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Biomedical subjects

V Snieckus

Publications and source records attributed to V Snieckus.

13 recordsLinked to original sources
PubMed2001

Selective ortho and benzylic functionalization of secondary and tertiary p-tolylsulfonamides. Ipso-bromo desilylation and Suzuki cross-coupling reactions.

Kinetic vs thermodynamic deprotonation studies on secondary and tertiary sulfonamides 1 and 2 using n-BuLi have been carried out. While both 1 and 2 show kinetic ortho-metalation, thermodynamic conditions lead to ortho and benzylic deprotonation, respectively (Figures 1 and 2). Metalation of 1 using the n-BuLi/KOtBu superbase led to regioselective benzylic metalation (Figure 4); LDA deprotonation was also briefly explored. Application of the developed conditions allows the synthesis of diverse sulfonamide products 5a-e, 6a-e, 7a,b, and 8a-e. Ipso-bromo desilylation reactions afford sulfonamides 9a,b while Suzuki cross-coupling reactions furnish biaryl sulfonamides 11a-c.

Journal Article↗
PubMed2001

Condensation of laterally lithiated o-methyl and o-ethyl benzamides with imines mediated by (-)-sparteine. Enantioselective synthesis of tetrahydroisoquinolin-1-ones.

The first asymmetric synthesis of tetrahydroisoquinolin-1-ones using a (-)-sparteine-mediated lateral metalation-imine addition sequence to furnish 3-phenyl tetrahydroisoquinolinones 3a with enantioselectivities up to 81% ee is described (Scheme 4). For amide 7b, imine addition products 10 and 11 have been obtained with high diastereoselectivities (91-97% de) and enantioselectivities (91-98% ee) (Scheme 8).

Journal Article↗
PubMed2000

Identification of a serine hydrolase as a key determinant in the microbial degradation of polychlorinated biphenyls.

The ability of 2-hydroxy-6-oxo-6-phenylhexa-2,4-dienoate (HOPDA) hydrolase (BphD) of Burkholderia cepacia LB400 to hydrolyze polychlorinated biphenyl (PCB) metabolites was assessed by determining its specificity for monochlorinated HOPDAs. The relative specificities of BphD for HOPDAs bearing chlorine substituents on the phenyl moiety were 0.28, 0.38, and 1.1 for 8-Cl, 9-Cl, and 10-Cl HOPDA, respectively, versus HOPDA (100 mm phosphate, pH 7.5, 25 degrees C). In contrast, HOPDAs bearing chlorine substituents on the dienoate moiety were poor substrates for BphD, which hydrolyzed 3-Cl, 4-Cl, and 5-Cl HOPDA at relative maximal rates of 2.1 x 10(-3), 1.4 x 10(-4), and 0.36, respectively, versus HOPDA. The enzymatic transformation of 3-, 5-, 8-, 9-, and 10-Cl HOPDAs yielded stoichiometric quantities of the corresponding benzoate, indicating that BphD catalyzes the hydrolysis of these HOPDAs in the same manner as unchlorinated HOPDA. HOPDAs also underwent a nonenzymatic transformation to products that included acetophenone. In the case of 4-Cl HOPDA, this transformation proceeded via the formation of 4-OH HOPDA (t(12) = 2.8 h; 100 mm phosphate, pH 7.5, 25 degrees C). 3-Cl HOPDA (t(12) = 504 h) was almost 3 times more stable than 4-OH HOPDA. Finally, 3-Cl, 4-Cl and 4-OH HOPDAs competitively inhibited the BphD-catalyzed hydrolysis of HOPDA (K(ic) values of 0.57 +/- 0. 04, 3.6 +/- 0.2, and 0.95 +/- 0.04 microm, respectively). These results explain the accumulation of HOPDAs and chloroacetophenones in the microbial degradation of certain PCB congeners. More significantly, they indicate that in the degradation of PCB mixtures, BphD would be inhibited, thereby slowing the mineralization of all congeners. BphD is thus a key determinant in the aerobic microbial degradation of PCBs.

