Synthesis, molecular modeling and biological evaluation of novel tadalafil analogues as phosphodiesterase 5 and colon tumor cell growth inhibitors, new stereochemical perspective.
Synthesis, molecular modeling and biological evaluation of novel tadalafil analogues as phosphodiesterase 5 and colon tumor cell growth inhibitors, new stereochemical perspective.
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DOI：
10.1016/j.ejmech.2009.10.046
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发表时间：
2010-04
影响因子：
6.7
通讯作者：
Abdel-Halim M
中科院分区：
文献类型：
--
作者：
Abadi AH;Gary BD;Tinsley HN;Piazza GA;Abdel-Halim M
报道了新型他达拉非类似物的合成，其中苯二恶酚部分被2-溴苯基取代，手性碳从R，R摆动到R，S，S，R和S，S，哌嗪二酮环被维持或还原为5元咪唑二酮或硫代咪唑烷酮。评价了合成的类似物对环鸟苷一磷酸(CGMP)选择性磷酸二酯酶5(PDE5)同工酶的抑制作用和对人结肠腺癌细胞的生长抑制作用。β-Caroline-Hyantoin中的C-5和β-Caroline-piperazinedione衍生物中的C-6的R绝对构型对PDE_5的抑制是必不可少的。此外，由L-色氨酸合成的他达拉非类似物比由D-色氨酸合成的类似物具有更高的活性，这不仅具有经济价值，而且为发现新的卡波林作为PDE5抑制剂开辟了广阔的前景。虽然一些类似物显示出很强的肿瘤细胞生长抑制活性，但与它们的PDE5抑制活性没有明显的相关性，这使得我们得出结论，其他PDE同工酶或PDE5剪接变异体可能参与其中。
The synthesis of novel tadalafil analogues in which the benzodioxole moiety is replaced by 2-bromophenyl; the chiral carbons swing from R,R to R,S, S,R and S,S; the piperazinedione ring is maintained or reduced to the 5-membered imidazolidinedione or thioxoimidazolinone is described. The prepared analogues were evaluated for their capacity to inhibit the cyclic guanosine monophosphate (cGMP) selective phosphodiesterase 5 (PDE5) isozyme and the growth of human HT-29 colon adenocarcinoma cells. The R absolute configuration of C-5 in the β-carboline-hydantoin and C-6 in the β-carboline-piperazinedione derivatives was found to be essential for the PDE5 inhibition. In addition, tadalafil analogues that were synthesized from L-tryptophan were more active than those derived from D-tryptophan, which is of economic value and expands the horizon for the discovery of new carbolines as PDE5 inhibitors. While some analogues displayed potent tumor cell growth inhibitory activity, there was no apparent correlation with their PDE5 inhibitory activity, which leads us to conclude that other PDE isozymes or PDE5 splice variants may be involved.