Robert Franzén

Synthetic Approaches towards Indoles on Solid phase - Recent Advances and Future Directions

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Determination of Chlorinated 5-Methyl-5-hydroxyfuranones in Drinking Water, in Chlorinated Humic Water, and in Pulp Bleaching Liquor.

published in Aduance ACS Abstracts, September 15,

Mutation spectra in Salmonella of analogues of MX: implications of chemical structure for mutational mechanisms

We determined the mutation spectra in Salmonella of four chlorinated butenoic acid analogues (BA-1 through BA-4) of the drinking water mutagen 3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone (MX) and compared the results with those generated previously by us for MX and a related compound, MCF. We then considered relationships between the properties of mutagenic potency and mutational specificity for these six chlorinated butenoic acid analogues. In TA98, the three most potent mutagens, BA-3, BA-4, MX, and the organic extract, all induced large percentages of complex frameshifts (33-67%), which distinguish these agents from any other class of compound studied previously. In TA100, which has only GC sites for mutation recovery, >71% of the mutations induced by all of the agents were GC-->TA transversions. The availability of both GC and TA sites for mutation in TA104 resulted in greater distinctions in mutational specificity than in TA100. MX targeted GC sites almost exclusively (98%); the structurally similar BA-4 and BA-2 produced mutations at similar frequencies at both GC and AT sites; and the structurally similar BA-3 and BA-1 induced most mutations at AT sites (69%). Thus, large variations in structural properties influencing relative mutagenic potency appeared to be distinct from the more localized similar structural features influencing mutagenic specificity in TA104. Among a set of physicochemical properties examined for the six butenoic acids, a significant correlation was found between pK(a) and mutagenic potency in TA100, even when the unionized fraction of the activity dose was considered. In addition, a correlation in CLOGP for BA-1 to BA-4 suggested a role for bioavailability in determining mutagenic potency. These results illustrate the potential value of structural analyses for exploring the relationship between chemical structure and mutational mechanisms. To our knowledge, this is the first study in which such analyses have been applied to structural analogues for which both mutagenic potency and mutation spectra date were available.

Genotoxic activity of chlorinated butenoic acids in Salmonella typhimurium strains TA98, TA100 and TA104

The mutagenic activities of several chlorinated butenoic acids, recently identified in chlorinated drinking waters, were determined by the Salmonella microsome assay. The Salmonella typhimurium tester strains TA98, TA100, and TA104 were used without S9 mix. The results from the investigation showed that (Z)-2-chloro-3-(dichloromethyl)-4-oxobutenoic acid (MX, in the open form) was the most potent mutagen of the compounds tested. However, a significant number of mutations was also induced by compounds with structural similarities to MX. In general, all the compounds, except the butenedioic acids, were mutagenic in the assays for both base-pair substitution strains (TA100, TA104) and for the frameshift strain TA98, with the highest mutagenic response observed in strain TA100. When the aldehyde group of MX and of 2-chloro-3-(chloromethyl)-4-oxobutenoic acid (CMCF, in the open form) was replaced by a dichloromethyl group, the mutagenic response in strains TA98 and TA104 changed. We concluded that a frame-shift mutation occurred because of the replacement. The increase of the TA104 mutagenicity suggested that adenosine could be the target for these types of compounds. Further evidence for such possibility were the modified adenosine adducts we could identify for some chlorinated butenoic acids.

Glycerol as an efficient medium for the petasis borono-mannich reaction.

The multicomponent Petasis borono–Mannich (PBM) reaction is a useful tool for the preparation of complex molecules in a single step from boronic acids, aldehydes/ketones, and amines. Here, we describe the use of glycerol in the PBM reaction of salicylaldehydes or 2-pyridinecarbaldehyde with several boronic acids and secondary amines. From these readily available starting materials, alkylaminophenols, 2-substituted pyridines, and 2H-chromenes were prepared in reasonable to good yields. Glycerol was compared with other solvents, and in some cases, it provided the reaction product in higher yield. Crude glycerol, as generated by the biodiesel industry, was evaluated and found to be a suitable solvent for the PBM reaction, successfully expanding the potential use of this industry by-product. Based on density functional theory (DFT) calculations and the obtained experimental results, the involvement of glycerol-derived boronic esters in the reaction mechanism is suggested to be competitive with the free boronic acid pathway. Similar Gibbs free energies for the aryl migration from the boronate species to the iminium were determined for both mechanisms.

