Design, synthesis and structure-activity relationships of novel taxane-based multidrug resistance reversal agents.
A series of novel taxane-based multidrug resistance (MDR) reversal agents (TRAs) has been designed and synthesized. Structure-activity relationship (SAR) study clearly indicates that modification of the C-7 position with hydrophobic arenecarbonylcinnamoyl groups brings about high potency against drug efflux mediated by P-glycoprotein (P-gp). Six TRAs exhibit ability to modulate a wide range of ATP-binding cassette (ABC) transporters, such as P-gp, multidrug resistance-associated protein 1 (MRP1), and breast cancer resistance protein (BCRP), which may serve as novel broad-spectrum modulators of ABC transporters.
Ojima
Iwao
I
Department of Chemistry, State University of New York at Stony Brook, Stony Brook, New York 11794-3400, USA. iojima@notes.cc.sunysb.edu
Borella
Christopher P
CP
Wu
Xinyuan
X
Bounaud
Pierre-Yves
PY
Oderda
Cecilia Fumero
CF
Sturm
Matthew
M
Miller
Michael L
ML
Chakravarty
Subrata
S
Chen
Jin
J
Huang
Qing
Q
Pera
Paula
P
Brooks
Tracy A
TA
Baer
Maria R
MR
Bernacki
Ralph J
RJ
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D020650:Combinatorial Chemistry Techniques; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008942:Mitoxantrone / Q000378:metabolism; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism; D017239:Paclitaxel / Q000494:pharmacology; D013329:Structure-Activity Relationship; D043823:Taxoids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D008942:Mitoxantrone; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D017239:Paclitaxel; D043823:Taxoids; C421109:multidrug resistance-associated protein 1