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W Korytnyk

Publications and source records attributed to W Korytnyk.

At least 37 records · Page 2Linked to original sources
PubMed1980

Spectroscopic studies of complexes between pyridoxamine (pyridoxine)-5'-phosphate oxidase and pyridoxyl 5'-phosphate compounds differing at position 4'.

The absorbance spectrum of pyridoxamine (pyridoxine)-5'-phosphate oxidase (EC 1.4.3.5) is altered upon the binding of pyridoxal 5'-phosphate or analogs with different substituents at position 4'. The absorbance difference spectra are similar for complexes of the oxidase and pyridoxal 5'-phosphate, 4'-desoxypyridoxine 5'-phosphate, and 4-ethynyl-4-deformylpyridoxal 5'-phosphate; hence, these perturb the flavoprotein absorbance by similar interactions primarily involving the pyridoxyl 5'-phosphate moiety, and not specifically the 4-formyl group or other relatively small and uncharged functions at this position. A different type of spectral perturbation is caused by analogs with larger substituents at position 4' (i.e. 4'-methoxypyridoxine 5'-phosphate, 4-methyl-vinyl-4-deformylpyridoxal 5'-phosphate, and pyridoxal 5'-phosphate oxime and hydrazone). These analogs impose bulky groups in a region of the active site that critically influences the environment of the flavin, and, thus, may reflect positioning of this portion of the substrates close to the flavin ring, as is required for their redox interaction.

Animals↗
PubMed1980

Synthesis and biological activity of some 1-N-substituted 2-acetamido-2-deoxy-beta-D-glycopyranosylamine derivatives and related analogs.

Several 1-N-substituted derivative [haloacetyl-, glycyl-, (dimethyl)amino-acetyl-, azidoacetyl-, trifluoroacetyl-, and trifluoromethylsulfonyl-] of 2-acetamido-2-deoxy-3,4,6-tri-O-acetyl-beta-D-glucopyranosylamine (1) were synthesized as potential metabolic inhibitors of cellular-membrane glycoconjugates. Several fully acetylated derivatives were found to inhibit growth of mouse mammary adenocarcinoma TA3, leukemia L1210, or leukemia P-288 cells at 1-0.01 mM concentration in vitro. Some of these derivatives were less active after O-deacetylation. Analogs of 1 in which NH2-1 was replaced by OH- or OAc-1 were also active on the same cell systems. The growth-inhibitory activity was correlated with inhibition of the incorporation of 2-amino-deoxy-D-glucose and L-leucine into a macromolecular fraction.

Acetylglucosamine↗
PubMed1980

Modifications at C-3 and C-4 of 2-amino-2-deoxy-D-glucose.

Modifications at C-3 and C-4 of 2-amino-2-deoxy-D-glucose have been developed. A 3,4-double bond was introduced into benzyl 2-acetamido-2-deoxy-3,4-di-O-methylsulfonyl-alpha-D-glucopyranoside by treatment with NaI and Zn. Epoxidation of the double bond with m-chloroperoxybenzoic acid gave an exo-epoxide exclusively. The stereochemistry of the epoxidation product has been confirmed by an alternative synthesis. An analysis of the 1H-n.m.r. spectra indicates that both the 3,4-unsaturated derivatives and the epoxide exist in the OH1 (D) conformation. Nucleophilic reagents (F-, I-) opened the 3,4-epoxide to give 4-substituted derivatives having the D-gulo configuration. Thus, 2-acetamido-1,3,6-tri-O-acetyl-2,4-dideoxy-4-iodo-alpha-D-gulopyranose and 2-acetamido-1,3,6-tri-O-acetyl-3,4-dideoxy-4-fluoro-alpha-D-gulopyranose have been synthesized. Reduction of the double bond in the key intermediate and deprotection gave 2-acetamido-2,3,4-trideoxy-D-glucopyranose. Some of the derivatives were active as inhibitors of growth of mouse, mammary adenocarcinoma cells in culture.

