Alex Khomutov - Academia.edu (original) (raw)

Papers by Alex Khomutov

Research paper thumbnail of The Use of Novel C-Methylated Spermidine Derivatives To Investigate the Regulation of Polyamine Metabolism

Journal of Medicinal Chemistry, Jun 3, 2011

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Research paper thumbnail of Polyfunctional O-Substituted Hydroxylamines: Modification of Nucleic Acids, Inhibition of Sam-Decarboxylase

Nucleosides, Nucleotides & Nucleic Acids, 1987

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Research paper thumbnail of α-Methyl Polyamines: Efficient Synthesis and Tolerance Studies in Vivo and in Vitro. First Evidence for Dormant Stereospecificity of Polyamine Oxidase

Journal of Medicinal Chemistry, Dec 15, 2005

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Research paper thumbnail of Role of Hypusinated Eukaryotic Translation Initiation Factor 5A in Polyamine Depletion-induced Cytostasis

Journal of Biological Chemistry, Nov 1, 2007

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Research paper thumbnail of Feedback regulation of S-adenosylmethionine decarboxylase synthesis

Biochemical Journal, Feb 1, 1989

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Research paper thumbnail of Convenient syntheses of phosphinic analogues of γ-aminobutyric- and glutamic acids

Russian Journal of Bioorganic Chemistry, Nov 1, 2016

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Research paper thumbnail of Effects of novel C-methylated spermidine analogs on cell growth via hypusination of eukaryotic translation initiation factor 5A

Amino Acids, Aug 23, 2011

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Research paper thumbnail of A New Synthesis of a -Methylspermidine

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Research paper thumbnail of ChemInform Abstract: Synthesis of Hydroxylamine Analogues of Polyamines

ChemInform, Aug 4, 2010

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Research paper thumbnail of New reaction for modification of nucleic acids and their components. II. Photochemically induced selective reduction of uracil and thymine

ChemPlusChem, 1990

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Research paper thumbnail of New oxaanalogues of spermine

Russian Journal of Bioorganic Chemistry, Mar 1, 2005

A new isosteric charge-deficient spermine analogue, 1,12-diamino-4,9-diaza-5-oxadodecan, and O-(7... more A new isosteric charge-deficient spermine analogue, 1,12-diamino-4,9-diaza-5-oxadodecan, and O-(7-amino-4-azaheptyl)oxime of 3-aminopropanal, a stable analogue of the Schiff base intermediate in the enzymatic oxidation of spermine, were synthesized. The possible use of these compounds for the inhibition of spermine oxidase is discussed.

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Research paper thumbnail of Hydroxylamine derivatives for regulation of spermine and spermidine metabolism

Biokhimiya, Dec 1, 2013

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Research paper thumbnail of The reduction of thymine residues in DNA by the combined action of UV light and hypophosphite

Journal of Photochemistry and Photobiology B-biology, Aug 1, 1995

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Research paper thumbnail of Methylated Polyamines as Research Tools

Methods in molecular biology, 2011

Earlier unknown racemic β-methylspermidine (β-MeSpd) and γ-methylspermidine (γ-MeSpd) were -synth... more Earlier unknown racemic β-methylspermidine (β-MeSpd) and γ-methylspermidine (γ-MeSpd) were -synthesized starting from crotononitrile or methacrylonitrile and putrescine. Lithium aluminum hydride reduction of the intermediate di-Boc-nitriles resulted in corresponding di-Boc-amines, which after deprotection gave target β- and γ-MeSpd's. To prepare α-MeSpd, the starting compound, 3-amino-1-butanol, was converted into N-Cbz-3-amino-1-butyl methanesulfonate, which alkylated putrescine to give (after deprotection of amino group) the required α-MeSpd. Novel β- and γ-MeSpd's in combination with earlier α-MeSpd are useful tools for studying enzymology and cell biology of polyamines.

