Separation and Detection of Tetracyclines by High-Speed Liquid Chromatography

Butterfield, A.G.; Hughes, David W.; Pound, N. J.; Wilson, William L.

doi:10.1128/aac.4.1.11

Cited by 42 publications

(8 citation statements)

References 23 publications

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“…Doxy and mino have dissociation constants (pKa) of 3.5, 7.7 and 9.5 and 2.8, 5.0, 7.8 and 9.3, respectively [26]. The isoelectric point is 5.0 for doxy and 6.4 for mino [30,31]. Thus, lysosomes may also be considered as a cellular target for doxy and mino as has been suggested by other authors [32,33].…”

Section: Effect Of Lysosomal Inhibitor Chloroquinementioning

confidence: 73%

DNA damage, lysosomal degradation and Bcl-xL deamidation in doxycycline- and minocycline-induced cell death in the K562 leukemic cell line

Fares

Abedi‐Valugerdi

Hassan

et al. 2015

Biochemical and Biophysical Research Communications

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We investigated mechanisms of cytotoxicity induced by doxycycline (doxy) and minocycline (mino) in the chronic myeloid leukemia K562 cell line. Doxy and mino induced cell death in exposure-dependent manner. While annexin V/propidium iodide staining was consistent with apoptosis, the morphological changes in Giemsa staining were more equivocal. A pancaspase inhibitor Z-VAD-FMK partially reverted cell death morphology, but concurrently completely prevented PARP cleavage. Mitochondrial involvement was detected as dissipation of mitochondrial membrane potential and cytochrome C release. DNA double strand breaks detected with γH2AX antibody and caspase-2 activation were found early after the treatment start, but caspase-3 activation was a late event. Decrement of Bcl-xL protein levels and electrophoretic shift of Bcl-xL molecule were induced by both drugs. Phosphorylation of Bcl-xL at serine 62 was ruled out. Similarly, Bcr/Abl tyrosine kinase levels were decreased. Lysosomal inhibitor chloroquine restored Bcl-xL and Bcr/Abl protein levels and inhibited caspase-3 activation. Thus, the cytotoxicity of doxy and mino in K562 cells is mediated by DNA damage, Bcl-xL deamidation and lysosomal degradation with activation of mitochondrial pathway of apoptosis.

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Section: Effect Of Lysosomal Inhibitor Chloroquinementioning

confidence: 73%

DNA damage, lysosomal degradation and Bcl-xL deamidation in doxycycline- and minocycline-induced cell death in the K562 leukemic cell line

Fares

Abedi‐Valugerdi

Hassan

et al. 2015

Biochemical and Biophysical Research Communications

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“…8(A). Here, all the TCs solutes bore positive values of effective charge on the tertiary amine substituents in the pH 2.9 medium (MNC: p K a =2.8, 5.0, 7.8, 9.5 for H 4 A +2 ; CTC: p K a =3.33, 7.55, 9.33 for H 3 A + ; doxycycline: p K a =3.02, 7.97, 9.15 for H 3 A + ; TC: p K a =3.32, 7.78, 9.58 for H 3 A + ; oxytetracycline: p K a =3.32, 7.46, 8.94 for H 3 A + ; methacycline: p K a =3.5, 7.6, 9.2 for H 3 A + ; meclocycline: p K a =4.05, 6.87, 9.59 for H 3 A + 65–67) and exhibited positive μ ep values. The μ ps values were also positive, but were smaller than μ ep values.…”

Section: Resultsmentioning

confidence: 99%

Thermodynamics and Kinetics of the Hydride‐Transfer Cycles for 1‐Aryl‐1,4‐dihydronicotinamide and Its 1,2‐Dihydroisomer