Adenocarcinoma↗
PubMed1980

Halogenated L-fucose and D-galactose analogues: synthesis and metabolic effects.

Several new analogues of L-fucose modified in the 2 position and the 5-methyl group have been synthesized as potential plasma-membrane glycoconjugate inhibitors or modifiers, and their biological effects have been studied. 2-Chloro-, 2-bromo-, and 2-iodo-2-deoxy-L-fucose (9a, 9b, and 13, respectively) have been prepared by addition of the appropriate halogen to 3,4-di-O-acetyl-L-fucal, followed by hydrolysis of the anomeric halogen and the acetyl groups. A series of four halogenated 5-methyl analogues of L-fucose (4, X = F, Cl, Br, and I) have been obtained starting from 1,2:3,4-di-O-isopropylidene-L-galactose. The synthesis of this latter compound has been improved. A corresponding series of 6-deoxy-6-halo-D-galactose analogues, which are enantiomers of the 5-(halomethyl)-L-fucose analogues, has also been synthesized. Analogues 4b, 4c, and 9b at 1 x 10(-3) M specifically inhibited the incorporation of L-[3H]fucose into macromolecular components of SW613 human mammary tumor cells. Analogue 13 inhibited the growth of L1210 murine leukemic cells with an IC50 of 6 x 10(5) M in culture. 6-Deoxy-6-fluoro-D-galactose and its enantiomer 4a were found to be effective inhibitors of D-[3H]galactose and L-[3H]fucose incorporation, respectively, into macromolecular components of human mammary tumor cells. The effectiveness of inhibition was reduced with an increase in size of the halogen atom. Analogue 4a and its enantiomer have been tritiated at C-1 and both were found to be activated to a nucleotide sugar, which was followed by incorporation into the macromolecular fraction of SW613 human mammary tumor cells in vitro.

Animals↗
PubMed1978

Alanine derivatives with reactive groups.

The synthesis of diazoketone analogs of amino acids and associated problems were investigated with N-phthaloyl-DL-alanine serving as a model. The carboxyl was activated by conversion to the acid chloride or, under mild conditions, to the mixed anhydride obtained with ethyl chloroformate or dicyclohexylcarbodiimide; the product was reacted with diazomethane. Deblocking the phthaloyl group with hydrazine gave 3-amino-1-diazo-2-butanone as a well-characterized solid salt and as a less stable oil. Further reactions of the blocked diazoketone of DL-alanine, such as conversion to alpha-haloketones, Wolff rearrangement, and deuterium exchange on C-1 were investigated. 3-A-mino-1-diazo-2-butanone had moderate inhibitory activity against mouse mammary adenocarcinoma in cell culture.

Adenocarcinoma↗
PubMed1977

Antagonists of vitamin B6. Simultaneous and stepwise modification of the 2 and 4 positions.

Methods for the simultaneous and stepwise modification of the 2 and 4 positions of vitamin B6 have been devloped and have been applied to the synthesis of several analogues of this vitamin. 3,alpha5-O-Dibenzylpyridoxol was converted to its N-oxide and was rearranged to an alpha2-hydroxy derivative with (CF3CO)2O. The 2,4-bis(hydroxymethyl) intermediate was oxidized (MnO2) to the 2,4-dialdehyde, which was converted by a Wittig reaction with triphenylmethylphosphorane to the 2,4-divinyl derivative. Removal of the benzyl groups with acid gave the 2,4-divinylpyridioxol analogue, which was phosphorylated in the 5' position to give the cofactor analogue. The 2-CH3 in the known vitamin B6 antagonists, 4-deoxypyridoxol and 4-vinylpyridoxal, was similarly modified to CH2OH, CHO, and CH = CH2. Modifications of the 2 position in the vitamin B6 antagonists are expected to be associated with changes in selectivity for enzymes in various tissues without a concomitant loss of biological activity, because of the well-established bulk tolerance in this position. Active analogues are expected to undergo, in vivo 5-phosphorylation, which is probably a prerequisite for their antagonist activity. Some of the compounds (e.g., the 2,4-divinyl analogue) have substantial growth-inhibitory activity for cultured mouse mammary adenocarcinoma. In contrast to that of the parent compounds, this activity was only partially reversed by pyridoxal.