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Research paper thumbnail of Charge Deficient Analogues of the Natural Polyamines

Current Pharmaceutical Design, Jan 31, 2014

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Research paper thumbnail of Insufficiently charged isosteric analogue of spermine: interaction with polyamine uptake, and effect on Caco-2 cell growth

Biochemical Pharmacology, Aug 1, 2002

We characterised a novel, charge-insufficient isosteric analogue of spermine, 11-[(amino)oxy]-4,9... more We characterised a novel, charge-insufficient isosteric analogue of spermine, 11-[(amino)oxy]-4,9-diaza-1-aminoundecane (AOSPM). This analogue was synthesised by displacing aminopropyl group by aminooxyethyl group, the latter having pK(a) of about 5. Charge deficiency of the AOSPM molecule was fixed at a definite atom, while pK(a) of the rest nitrogen was similar to the parent polyamine. AOSPM competed with putrescine, spermidine and spermine for the uptake into the cell, and was accumulated in the cells in high amounts when exogenous polyamine synthesis was impaired. It was not recognised by the cells as growth-promoting polyamine, since it was unable to restore growth arrest due to polyamine deprivation. Like natural spermine, this polyamine analogue prevented oxidative DNA damage. AOSPM could be used not only as a tool to study polyamine homeostasis in the cell, but may have distinct applications either as radiation protector, a stable and non-toxic inhibitor of polyamine uptake or, as an appropriate vector, to enhance the uptake of impermeable compounds into the cell.

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Research paper thumbnail of Uptake of 3H-Labeled 1-Aminooxy-3-Aminopropane by Baby Hamster Kidney Cells1

Journal of Biochemistry, Jun 1, 1990

The uptake, catabolism, and release of H-labeled 1-aminooxy-3-aminopropane, a new putrescine anal... more The uptake, catabolism, and release of H-labeled 1-aminooxy-3-aminopropane, a new putrescine analog shown to be a potent polyamine antimetabolite, into and from baby hamster kidney cells (BHK21/C13) were studied. The results show that [3H]-1-aminooxy-3-aminopropane (APA) is not concentrated in the cell, does not compete with polyamines for transport and reveals no difference in uptake between polyamine-depleted and control cells. After a 12-h culture, 60% of APA was recovered intact in the culture media. At this time point, only 30% of the intracellular radioactivity was intact APA, showing that the drug is catabolized in the cells. This intracellular ratio persisted throughout the 4-day culture period. The metabolites of APA were not characterized further. The results indicate that the drug is not recognized as a polyamine by the cells and does not replace or interfere with the polyamines in cellular functions. Thus, its potent affinity to ornithine decarboxylase and spermidine synthase is likely to be due to close structural similarity with the intermediates formed in these reactions. This has implications for the mechanisms involved.

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Research paper thumbnail of Novel isosteric charge-deficient spermine analogue—1,12-diamino-3,6,9-triazadodecane: synthesis, pK a measurement and biological activity

Amino Acids, Dec 2, 2009

Ionic interactions are essential for the biological functions of the polyamines spermidine and sp... more Ionic interactions are essential for the biological functions of the polyamines spermidine and spermine in mammalian physiology. Here, we describe a simple gram scale method to prepare 1,12-diamino-3,6,9-triazadodecane (SpmTrien), an isosteric charge-deficient spermine analogue. The protonation sites of SpmTrien were determined at pH range of 2.2-11.0 using two-dimensional (1)H-(15)N NMR spectroscopy, which proved to be more feasible than conventional methods. The macroscopic pK(a) values of SpmTrien (3.3, 6.3, 8.5, 9.5 and 10.3) are significantly lower than those of 1,12-diamino-4,9-diazadodecane (spermine). The effects of SpmTrien and its parent molecule, 1,8-diamino-3,6-diazaoctane (Trien), on cell growth and polyamine metabolism were investigated in DU145 prostate carcinoma cells. SpmTrien downregulated the biosynthetic enzymes ornithine decarboxylase (ODC) and S-adenosyl-L: -methionine decarboxylase and decreased intracellular polyamine levels, whereas the effects of Trien alone were minor. Interestingly, both SpmTrien and Trien were able to partially overcome growth arrest induced by an ODC inhibitor, alpha-difluoromethylornithine, indicating that they are able to mimic some functions of the natural polyamines. Thus, SpmTrien is a novel tool to influence polyamine interaction sites at the molecular level and offers a new means to study the contribution of the protonation of spermine amino group(s) in the regulation of polyamine-dependent biological processes.