Zhu

Cao

Liu

et al. 2003

Chemistry A European J

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Five 1-(p-substituted phenyl)-1,4-dihydronicotinamides (GPNAH-1,4-H(2)) and five 1-(p-substituted phenyl)-1,2-dihydronicotinamides (GPNAH-1,2-H(2)) were synthesized, which were used to mimic NAD(P)H coenzyme and its 1,2-dihydroisomer reductions, respectively. When the 1,4-dihydropyridine (GPNAH-1,4-H(2)) and the 1,2-dihydroisomer (GPNAH-1,2-H(2)) were treated with p-trifluoromethylbenzylidenemalononitrile (S) as a hydride acceptor, both reactions gave the same products: pyridinium derivative (GPNA(+)) and carbanion SH(-) by a hydride one-step transfer. Thermodynamic analysis on the two reactions shows that the hydride transfer from the 1,2-dihydropyridine is much more favorable than the hydride transfer from the corresponding 1,4-dihydroisomer, but the kinetic examination displays that the former reaction is remarkably slower than the latter reaction, which is mainly due to much more negative activation entropy for the former reaction. When the formed pyridinium derivative (GPNA(+)) was treated with SH(-), the major reduced product was the corresponding 1,4-dihydropyridine along with a trace of the 1,2-dihydroisomer. Thermodynamic and kinetic analyses on the hydride transfer from SH(-) to GPNA(+) all suggest that the 4-position on the pyridinium ring in GPNA(+) is much easier to accept the hydride than the 2-position, which indicates that when the 1,4-dihydropyridine is used the hydride donor to react with S, the formed pyridinium derivative GPNA(+) may return to the 1,4-dihydropyridine by a hydride transfer cycle; but when the 1,2-dihydropyridine is used as the hydride donor, the formed pyridinium derivative can not return to the 1,2-dihydropyridine by the hydride reverse transfer from SH(-) to GPNA(+). These results clearly show that the hydride-transfer cycle is favorable for the 1,4-dihydronicotinamides, but unfavorable for the corresponding 1,2-dihydroisomers.

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“…Solvent system B: 100% MeOH. 21 The synthetic methods, isolation procedures, and chemical characterization used for the 13-(propylthio) derivatives (compounds 30-32) were as previously reported.10…”

Section: Methodsmentioning

confidence: 99%

Molecular Requirements for the Inhibition of the Tetracycline Antiport Protein and the Effect of Potent Inhibitors on the Growth of Tetracycline-Resistant Bacteria

Nelson¹,

Park²,

Levy³

1994

J. Med. Chem.

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Forty-seven compounds and tetracycline (Tc) structural analogues were tested for their ability to interfere with [3H]Tc uptake in everted inner membrane vesicles derived from Tc-resistant Escherichia coli D1-209, bearing the class B tetracycline resistance efflux protein (Tet protein). For effective inhibition of Tc uptake, the molecule had to have an intact ABCD tetracyclic carbon skeleton and a conjugated phenolic beta-diketone substructure at positions 10-12a with the subsequent development of keto-enol tautomerization. Molecular variations at carbon positions 2, 4, 5, 6, 7, 8, and 9 did not decrease, and some increased, the inhibitory activity as compared to that of Tc. Among these compounds, the highest inhibition of uptake occurred with certain position 6 and 13 derivatives of 5-hydroxytetracycline. In a group of 13-(propylthio) derivatives of 5-OH-Tc [13-propyl, 13-(3-chloropropyl), and 13-(2-carboxyethyl)] there was a correlation between uptake inhibitory activity and antibacterial activity. The 13-(3-chloropropyl) derivative, with the best efflux inhibitory activity, exhibited synergistic activity when tested in combination with doxycycline against Tc-resistant E. coli bearing the class A or B determinant, against Staphylococcus aureus bearing class K, and against Enterococcus faecalis bearing the class L determinant. The 13-propyl analogue also showed high transport blocking activity and showed synergistic antibacterial activity against E. coli bearing the class A determinant and additive activity against the other Tc-resistant bacteria. The synergistic antibacterial activity of these compounds was not shown by the 13-[(2-carboxyethyl)thio] homologue, whose efflux blocking activity was 70-fold less. These findings suggest that multiple sites on the Tc molecule are available for synthetic modification toward the development of an effective Tc blocking agent. Such compounds, used alone or in combination with a standard tetracycline, show improved antibacterial activity.

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Separation and Detection of Tetracyclines by High-Speed Liquid Chromatography

Cited by 42 publications

References 23 publications

DNA damage, lysosomal degradation and Bcl-xL deamidation in doxycycline- and minocycline-induced cell death in the K562 leukemic cell line

DNA damage, lysosomal degradation and Bcl-xL deamidation in doxycycline- and minocycline-induced cell death in the K562 leukemic cell line

Thermodynamics and Kinetics of the Hydride‐Transfer Cycles for 1‐Aryl‐1,4‐dihydronicotinamide and Its 1,2‐Dihydroisomer

Molecular Requirements for the Inhibition of the Tetracycline Antiport Protein and the Effect of Potent Inhibitors on the Growth of Tetracycline-Resistant Bacteria

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