Adenocarcinoma↗
PubMed1977

4-Halovinyl- and 4-ethynyl-4-deformylpyridoxal derivatives and related analogues as potentially irreversible antagonists of vitamin B6.

Analogues of pyridoxal bearing alpha- and beta-chlorovinyl, beta-bromovinyl, butadienyl, acetyl, and 1-butenyl groups in place of the formyl group have been synthesized by subjecting 3,alpha5-di-O-benzylpyridoxal to appropriate Wittig or Grignard reactions. Similar methods yielded one-carbon homologues of pyridoxal and pyridoxol. Synthesis of the 4-ethynyl analogue of pyridoxal was achieved by dehalogenating blocked beta-halovinyl derivatives. The substituted vinyl and the ethynyl analogues were found to be active as inhibitors of mouse mammary adenocarcinoma cells grown in cell culture at an ID50 of 10(-5)-10(-6) M. The inhibitory activity of the 4-ethynyl analogue could be partially reversed by pyridoxal. This analogue was found to inhibit pyridoxal phosphokinase, and its 5'-phosphate was likewise found to be a potent noncompetitive inhibitor of pyridoxine-P oxidase.

Adenocarcinoma↗
PubMed1977

Vitamin B6 antagonists obtained by replacing or modifying the 2-methyl group.

The 2-methyl group of pyridoxol was replaced with various other groups, including 2-amino and 2-methylamino as examples of electron-donating substituents and including 2-carboxyl, 2-carboxamide, and 2-halo as examples of electron-withdrawing substituents. The key intermediate in the synthesis was 3-O-benzyl-alpha4,alpha5-O-isopropylidene-alpha2-pyridoxol (15) or the corresponding 2-aldehyde (2). Another approach for modifying the 2 position, but chemically less successful, started with 3-O-methylpyridoxol, which was oxidized to the tricarboxylic acid, decarboxylated, esterfied, and reduced with LiAlH4, providing derivatives in which the 2-CH3 group was replaced with H. The analogues were tested for their growth-inhibitory activity against mouse mammary adenocarcinoma cells in culture. The 2-azine, 2-chloro, and 2-amino analogues were active as inhibitors at ID50 approximately or equal to 10(-5) M, whereas the 2-fluoro and 2-carboxylic acid analogues were inactive at 1 X 10(-4) M. The results are contrasted with those found earlier for similar modifications in other positions of the vitamin B6 molecule. Although the 2-chloro analogue was found to inhibit pyridoxal phosphokinase (KI=24 micron), the 6-chloro analogue was inactive as an inhibitor at 1 mM.

Adenocarcinoma↗
PubMed1976

On the inhibitory activity of 4-vinyl analogues of pyridoxal: enzyme and cell culture studies.

Analogues of pyridoxal and of pyridoxal phosphate in which the 4-CHO group is replaced with CH = CH2 were synthesized and were found to be potent inhibitors of pyridoxal kinase and pyridoxine phosphate oxidase of rat liver. They also inhibited the growth of mouse Sarcoma 180 and mammary adenocarcinoma TA3 in cell culture. Saturation of the vinyl double bond, replacement of the 5-CH2OH with methyl, methylation of the phenolic hydroxyl, or conversion to the N-oxide resulted in diminution or loss of all these activities. Similarly, the introduction of a beta-methyl group into the vinyl analogues of pyridoxal reduced all these inhibitory activities. The 4-vinyl anatogue of pyridoxal was shown to be a substrate of pyridoxal kinase and the product a potent inhibitor of pyridoxine oxidase, competing with pyridoxal phosphate. The affinity of this phosphorylated pyridoxal analogue to some apoenzymes varied greatly, indicating striking differences among the cofactor binding sites of these enzymes. The growth inhibitory effects of these analogues on cells in culture correlated well with their effects on pyridoxal kinase and pyridoxine phosphate oxidase in cell-free systems.

