Self-Association of Doxorubicin and Related Compounds in Aqueous Solution

Menozzi, Milena; Valentini, Luigi; E, Vannini; Arcamone, Federico

doi:10.1002/jps.2600730615

Cited by 122 publications

(79 citation statements)

References 14 publications

(2 reference statements)

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“…Very recently, cocrystal structures from 3.3-Å X-ray data showed the binding of high-molecular-mass drugs erythromycin and rifampicin to the access pocket, whereas the low-molecular-mass substrates like minocyclin and doxorubicin were postulated to be transported directly to the deep binding pocket, without binding first to the access pocket (32). Because doxorubicin is mainly present as dimer in solution at concentrations at which the AcrAB-TolC efflux system confers resistance to E. coli against the drug (and at the concentrations used for cocrystallization) (33), the binding in a dimeric state in the access pocket might represent a preliminary stage to the binding of the doxorubicin monomer in the deep binding pocket. This entails prerequisite conformation flexibility between the L and T monomer, as well as a binding affinity difference of the access pocket (low affinity) and deep binding pocket (high affinity).…”

Section: Resultsmentioning

confidence: 99%

Transport of drugs by the multidrug transporter AcrB involves an access and a deep binding pocket that are separated by a switch-loop

Eicher

Cha

Seeger

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

293

573

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AcrAB-TolC is the major efflux protein complex in Escherichia coli extruding a vast variety of antimicrobial agents from the cell. The inner membrane component AcrB is a homotrimer, and it has been postulated that the monomers cycle consecutively through three conformational stages designated loose (L), tight (T), and open (O) in a concerted fashion. Binding of drugs has been shown at a periplasmic deep binding pocket in the T conformation. The initial drug-binding step and transport toward this drug-binding site has been elusive thus far. Here we report high resolution structures (1.9–2.25 Å) of AcrB/designed ankyrin repeat protein (DARPin) complexes with bound minocycline or doxorubicin. In the AcrB/doxorubicin cocrystal structure, binding of three doxorubicin molecules is apparent, with one doxorubicin molecule bound in the deep binding pocket of the T monomer and two doxorubicin molecules in a stacked sandwich arrangement in an access pocket at the lateral periplasmic cleft of the L monomer. This access pocket is separated from the deep binding pocket apparent in the T monomer by a switch-loop. The localization and conformational flexibility of this loop seems to be important for large substrates, because a G616N AcrB variant deficient in macrolide transport exhibits an altered conformation within this loop region. Transport seems to be a stepwise process of initial drug uptake in the access pocket of the L monomer and subsequent accommodation of the drug in the deep binding pocket during the L to T transition to the internal deep binding pocket of the T monomer.

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Section: Resultsmentioning

confidence: 99%

Transport of drugs by the multidrug transporter AcrB involves an access and a deep binding pocket that are separated by a switch-loop

Eicher

Cha

Seeger

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

293

573

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“…Doxorubicin is known to form doxo-doxo dimer in solution by a chemical reaction between 3¢-NH 2 and C 9 -a ketol side chain and P-P stacking of their planer ring (Menozzi et al 1984;McLennan et al 1985;Yokoyama et al 1998). The dimeric form of doxorubicin is hydrophobic in nature, which enhances entrapment of doxorubicin in the PLA fraction (Fig.…”

Section: Discussionmentioning

confidence: 99%

Nanospheres Encapsulating Anti-Leishmanial Drugs for Their Specific Macrophage Targeting, Reduced Toxicity, and Deliberate Intracellular Release

Shukla

Patra²,

Dubey³

2012

Vector-Borne and Zoonotic Diseases

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The current work focuses on the study of polymeric, biodegradable nanoparticles (NPs) for the encapsulation of doxorubicin and mitomycin C (anti-leishmanial drugs), and their efficient delivery to macrophages, the parasite's home. The biodegradable polymer methoxypoly-(ethylene glycol)-b-poly (lactic acid) (MPEG-PLA) was used to prepare polymeric NPs encapsulating doxorubicin and mitomycin C. The morphology, mean diameter, and surface area of spherical NPs were determined by transmission electron microscopy (TEM), field emission scanning electron microscopy (FESEM), and BET surface area analysis. X-ray diffraction was performed to validate drug encapsulation. An in vitro release profile of the drugs suggested a fairly slow release. These polymeric NPs were efficiently capable of releasing drug inside macrophages at a slower pace than the free drug, which was monitored by epi-fluorescence microscopy. Encapsulation of doxorubicin and mitomycin C into NPs also decreases cellular toxicity in mouse macrophages ( J774.1A).

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“…The self-association of daunorubicin in aqueous buffer systems of varying ionic strength has been studied extensively by a variety of experimental techniques and there is a considerable disagreement regarding either the measured association constants of the nature of the aggregated species [20,21]. UV measurements are generally carried out in dilute solution, where self-association would not interfere with the interpretation of binding data, but at higher concentration and ionic strength the aggregation is enhanced and must be taken into account in the calculation of binding constants [19,20].…”

Section: Association Constants Calculationmentioning

confidence: 99%

31P NMR studies on the interaction of morpholinyl anthracyclines and related compounds with d(CGTACG)2. Thermodynamic and kinetic parameters

et al. 1994

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3lp N]V[R spectroscopy has been used to study the intercalation of the anthracyclines doxorubicin 1, daunorubicin 2, 4-demethoxydaunorubicin 3, morpholinodoxorubicin 4, methoxymorpholinodoxorubicin 5 and 9-deoxydaunorubicin 6 with the DNA fragment d(CGTACG)2. The individual phosphate resonances of the oligonucleotide were assigned in the free as well as in the intercalated species. The 3~p chemical shitt vadations allowed us to identify the intercalation sites, which resulted to be the same for all compounds i e. between the terminal CG base-pairs of the helix (two molecules of drug per duplex). The binding coustants, the dissociation rete constants and AG ~ values have been determined in different conditions of ionic strength and temperature. The kinetic constant (ko~) of the slow step of the anthracycline/duplex intercalation process has been directly measured by NOE exchange techniques. Binding constants depend on the ionic strength and on the self-association process so greatly, that their use to study by NMR anthracycline/DNA interactions is questionable. On the contrary, the kof r are not affected by these phenomena and presentan interesting trend for 1~, thus showing that the average lifetime of the drug in the intercalation site appears to be important for determining the cytotoxicity and the antimitotic activity.

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Self-Association of Doxorubicin and Related Compounds in Aqueous Solution

Cited by 122 publications

References 14 publications

Transport of drugs by the multidrug transporter AcrB involves an access and a deep binding pocket that are separated by a switch-loop

Transport of drugs by the multidrug transporter AcrB involves an access and a deep binding pocket that are separated by a switch-loop

Nanospheres Encapsulating Anti-Leishmanial Drugs for Their Specific Macrophage Targeting, Reduced Toxicity, and Deliberate Intracellular Release

31P NMR studies on the interaction of morpholinyl anthracyclines and related compounds with d(CGTACG)2. Thermodynamic and kinetic parameters

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