C3 Halogen and C8" Substituents on Stilbene Arotinoids Modulate Retinoic Acid Receptor Subtype Function
C3 Halogen and C8" Substituents on Stilbene Arotinoids Modulate Retinoic Acid Receptor Subtype Function
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DOI：
10.1002/cmdc.200900214
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发表时间：
2009-10-01
期刊：
影响因子：
3.4
通讯作者：
de Lera, Angel R.
中科院分区：
文献类型：
--
作者：
Alvarez, Susana;Khanwalkar, Harshal;de Lera, Angel R.
进行了基于芪的母体RAR β选择性激动剂BMS 641 4c的C3-卤代衍生物和C8 "位置处的较大取代基的整个系列的合成和生物学评价。该合成使用C8-取代的C5-二甲基二氢萘醛和衍生自C3-卤代苯甲酸酯的苄基膦酸酯的E-选择性Horner-Wadsworth-Emmons（HWE）缩合来构建芪骨架。反式激活研究揭示了C3（F，Cl）处的小卤素原子和C8“”处的中等体积的苯基（在4 B和4 c中）的协同效应，以实现RAR β选择性。我们的研究结果，计算研究的支持，提供了一个结构的理由，这些arotinoids，这是有效的RAR β亚型激动剂和拮抗剂的RAR α parabolism的混合激动剂-拮抗剂的活动。此外，从部分激动剂到反向激动剂和拮抗剂的转变可以通过将相同的卤素原子掺入已知调节剂BMS 701（5a）和BMS 493（6a）的结构中来实现，所述已知调节剂BMS 701（5a）和BMS 493（6a）在C8“处具有比苯基更大的取代基（分别为对甲苯基和苯乙炔基）。相反，在6 a中掺入卤素原子将配体从RAR β反向激动剂（6 B）转化为拮抗剂（6 c）或激动剂（6 d）。令人惊讶的是，6 a-c通常充当RAR α的反向激动剂，而6 d和6 e充当常规RAR α拮抗剂，不影响共阻遏物相互作用。在混合激动剂/拮抗剂5a的情况下，C3-卤化产生反向RAR α和RAR β激动剂（5 b-d），除了碘化的5e，其是这两种受体的常规拮抗剂。由于RAR β基因表达在几种肿瘤细胞中经常缺失或表观遗传学沉默，因此受体和功能选择性RAR激动剂、混合激动剂/拮抗剂、常规拮抗剂和反向激动剂的新库将有助于阐明类维生素A抑制肿瘤的机制。
The synthesis and biological evaluation of the entire series of C3-halogenated derivatives and bulkier substituents at the C8 '' position of the parent stilbene-based RAR beta-selective agonist BMS641 4c was undertaken. The synthesis uses an E-selective Horner-Wadsworth-Emmons (HWE) condensation of C8-substituted C5-dimethyl dihydronaphthaldehyde and the benzylic phosphonates derived from the C3-halogenated benzoates to construct the stilbene skeleton. Transactivation studies revealed the synergistic effect of small halogen atoms at C3 (F, CI) and the moderately bulky phenyl group at C8 '' (in 4 b and 4 c) to achieve RAR beta selectivity. Our results, supported by computational studies, provide a structural rationale for the mixed agonist-antagonist activities of these arotinoids, which are potent agonists of the RAR beta subtype and antagonists of the RAR alpha paralogue. Moreover, transitions from partial agonists to inverse agonists and antagonists can be accomplished with the incorporation of the same halogen atoms into the structures of known modulators BMS701 (5a) and BMS493 (6a), which have bulkier substituents than phenyl (p-tolyl and phenylethynyl, respectively) at C8 ''. Conversely, incorporation of halogen atoms in 6 a converted the ligand from an RAR beta inverse agonist (6 b) to an antagonist (6 c) or an agonist (6 d). Amazingly, 6 a-c commonly acted as inverse agonists for RARa, while 6 d and 6 e acted as regular RAR alpha antagonists, not affecting co-repressor interaction. In the case of the mixed agonist/antagonist 5a, C3-halogenation yields inverse RAR alpha and RAR beta agonists (5 b-d) with the exception of iodinated 5 e, which is a regular antagonist for both these receptors. Because RAR beta gene expression is frequently deleted or epigenetically silenced in several tumor cells, the novel repertoire of receptor and function-selective RAR agonists, mixed agonist/antagonists, regular antagonists, and inverse agonists will be useful in the elucidation of the mechanism of tumor suppression by retinoids.