Antagonist analogue of 6-[3′-(1-adamantyl)-4′-hydroxyphenyl]-2-naphthalenecarboxylic acid (AHPN) family of apoptosis inducers that effectively blocks AHPN-induced apoptosis but not cell-cycle arrest

被引:39
作者
Dawson, MI
Harris, DL
Liu, G
Hobbs, PD
Lange, CW
Jong, L
Bruey-Sedano, N
James, SY
Zhang, XK
Peterson, VJ
Leid, M
Farhana, L
Rishi, AK
Fontana, JA
机构
[1] Burnham Inst, Ctr Canc, La Jolla, CA 92037 USA
[2] Mol Res Inst, Mountain View, CA 94043 USA
[3] SRI Int, Retinoid Program, Menlo Pk, CA 94025 USA
[4] Oregon State Univ, Coll Pharm, Corvallis, OR 97331 USA
[5] Wayne State Univ, Detroit, MI 48201 USA
[6] Dept Vet Affairs, John D Dingell Med Ctr, Detroit, MI 48201 USA
关键词
D O I
10.1021/jm030524k
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
The retinoid 6-[3'-(1-adamantyl)-4'-hydroxyphenyl] -2-naphthalenecarboxylic acid (AHPN) and its active analogues induce cell-cycle arrest and programmed cell death (apoptosis) in cancer cells independently of retinoic acid receptor (RAR) interaction. Its analogue, (E)-4-[3'-(1-adamantyl)-4'-hydroxyphenyl]-3-(3'-acetamidopropyloxy)cinnamic acid (3-A-AHPC) selectively antagonized cell apoptotic events (TR3/nur77/NGFI-B expression and nuclear-to-mitochondrial translocation) but not the proliferative events (cell-cycle arrest and p21(WAF1/CIP1) expression) induced by proapoptotic AHPN and its analogues. The syntheses of 3-A-AHPC and proapoptotic (E)-6-[3'-(1-adamantyl)-4'-hydroxyphenyl]-5-chloronaphthalenecarboxylic acid (5-Cl-AHPN) are described. Computational studies on AHPN, AHPC, and three substituted analogues (5-Cl-AHPN, 3-Cl-AHPC, and 3-A-AHPC) suggested reasons for their diametric effects on RAR activation. Density functional theory studies indicated that the 1-adamantyl (1-Ad) groups of the AHPN and AHPC configurations assumed positions that were nearly planar with the aromatic rings of their polar termini. In contrast, in the configurations of the substituted analogues having chloro and 3-acetamidopropyloxy groups, rather than a hydrogen, ortho to the diaryl bonds, the diaryl bond torsion angles increased so that the 1-Ad groups were oriented out of this plane. Docking and molecular dynamics of AHPN, AHPC, and these substituted analogues in the RARgamma ligand-binding domain illustrated how specific substituents on the AHPN and AHPC scaffolds modulated the positions and dynamics of the 1-Ad groups. As a result, the position of RARgamma helix H12 in forming the coactivator-binding site was impacted in a manner consistent with the experimental effect of each analogue on RARgamma transcriptional activation.
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收藏
页码:3518 / 3536
页数:19
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