Prieto Lidia, Gaviña Daniel, Escolano Marcos, Cánovas-Belchí María, Sánchez-Roselló María, Del Pozo Carlos, Falomir Eva, Díaz-Oltra Santiago
Department of Organic Chemistry, University of Valencia, E-46100 Burjassot, Spain.
Department of Organic and Inorganic Chemistry, University Jaume I, E-12071 Castellón, Spain.
Molecules. 2025 Jan 15;30(2):317. doi: 10.3390/molecules30020317.
The natural products combretastatins A-1 and A-4 are potent antimitotic and vascular-disrupting agents through their binding at the colchicine site in tubulin. However, these compounds suffer from a low water solubility and a tendency to isomerize to the inactive stilbenes. In this study, we have prepared a series of 18 -restricted triazole analogues of combretastatin A-4 (CA-4), maintaining, in all cases, the 3,4,5-trimethoxy phenyl ring A, with the aim of investigating the substitution pattern on the B-ring in a systematic way. To this end, cytotoxic activities of the -restricted analogues of CA-4 prepared were determined in two tumor cell lines, namely, HT-29 and A-549, as well as in the non-tumor cell line HEK-293, to pre-evaluate the selectivity profile of the compounds for the tumor cell lines. The main conclusion was the essential presence of methoxyl or ethoxyl groups at the position of the B-ring in order to obtain good antitumor activities. Thus, the more active compounds in our study displayed IC values in the nanomolar range for the tumor cell lines but not for the normal cells. Consequently, these triazole analogues of CA-4 could serve as promising alternatives to the natural product, although further studies about their biological activity are essential in order to fully determine their viability as therapeutic agents in the treatment of cancer.
天然产物康普他汀A-1和A-4是强效抗有丝分裂剂和血管破坏剂，它们通过与微管蛋白中的秋水仙碱结合位点结合发挥作用。然而，这些化合物存在水溶性低以及易异构化为无活性的芪类化合物的问题。在本研究中，我们制备了一系列18种康普他汀A-4（CA-4）的受限三唑类似物，在所有情况下均保留3,4,5-三甲氧基苯环A，旨在系统研究B环上的取代模式。为此，在两种肿瘤细胞系（即HT-29和A-549）以及非肿瘤细胞系HEK-293中测定了所制备的CA-4受限类似物的细胞毒性活性，以预先评估这些化合物对肿瘤细胞系的选择性概况。主要结论是，为了获得良好的抗肿瘤活性，B环的位置必须存在甲氧基或乙氧基。因此，我们研究中活性较高的化合物对肿瘤细胞系的IC值在纳摩尔范围内，而对正常细胞则无此活性。因此，这些CA-4的三唑类似物有望成为天然产物的替代物，不过为了全面确定它们作为癌症治疗药物的可行性，还需要对其生物活性进行进一步研究。
