http://www.cnr.it/ontology/cnr/individuo/prodotto/ID186441
N,N-Bis(cyclohexanol)amine aryl esters inhibit P-glycoprotein as transport substrates§ (Articolo in rivista)
- Type
- Label
- N,N-Bis(cyclohexanol)amine aryl esters inhibit P-glycoprotein as transport substrates§ (Articolo in rivista) (literal)
- Anno
- 2011-01-01T00:00:00+01:00 (literal)
- Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#doi
- 10.1016/j.bcp.2011.08.025 (literal)
- Alternative label
Annalisa Neri a,b,; Maria Frosini a,b,; Massimo Valoti a,b,; Marcello G. Cacace d,;
Elisabetta Teodori c,; Giampietro Sgaragli a,b,* (2011)
N,N-Bis(cyclohexanol)amine aryl esters inhibit P-glycoprotein as transport substrates§
in Biochemical pharmacology
(literal)
- Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#autori
- Annalisa Neri a,b,; Maria Frosini a,b,; Massimo Valoti a,b,; Marcello G. Cacace d,;
Elisabetta Teodori c,; Giampietro Sgaragli a,b,* (literal)
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- a Dipartimento di Neuroscienze, Universita` degli Studi di Siena, via A. Moro 2, 53100 Siena, Italy
b Istituto Toscano Tumori, via T. Alderotti 26N, 50139 Firenze, Italy
c Dipartimento di Scienze Farmaceutiche, Universita` degli Studi di Firenze, via U. Schiff 6, 50019 Sesto Fiorentino (FI), Italy
d Unita` ISMN (Istituto per lo Studio dei Materiali Nanostrutturati) Consiglio Nazionale delle Ricerche, Dipartimento di Chimica, Universita` degli Studi di Siena,
via A. Moro 2, 53100 Siena, Italy (literal)
- Titolo
- N,N-Bis(cyclohexanol)amine aryl esters inhibit P-glycoprotein as transport substrates§ (literal)
- Abstract
- P-Glycoprotein (Pgp) inhibition by three sets of four isomers of N,N-bis(cyclohexanol)amine aryl esters
was assessed on rhodamine 123 (R123) efflux in human MDR1-gene transfected mouse T-lymphoma
L5178 cells and on Sf9 ATPase activity. The most active compounds inhibited Pgp with IC50 values much
lower than those of either cyclosporin A (CSA) or GF120918. As to R123 efflux inhibition, the role of the
bond present in the second aryl moiety appeared important since the triple bond derivatives (3a-d) were
the most powerful as compared to the double bond (2a-d) and the single bond (1a-d) counterparts.
Concentration-inhibition curves of 2c and 3d exhibited a biphasic behaviour suggesting the existence of
two binding sites in the recognition domain of Pgp. Persistence of inhibition by these compounds resulted
to be intermediate between that caused by CSA and GF120918. R123 exhibited positive interaction with
CSA, 1d, 1c, 2d, 2c and 3c, the concentration-inhibition curves being shifted leftward when R123
concentration was increased, while it exhibited negative interaction with 3d and no effect with
GF120918. Sf9 ATPase activity was stimulated in an increasing order of potency by 2c, 3c, 2d, CSA,
epirubicin and 3d. In a decreasing order of potency 3d, 2c, GF120918, CSA, 2d and 3c inhibited at subnanomolar
concentrations epirubicin-stimulated ATPase activity. In conclusion, isomeric geometry and
restriction of molecular flexibility of N,N-bis(cyclohexanol)amine aryl esters were crucial for their
presentation to and inhibition of Pgp as transport substrates, R123 and epirubicin cooperating with them
to this inhibition. (literal)
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