Bacterial Proteins↗
PubMed2000

C2-symmetric planar chiral ferrocene diamides by (-)-sparteine-mediated directed ortho-lithiation. Synthesis and catalytic activity

[reaction: see text] A variety of highly enantioenriched singly and doubly (4) functionalized derivatives of 1,1'-N,N,N',N'-tetraisopropylferrocenedicarboxamide 1 have been synthesized by (-)-sparteine (2)-mediated directed ortho-metalation and Pd-catalyzed cross coupling reactions. The synthetic applications of these chiral ligands in asymmetric alkylation of benzaldehyde and Pd(0)-catalyzed allylic substitution have been demonstrated.

Journal Article↗
PubMed1999

Impacts of structural photomodification on the toxicity of environmental contaminants: anthracene photooxidation products.

The toxicity of polycyclic aromatic hydrocarbons (PHAs) is known to be enhanced by light via photosensitization reactions (production of active oxygen) and photomodification of the chemicals (e.g., oxidation) to more toxic compounds. Anthracene (ANT) toxicity in particular has been found to increase dramatically following photomodification. The objective of this study was to identify the photooxidation products of ANT and assess the toxicity of selected photoproducts. High performance liquid chromatography (HPLC) analysis of anthracene photooxidation revealed a complex array of oxidation products; prevalent among these were anthraquinone (ATQ) and hydroxy-anthraquinones (hATQs). Eleven of these compounds were tested for toxicity using growth inhibition of the duckweed Lemna gibba L. G-3. All but one of the compounds tested were found to be toxic, and when UV radiation was present in the light source toxicity was generally enhanced. The chemicals were also irradiated under SSR prior to toxicity testing. In about half the cases, the ATQ compounds were rapidly photooxidized and the resultant photoproducts were more toxic than the parent compounds. Interestingly, 2-hydroxyanthraquinone, which was not subject to photooxidation, was the most toxic of the compounds tested. As a light stable compound it presents the risk of a persistent environmental hazard.

Anthracenes↗
PubMed1998

Purification and preliminary characterization of a serine hydrolase involved in the microbial degradation of polychlorinated biphenyls.

2-Hydroxy-6-oxo-6-phenylhexa-2,4-dienoate (6-phenyl-HODA) hydrolase (BphD), an enzyme of the biphenyl biodegradation pathway encoded by the bphD gene of Burkholderia cepacia LB400, was hyperexpressed and purified to apparent homogeneity. SDS-polyacrylamide gel electrophoresis confirmed that BphD has a subunit molecular mass of 32 kDa, while gel filtration demonstrated that it is a homotetramer of molecular weight 122,000. The enzyme hydrolyzed 6-phenyl-HODA with a kcat of 5.0 (+/- 0.07) s-1 and a kcat/Km of 2.0 (+/- 0.08) x 10(7) M-1 s-1 (100 mM phosphate, pH 7.5, 25 degreesC). The specificity of BphD for other 2-hydroxy-6-oxohexa-2,4-dienoates (HODAs) decreased markedly with the size of the C6 substituent; 6-methyl-HODA, the meta cleavage product of 3-methylcatechol, was hydrolyzed approximately 2300 times less specifically than 6-phenyl-HODA. By comparison, the homologous hydrolase from the toluene degradation pathway, TodF, showed highest specificity for 6-methyl- and 6-ethyl-HODA (kcat/Km of 2.0 (+/- 0.05) x 10(6) M-1 s-1 and 9.0 (+/- 0.5) x 10(6) M-1 s-1, respectively). TodF showed no detectable activity toward 6-phenyl-HODA and 6-tert-butyl-HODA. Neither BphD nor TodF hydrolyzed 5-methyl-HODA efficiently. The kcat of BphD determined by monitoring product formation was about half that determined by monitoring substrate disappearance, suggesting that some uncoupling of substrate utilization and product formation occurs during the enzyme catalyzed reaction. Crystals of BphD were obtained using ammonium sulfate combined with polyethylene glycol 400 as the precipitant. Diffraction was observed to a resolution of at least 1.9 A, and the evaluation of self-rotation functions confirmed 222 (D2) molecular symmetry.

