experimental measurement or density-functional calculations. The models require 6–8 orders of magnitude less computer time than do full a priori simulations of the properties of molecular components. Consequently, molecular components can be efficiently implemented in circuit simulators. The molecular-component models are tested by comparison with experimental results reported for 1,4-benzenedithiol.     

Total synthesis of (+)-kalkitoxin

The neurotoxic lipopeptide (+)-kalkitoxin was synthesized by a route which employed asymmetric organocopper conjugate addition followed by in situ enolate alkylation to install the anti,anti-1,2,4-trimethyl relationship of the toxin; the synthesis of kalkitoxin required sixteen steps and proceeded in 3% overall yield.     

EFFICACY OF PHOTODYNAMIC THERAPY ON ORIGINAL AND RECURRENT RAT MAMMARY TUMORS

Abstract— Photodynamic therapy has demonstrated efficacy toward primary, metastatic and recurrent human tumors. Here, we investigated the ability of photodynamic therapy, using Photofrin, to inhibit growth of R3230AC mammary adenocarcinomas when tumors were treated as original implants and again as lesions recurring at the initial treatment site. The results demonstrate that both initial implants and lesions recurring after the first photodynamic treatment respond similarly to the same photodynamic therapy protocol, with mean tumor volume doubling times of ˜ 11 days in both cases. Cells cultured from original tumor implants or tumors that recurred after photodynamic treatment accumulate equivalent amounts of [¹⁴C]polyhematoporphyrin. Single cell suspensions prepared from either original or recurrent tumors from animals administered 5 mg/kg Photofrin and exposed to light in vitro displayed comparable phototoxicity. Additionally, examination of tumors by light microscopy revealed no morphological differences between the original tumor implants and the recurrent lesions. Taken together, these data indicate that lesions which recurred at the site of the initial photodynamic treatment were not resistant to a second identical course of photodynamic therapy.     

Reactive intermediates in asymmetric cross-coupling catalysed by palladium P-N chelates

The palladium dibromide complexes of (S,R)-(1,1′-bis-diphenylphosphino)-2-ferrocencylthyldimethylamine and (S,R)-(1-diphenylphosphino)-2-ferrocenylethyldimethylamine have been reduced with dilithiocyclooctatetraene to form the corresponding Pd⁰ cyclooctatetraene complexes. Their reactions with E-4-methoxy-2′-bromophenylethene, and then benzylmagnesium chloride at −60 to −30°C, provide information on the structure of intermediates in asymmetric cross-coupling.     

Single-strand conformation polymorphism-based analysis of mitochondrial cytochrome c oxidase subunit 1 reveals significant substructuring in hookworm populations

Sequence heterogeneity in a portion of the mitochondrial cytochrome c oxidase subunit 1 gene (pcox1) was measured for the hookworms, Ancylostoma caninum from Australia, A. duodenale from China, and Necator americanus from China and Togo using single-strand conformation polymorphism (SSCP) analysis combined with DNA sequencing. The pcox1 sequences were characterised for individual nematodes displaying genetic variation within each of the three species, and those were compared with pcox1 sequences of four other species of hookworm. While intraspecific variation in the pcox1 sequence ranged from 0.5 to 8.6% for A. caninum, 0.3 to 3.3% forA. duodenale, and 0.3 to 4.3% for N. americanus, interspecific differences varied from 4.8 to 12.9%. Sequence data also provided information on nucleotide compositions and substitution patterns. Genetically distinct groups were detected within A. caninum and A. duodenale, indicating significant population substructuring within these species. Also, N. americanus individuals from China all differed from those from Togo at four nucleotide positions, supporting a previous proposal (based on ribosomal DNA sequence data) that N. americanus may represent a species complex. The findings indicated the value of pcox1 sequence data and the mutation scanning approach for studying the genetic structures of hookworm populations, which should have important epidemiological relevance.     

Shot noise sets the limit of quantification in electrochemical measurements

Detection of single molecules, particles, and rapid redox events is a challenge of electrochemical investigations and requires either an amplification strategy or significant averaging for the electrochemical current to exceed the noise level. We consider the minimum number of electrons required to reach the limit of quantification in these electrochemical measurements. A survey of the literature indicates that the state-of-the-art limit in current detection for different types of measurements (e.g. voltammetry, single-molecule redox cycling, ion channel recordings of single molecules, metal nanoparticle collision, and phase nucleation) is independent of the nature of the measurement and increases linearly with reciprocal response time, Δt^?1, over ～5 orders of magnitude (from ～10 to ～10⁶ s^?1). We demonstrate that the practical limit of quantification requires cumulative measurement of ～2100 electrons during Δt and is determined by statistics of counting electrons, that is, the shot noise in the current.