Isolation of a MX-guanosine adduct formed at physiological conditions

3-Chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone (MX), a highly potent mutagen present in chlorine-disinfected drinking water, was allowed to react with adenosine, guanosine, and cytidine in aqueous solutions. HPLC analyses, with detection at 254 and 310 nm, showed that a clearly detectable base adduct was formed in the reaction with guanosine. This substance was isolated by C18 column chromatography and characterized by UV absorbance, 1H NMR spectroscopy, and mass spectrometry. The compound was identified as 10-formyl-1, N2-benzoquinone propenoguanosine (I), and the yield was estimated to be approximately 0.1% in reactions performed at pH 7.4 and 37 degrees C.

Mutation spectra of the drinking water mutagen 3-chloro-4-methyl-5-hydroxy-2(5H)-furanone (MCF) in Salmonella TA100 and TA104: comparison to MX

The chlorinated drinking water mutagen 3‐chloro‐4‐methyl‐5‐hydroxy‐2(5H)‐furanone (MCF) occurs at concentrations similar to or greater than that of the related furanone 3‐chloro‐4‐(dichloromethyl)‐5‐hydroxy‐2(5H)‐furanone (MX). MCF and MX differ structurally only by replacement of a 3‐methyl in MCF with a 3‐dichloromethyl in MX; yet, MCF is significantly less mutagenic than MX and produces different adducts when reacted with nucleosides or DNA. To explore further the effects that these structural differences might have on the biological activity of MCF and MX, we determined the mutation spectra of MCF in Salmonella strains TA100 and TA104 and of MX in strain TA104; the spectrum of MX in TA100 had been determined previously. In TA100, which presents only GC targets for mutagenesis, MCF induced primarily (75%) GC → TA transversions, with most of the remaining revertants (20%) being GC → AT transitions. This spectrum was not significantly different from that of MX in TA100 (P = 0.07). In TA104, which presents both GC and AT targets, MCF induced a lower percentage (57%) of GC → TA transversions, with most of the remaining revertants (33%) being AT → TA transversions. In contrast, MX induced almost only (98%) GC → TA transversions in TA104, with the remaining revertants (2%) being AT → TA transversions. Thus, almost all (98%) of the MX mutations were targeted at GC sites in TA104, whereas only 63% of the MCF mutations were so targeted. These results are consistent with the published findings that MX: (1) forms an adduct on guanosine when reacted with guanosine, (2) induces apurinic sites in DNA, and (3) forms a minor adduct on adenosine when reacted with adenosine or DNA. The results are also consistent with evidence that MCF forms adenosine adducts when reacted with adenosine. Our results show that the replacement of the 4‐methyl in MCF with a 4‐dichloromethyl to form MX not only increases dramatically the mutagenic potency but also shifts significantly the mutagenic specificity from almost equal targeting of GC and AT sites by MCF to almost exclusive targeting of GC sites by MX. Environ. Mol. Mutagen. 35:106–113, 2000 Published 2000 Wiley‐Liss, Inc.

Ring-chain tautomerism of chlorinated hydroxyfuranones and reaction with nucleosides

Abstract Several genotoxic hydroxyfuranones present in chlorine disinfected drinking water, were reacted with adenosine, guanosine, and cytidine in aqueous solution. HPLC analyses with UV detection at 254 and 325 nm showed that adducts were formed. The compounds MCF , 3-chloro-4-methyl-5-hydroxy-2(5 H )-furanone and mCMF , 4-(chloromethyl)-5-hydroxy-2(5 H )-furanone tautomerized to the corresponding oxobutenoic acids at pH 7.4 and formed 4-(N 6 -adenosinyl)-3-formyl-3-butenoic acid ( I ) as the major product. The hydroxyfuranone MX , 3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone reacted with guanosine, and formed 10-fonnyl-1,N 2 -benzoquinone propenoguanosine. The adducts were isolated by C18 column chromatography, and characterized by UV absorbance, 1 H spectroscopy, and mass spectrometry.

Preparation of Triethylammonium Tetra-Arylborates (TEATABs): Coupling Partners for the Suzuki Reaction

Abstract Six triethylammonium tetra-arylborates (TEATABs) were synthesized via a convenient reproducible procedure and characterized by spectroscopic methods (1H, 13C, 11B NMR and electrospray ionization–high-resolution mass spectrometry). The compounds could be stored at ambient temperature and were useful as reactants in the Suzuki reaction in aqueous conditions when using commercially available catalysts.

Synthesis of Xenbucin using Suzuki reaction catalyzed by Pd/C in water

Xenbucin 1, an analgesic drug, was synthesized in 4 steps using two different routes. The biaryl fragment could successfully be produced via a Pd/C catalysed Suzuki coupling in water using sodium tetraphenylborate as a phenylation reagent. Overall yields of the routes were 36% and 59%, respectively.