Burkholderia cepacia↗
PubMed1998

Synthesis of 2-iodo- and 2-phenyl-[11C]melatonin: potential PET tracers for melatonin binding sites.

Two 11C-labelled melatonin derivatives, 2-iodo-[11C]melatonin (2-iodo-5-methoxy-N[11C-acetyl]-tryptamine, an agonist) and 2-phenyl-[11C]melatonin (2-phenyl-5-methoxy-N[11C-acetyl]tryptamine, a putative antagonist) were synthesized from [11C]carbon dioxide. The reaction sequence was common to both compounds and consisted of three steps: (i) carbonylation of methyl magnesium bromide with [11C]carbon dioxide, (ii) conversion of the adduct to [11C]acetyl chloride, (iii) acetylation of the amine precursors (2-iodo-5-methoxy-tryptamine or 2-phenyl-5-methoxy-tryptamine) with [11C]acetyl chloride. The precursors were especially prepared. The radiochemical yield was 19% for 2-iodomelatonin and 32% for 2-phenymelatonin, based on [11C]carbon dioxide; the specific activity ranged from 300 to 600 mCi/mumol. Both labelled 2-substituted-melatonins are intended to be used as radiotracers to study melatonin binding sites in man with positron emission tomography.

Acetylation↗
PubMed1997

Radiolabeling of monoclonal antibody B43.13 with rhenium-188 for immunoradiotherapy.

In this study we report a novel method for direct radiolabeling of monoclonal antibody B43.13 (MAb-B43.13) with 188Re and have evaluated the product's radiochemical, biochemical, immunochemical and selected biological properties. 188Re-MAb-B43.13 was readily prepared by the addition of generator produced perrhenate to a preformulated antibody vial after an optimal amount of supplemental stannous ion, in the form of stannous tartrate, was added. The final radiolabeled product retained its biochemical purity (as determined by size-exclusion HPLC and R/NR-SDS-PAGE), its immunoreactivity (as determined by immunoassay) and presented with a typical stability (in the presence of serum and cysteine) and biodistribution (in tumored mice) profile. The evaluation of the product for immunoradiotherapy of ovarian cancer in a clinical setting requires further studies.

Animals↗
PubMed1983

Antibodies to indolealkylamines II: site of conjugation of melatonin to protein using formaldehyde.

The site of coupling on the hapten was investigated for melatonin, formaldehyde, and protein conjugates. Model reactions of glycine ethyl ester and piperidine with formaldehyde and melatonin suggested that coupling first occurred through the indole nitrogen and then a stable bond was formed at C-2. Cross-reaction studies of antisera stimulated by melatonin, formaldehyde, and protein conjugates support the hypothesis that C-2 is the site of conjugation of melatonin to protein.

Animals↗
PubMed1982

Behavioral effects of 5-hydroxy-N-acetyltryptophan, a putative synthetic precursor of N-acetylserotonin.

1. Adult male rats were injected with either 5-hydroxy-N-acetyltryptophan (5-OHNAT), a synthetic putative precursor of N-acetylserotonin, or 5-hydroxytryptophan (5-HTP), the serotonin precursor, and behavioral effects were observed. Pretreatment consisted of carbidopa and nialamide. 2. The behavioral effects of systemic injections of 5-OHNAT and 5-HTP were qualitatively similar i.e. head weaving, forepaw treading, etc., but the effect of 5-OHNAT was appreciably delayed in onset. 3. 5-OHNAT loading may cause an increase in central nervous system 5-HT via initial deacetylation to 5-HTP. Alternatively, 5-OHNAT may cause a delayed increase in brain NAS and the "serotonin syndrome" may reflect increased conversion of 5-HT to NAS.

5-Hydroxytryptophan↗