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Research paper thumbnail of Divergent regulation of the key enzymes of polyamine metabolism by chiral α-methylated polyamine analogues

Biochemical Journal, Aug 13, 2009

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Research paper thumbnail of Guide Molecule-driven Stereospecific Degradation of α-Methylpolyamines by Polyamine Oxidase

Journal of Biological Chemistry, Feb 1, 2006

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Research paper thumbnail of The Use of Novel C-Methylated Spermidine Derivatives To Investigate the Regulation of Polyamine Metabolism

Journal of Medicinal Chemistry, Jun 3, 2011

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Research paper thumbnail of Polyfunctional O-Substituted Hydroxylamines: Modification of Nucleic Acids, Inhibition of Sam-Decarboxylase

Nucleosides, Nucleotides & Nucleic Acids, 1987

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Research paper thumbnail of α-Methyl Polyamines: Efficient Synthesis and Tolerance Studies in Vivo and in Vitro. First Evidence for Dormant Stereospecificity of Polyamine Oxidase

Journal of Medicinal Chemistry, Dec 15, 2005

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Research paper thumbnail of Role of Hypusinated Eukaryotic Translation Initiation Factor 5A in Polyamine Depletion-induced Cytostasis

Journal of Biological Chemistry, Nov 1, 2007

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Research paper thumbnail of Feedback regulation of S-adenosylmethionine decarboxylase synthesis

Biochemical Journal, Feb 1, 1989

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Research paper thumbnail of Convenient syntheses of phosphinic analogues of γ-aminobutyric- and glutamic acids

Russian Journal of Bioorganic Chemistry, Nov 1, 2016

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Research paper thumbnail of Effects of novel C-methylated spermidine analogs on cell growth via hypusination of eukaryotic translation initiation factor 5A

Amino Acids, Aug 23, 2011

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Research paper thumbnail of A New Synthesis of a -Methylspermidine

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Research paper thumbnail of ChemInform Abstract: Synthesis of Hydroxylamine Analogues of Polyamines

ChemInform, Aug 4, 2010

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Research paper thumbnail of New reaction for modification of nucleic acids and their components. II. Photochemically induced selective reduction of uracil and thymine

ChemPlusChem, 1990

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Research paper thumbnail of New oxaanalogues of spermine

Russian Journal of Bioorganic Chemistry, Mar 1, 2005

A new isosteric charge-deficient spermine analogue, 1,12-diamino-4,9-diaza-5-oxadodecan, and O-(7... more A new isosteric charge-deficient spermine analogue, 1,12-diamino-4,9-diaza-5-oxadodecan, and O-(7-amino-4-azaheptyl)oxime of 3-aminopropanal, a stable analogue of the Schiff base intermediate in the enzymatic oxidation of spermine, were synthesized. The possible use of these compounds for the inhibition of spermine oxidase is discussed.

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Research paper thumbnail of Hydroxylamine derivatives for regulation of spermine and spermidine metabolism

Biokhimiya, Dec 1, 2013

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Research paper thumbnail of The reduction of thymine residues in DNA by the combined action of UV light and hypophosphite

Journal of Photochemistry and Photobiology B-biology, Aug 1, 1995

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Research paper thumbnail of Methylated Polyamines as Research Tools

Methods in molecular biology, 2011

Earlier unknown racemic β-methylspermidine (β-MeSpd) and γ-methylspermidine (γ-MeSpd) were -synth... more Earlier unknown racemic β-methylspermidine (β-MeSpd) and γ-methylspermidine (γ-MeSpd) were -synthesized starting from crotononitrile or methacrylonitrile and putrescine. Lithium aluminum hydride reduction of the intermediate di-Boc-nitriles resulted in corresponding di-Boc-amines, which after deprotection gave target β- and γ-MeSpd's. To prepare α-MeSpd, the starting compound, 3-amino-1-butanol, was converted into N-Cbz-3-amino-1-butyl methanesulfonate, which alkylated putrescine to give (after deprotection of amino group) the required α-MeSpd. Novel β- and γ-MeSpd's in combination with earlier α-MeSpd are useful tools for studying enzymology and cell biology of polyamines.

