N,N-bis(cyclohexanol)amine aryl esters: a new class of highly potent transporter-dependent multidrug resistance inhibitors.
A new series of Pgp-dependent MDR inhibitors having a N,N-bis(cyclohexanol)amine scaffold was designed on the basis of the frozen analogue approach. The scaffold chosen gives origin to different geometrical isomers. The new compounds showed a wide range of potencies and efficacies on doxorubicin-resistant erythroleukemia K562 cells in the pirarubicin uptake assay. The most interesting compounds (isomers of 3) were studied further evaluating their action on the ATPase activity present in rat small intestine membrane vesicles and doxorubicin cytotoxicity potentiation on K562 cells. The latter assay was performed also on the isomers of 4. The four isomers of each set present different behavior in each of these tests. Compound 3d shows the most promising properties as it was able to completely reverse Pgp-dependent pirarubicin extrusion at low nanomolar concentration, inhibited ATPase activity at 5 x 10(-9) and increased the cytotoxicity of doxorubicin with a reversal fold (RF) of 36.4 at 3 microM concentration.
Martelli
Cecilia
C
Dipartimento di Scienze Farmaceutiche, Universita di Firenze, via U. Schiff 6, 50019 Sesto Fiorentino (FI), Italy.
Alderighi
Daniela
D
Coronnello
Marcella
M
Dei
Silvia
S
Frosini
Maria
M
Le Bozec
Bénédicte
B
Manetti
Dina
D
Neri
Annalisa
A
Romanelli
Maria Novella
MN
Salerno
Milena
M
Scapecchi
Serena
S
Mini
Enrico
E
Sgaragli
Giampietro
G
Teodori
Elisabetta
E
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D003511:Cyclohexanols / Q000138:chemical synthesis* / Q000494:pharmacology; D003514:Cyclohexylamines / Q000138:chemical synthesis* / Q000494:pharmacology; D004317:Doxorubicin / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D006801:Humans; D020128:Inhibitory Concentration 50; D020014:K562 Cells / Q000187:drug effects; D051381:Rats; D013329:Structure-Activity Relationship
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D003511:Cyclohexanols; D003514:Cyclohexylamines; D004317:Doxorubicin; C027260:pirarubicin