Phenylsulfonylfuroxans as modulators of multidrug-resistance-associated protein-1 and P-glycoprotein.
A series of furoxan derivatives were studied for their ability to interact with P-gp and MRP1 transporters in MDCK cells overexpressing these proteins. 3-Phenylsulfonyl substituted furoxans emerged as the most interesting compounds. All of them were capable of inhibiting P-gp, and a few also were capable of inhibiting MRP1. Substituents at the 4-position of 3-phenylsulfonylfuroxan scaffold were able to modulate the selectivity and the intensity of inhibition. In some cases, they reverted MRP1 inhibitor activity, namely, they were capable of potentiating MRP1 dependent efflux. When compounds 16 and 17 were coadministered with doxorubicin, they restored a high degree of the activity of the antibiotic. Preliminary immunoblotting studies carried out on these two compounds indicate that they are capable of nitrating P-gp, which in this form is likely unable to efflux the antibiotic.
Fruttero
Roberta
R
Dipartimento di Scienza e Tecnologia del Farmaco, Universita degli Studi di Torino, Torino, Italy.
Crosetti
Marco
M
Chegaev
Konstantin
K
Guglielmo
Stefano
S
Gasco
Alberto
A
Berardi
Francesco
F
Niso
Mauro
M
Perrone
Roberto
R
Panaro
Maria Antonietta
MA
Colabufo
Nicola Antonio
NA
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000502:physiology*; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D004285:Dogs; D004317:Doxorubicin / Q000494:pharmacology; D004347:Drug Interactions; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D010069:Oxadiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013450:Sulfones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
C551937:4-butoxy-3-phenylsulfonylfuroxan; C551938:4-hexyloxy-3-phenylsulfonylfuroxan; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D010069:Oxadiazoles; D013450:Sulfones; C010166:furoxans; D004317:Doxorubicin