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Research paper thumbnail of Charge Deficient Analogues of the Natural Polyamines

Current Pharmaceutical Design, Jan 31, 2014

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Research paper thumbnail of Insufficiently charged isosteric analogue of spermine: interaction with polyamine uptake, and effect on Caco-2 cell growth

Biochemical Pharmacology, Aug 1, 2002

We characterised a novel, charge-insufficient isosteric analogue of spermine, 11-[(amino)oxy]-4,9... more We characterised a novel, charge-insufficient isosteric analogue of spermine, 11-[(amino)oxy]-4,9-diaza-1-aminoundecane (AOSPM). This analogue was synthesised by displacing aminopropyl group by aminooxyethyl group, the latter having pK(a) of about 5. Charge deficiency of the AOSPM molecule was fixed at a definite atom, while pK(a) of the rest nitrogen was similar to the parent polyamine. AOSPM competed with putrescine, spermidine and spermine for the uptake into the cell, and was accumulated in the cells in high amounts when exogenous polyamine synthesis was impaired. It was not recognised by the cells as growth-promoting polyamine, since it was unable to restore growth arrest due to polyamine deprivation. Like natural spermine, this polyamine analogue prevented oxidative DNA damage. AOSPM could be used not only as a tool to study polyamine homeostasis in the cell, but may have distinct applications either as radiation protector, a stable and non-toxic inhibitor of polyamine uptake or, as an appropriate vector, to enhance the uptake of impermeable compounds into the cell.

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Research paper thumbnail of Uptake of 3H-Labeled 1-Aminooxy-3-Aminopropane by Baby Hamster Kidney Cells1

Journal of Biochemistry, Jun 1, 1990

The uptake, catabolism, and release of H-labeled 1-aminooxy-3-aminopropane, a new putrescine anal... more The uptake, catabolism, and release of H-labeled 1-aminooxy-3-aminopropane, a new putrescine analog shown to be a potent polyamine antimetabolite, into and from baby hamster kidney cells (BHK21/C13) were studied. The results show that [3H]-1-aminooxy-3-aminopropane (APA) is not concentrated in the cell, does not compete with polyamines for transport and reveals no difference in uptake between polyamine-depleted and control cells. After a 12-h culture, 60% of APA was recovered intact in the culture media. At this time point, only 30% of the intracellular radioactivity was intact APA, showing that the drug is catabolized in the cells. This intracellular ratio persisted throughout the 4-day culture period. The metabolites of APA were not characterized further. The results indicate that the drug is not recognized as a polyamine by the cells and does not replace or interfere with the polyamines in cellular functions. Thus, its potent affinity to ornithine decarboxylase and spermidine synthase is likely to be due to close structural similarity with the intermediates formed in these reactions. This has implications for the mechanisms involved.

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Research paper thumbnail of Novel isosteric charge-deficient spermine analogue—1,12-diamino-3,6,9-triazadodecane: synthesis, pK a measurement and biological activity

Amino Acids, Dec 2, 2009

Ionic interactions are essential for the biological functions of the polyamines spermidine and sp... more Ionic interactions are essential for the biological functions of the polyamines spermidine and spermine in mammalian physiology. Here, we describe a simple gram scale method to prepare 1,12-diamino-3,6,9-triazadodecane (SpmTrien), an isosteric charge-deficient spermine analogue. The protonation sites of SpmTrien were determined at pH range of 2.2-11.0 using two-dimensional (1)H-(15)N NMR spectroscopy, which proved to be more feasible than conventional methods. The macroscopic pK(a) values of SpmTrien (3.3, 6.3, 8.5, 9.5 and 10.3) are significantly lower than those of 1,12-diamino-4,9-diazadodecane (spermine). The effects of SpmTrien and its parent molecule, 1,8-diamino-3,6-diazaoctane (Trien), on cell growth and polyamine metabolism were investigated in DU145 prostate carcinoma cells. SpmTrien downregulated the biosynthetic enzymes ornithine decarboxylase (ODC) and S-adenosyl-L: -methionine decarboxylase and decreased intracellular polyamine levels, whereas the effects of Trien alone were minor. Interestingly, both SpmTrien and Trien were able to partially overcome growth arrest induced by an ODC inhibitor, alpha-difluoromethylornithine, indicating that they are able to mimic some functions of the natural polyamines. Thus, SpmTrien is a novel tool to influence polyamine interaction sites at the molecular level and offers a new means to study the contribution of the protonation of spermine amino group(s) in the regulation of polyamine-dependent biological processes.

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Research paper thumbnail of Divergent regulation of the key enzymes of polyamine metabolism by chiral α-methylated polyamine analogues

Biochemical Journal, Aug 13, 2009

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Research paper thumbnail of Guide Molecule-driven Stereospecific Degradation of α-Methylpolyamines by Polyamine Oxidase

Journal of Biological Chemistry, Feb 1, 2006

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