A novel class of highly potent multidrug resistance reversal agents: disubstituted adamantyl derivatives.
Novel disubstituted adamantyl derivatives were synthesized and evaluated in a P-glycoprotein dependent multidrug resistance cancer cell line. The hit to lead optimization provided potent MDR reversal agents. Some potent adamantyl derivatives were more than 10-fold more potent than verapamil without considerable intrinsic cytotoxicity. The 3-trifluorophenyl derivative 14f did not affect the metabolism of CYP450 3A4, whereas most of MDR revertants had a weak inhibitory effect.
Min
Kyung Hoon
KH
College of Pharmacy, Chung-Ang University, Seoul 156-756, Republic of Korea. khmin@cau.ac.kr
Xia
Yan
Y
Kim
Eun Kyung
EK
Jin
Yinglan
Y
Kaur
Navneet
N
Kim
Eun Seon
ES
Kim
Dae Kyong
DK
Jung
Hwa Young
HY
Choi
Yongseok
Y
Park
Mi-Kyung
MK
Min
Yong Ki
YK
Lee
Kiho
K
Lee
Kyeong
K
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000218:Adamantane / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D006801:Humans; D012509:Sarcoma / Q000188:drug therapy; D013329:Structure-Activity Relationship
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D000218:Adamantane