Unidad Multidisciplinaria de Investigación Experimental, Facultad de Estudios Superiores Zaragoza, Universidad Nacional Autónoma de México, México DF 09230, Mexico.
Bioorg Chem. 2013 Oct;50:17-25. doi: 10.1016/j.bioorg.2013.07.001. Epub 2013 Jul 25.
Chromone (4), which form the base structure of various flavonoids isolated as natural products, is capable of relaxing smooth muscle. This is relevant to the treatment of high blood pressure, asthma and chronic obstructive pulmonary disease. The former disorder involves the contraction of vascular smooth muscle (VSM), and the latter two bronchoconstriction of airway smooth muscle (ASM). One of the principal mechanisms by which flavonoids relax muscle tissue is the inhibition of phosphodiesterases (PDEs), present in both VSM and ASM. Therefore, a study was designed to analyze the structure-activity relationship of chromone derivatives in vaso- and bronchorelaxation through the inhibition of PDE. Docking studies showed that these chromones bind at the catalytic site of PDEs. Consequently, we synthesized analogs of chromones substituted at position C-2 with alkyl and naphthyl groups. These compounds were synthesized from 2-hydroxyacetophenone and acyl chlorides in the presence of DBU and pyridine, modifying the methodology reported for the synthesis of 3-acylchromones by changing the reaction temperature from 80 to 30°C and using methylene chloride as solvent, yielding the corresponding phenolic esters 10a-10h. These compounds were cyclized with an equivalent of DBU, pyridine as solvent, and heated at reflux temperature, yielding the chromones 11a-11h. Evaluation of the vasorelaxant effect of 4, 11a-11h on rat aorta demonstrated that potency decreases with branched alkyl groups. Whereas the EC50 of compound 11d (substituted by an n-hexyl group) was 8.64±0.39 μM, that of 11f (substituted by an isobutyl group) was 14.58±0.64 μM. Contrarily, the effectiveness of the compound is directly proportional to the length of the alkyl chain, as evidenced by the increase in maximal effect of compound 11c versus 11d (66% versus 100%) and 11e versus 11f (60% versus 96%). With an aromatic group like naphthyl as the C-2 substituent, the effectiveness was only 43%. All compounds tested on guinea pig trachea showed less than 55% effectiveness. Compounds 4, 11a-11h were evaluated as PDE inhibitors in vitro, with 11d showing the greatest effect (73%), corroborating the importance of a long alkyl chain, which inhibits the decomposition of cGMP. Docking studies showed that the compound 11d was selective for the inhibition of PDE-5.
色满酮（4）是各种黄酮类天然产物的基本结构，能够使平滑肌松弛。这与高血压、哮喘和慢性阻塞性肺疾病的治疗有关。前一种疾病涉及血管平滑肌（VSM）的收缩，而后两种疾病涉及气道平滑肌（ASM）的支气管收缩。黄酮类化合物使肌肉组织松弛的主要机制之一是抑制磷酸二酯酶（PDEs），这些酶存在于 VSM 和 ASM 中。因此，设计了一项研究，通过抑制 PDE 来分析色满酮衍生物在血管舒张和支气管舒张方面的构效关系。对接研究表明，这些色满酮结合在 PDE 的催化部位。因此，我们用烷基和萘基取代 C-2 位合成了色满酮的类似物。这些化合物是由 2-羟基苯乙酮和酰氯在 DBU 和吡啶存在下合成的，通过改变反应温度（从 80°C 到 30°C）并使用二氯甲烷作为溶剂，对合成 3-酰基色满酮的方法进行了修改，得到了相应的酚酯 10a-10h。这些化合物与等当量的 DBU 和吡啶在回流温度下环化，得到色满酮 11a-11h。评价了 4、11a-11h 对大鼠主动脉的血管舒张作用，结果表明，随着支链烷基的增加，其活性降低。化合物 11d（取代为正己基）的 EC50 为 8.64±0.39 μM，化合物 11f（取代为异丁基）的 EC50 为 14.58±0.64 μM。相反，化合物的效力与烷基链的长度成正比，化合物 11c 与 11d（66% 对 100%）和 11e 与 11f（60% 对 96%）之间最大效应的增加证明了这一点。当 C-2 取代基为芳香基团萘基时，效力仅为 43%。所有在豚鼠气管上测试的化合物的效力均小于 55%。在体外，对 4、11a-11h 进行了 PDE 抑制剂评价，其中 11d 表现出最大的效果（73%），这证实了长烷基链抑制 cGMP 分解的重要性。对接研究表明，化合物 11d 对 PDE-5 的抑制具有选择性。