Animals↗
PubMed1976

Synthesis and biological properties of 4-amino- and 4-bromo-4-norpyridoxol. New approaches for the modification of the 4 position of vitamin B6.

4-Amino-4-norpyridoxol, a new key intermediate for the modification of the 4 position of vitamin B6, has been obtained by an unusual photochemical rearrangement of pyridoxal oxime. It has also been synthesized starting from 3,-alpha5-O-dibenzylpyridoxal, which was converted to 3,alpha5-O-dibenzylpyridoxamide. The latter, on Hoffman reaction, gave the desired 3,5-blocked 4-amino derivative. Several derivatives of this analogue have been prepared, and its existence in the amino tautomeric form has been established by NMR spectroscopy. A modified Sandmeyer reaction on 4-amino-4-norpyridoxol gave the 4-bromo analogue, which was found to be moderately active as an inhibitor of mouse mammary adenocarcinoma cells grown in cell culture, whereas the 4-amino analogue was not active at 10(-4)M. Other analogues containing electron-withdrawing and electron-donating substituents in the 4 position of pyridoxine were also tested.

Adenocarcinoma↗
PubMed1976

Cysteine derivatives with reactive groups as potential antitumor agents.

Cysteine derivatives having diazo ketone and chloro ketone functions have been prepared. In order to effect adequate protection for modifying the carboxyl group, cysteine was converted to a thiazolidine derivative I, which was then converted to the N-acetyl derivative VII. The active ester method or activation with DCC yielded the diazo ketone derivative VIII. Similar treatment of the parent compound I with DCC led to a self-condensation reaction giving a diketopiperazine VI. The diazo ketone derivative VIII has been used in preparing alpha-chloro ketone derivative X and a homologue of cysteine. Deblocking N-acetylated thiazolidine derivatives with various reagents did not proceed satisfactorily. Interaction of the N-acetylated blocked ester XII with trifluoroacetic acid opened the thiazolidine ring to give the N-acetylated blocked diester XIII and other products. The chloro ketone derivative X was found to have a moderate inhibitory activity against mouse mammary adenocarcinoma in cell culture. S-(1-Adamantyl)-L-cysteine was prepared and was found to be inactive.

Adenocarcinoma↗
PubMed1975

Properties of 4-ethenyl and 4-ethynyl analogs of pyridoxal phosphate and their reactions with the apo form of asparatate aminotransferase.

The binding to apoaspartate aminotransferase of analogs of pyridoxal phosphate bearing vinyl, cis- and trans-methylvinyl, and ethynyl groups in place of the fomyl group of the coenzyme has been studied. Details of synthesis of the ethynyl compound are given. The absorption spectra of all of the compounds have been analyzed and pKa values have been determined. The positions of the absorption bands can be related to those of pyridoxine but with bathochromic shifts induced by the ethenyl and ethynyl groups. However, this shift is almost completely lacking for the cis-methylvinyl compound suggesting nonplanarity of the molecule. Binding of the analogs to the apoenzyme is accompanied by a strong bathochromic shift which, from a study of solvent effects on the free analogs, appears to indicate a hydrophobic environment on the enzyme. Nevertheless, the analogs are bound as dipolar ions exclusively. Binding is accompanied by a distinct perturbation of the protein spectrum in the aromatic region. An effect on the spectrum of 1 or more tryptophan residues is indicated. Bands of the bound analogs exhibit positive circular dichroism except for that of the 4-vinyl analog. The 4-ethynyl analog reacts in a more complex way, giving at least two successive products in addition to the initial complex. The final product is reducible by sodium borohydride, is released from the enzyme by boiling, and appears to have the properties of a Schiff base. We postulate that the addition of an amino group of the enzyme to the ethynyl group is followed by tautomeric rearrangement to a Schiff base in which the ring is in a p-quinonoid structure.

Animals↗