Synthetic Bioactive Molecules Section, LBC, NIDDK, NIH, Bethesda, Maryland, USA.
Department of Pharmacy, University of Pisa, Pisa, Italy.
Arch Pharm (Weinheim). 2022 Nov;355(11):e2200295. doi: 10.1002/ardp.202200295. Epub 2022 Jul 29.
A series of novel 3,4-dihydrobenzo[4,5]imidazo[1,2-a][1,3,5]triazine (BIT) derivatives were designed and synthesized. In vitro antiproliferative activity was detected toward two human colorectal adenocarcinoma cell lines (CaCo-2 and HT-29) and one human dermal microvascular endothelial cell line (HMVEC-d). The most active compounds, namely 2-4 and 8, were further investigated to clarify the mechanism behind their biological activity. Through immunofluorescence assay, we identified the target of these molecules to be the microtubule cytoskeleton with subsequent formation of dense microtubule accumulation, particularly at the periphery of the cancer cells, as observed in paclitaxel-treated cells. Overall, these results highlight BIT derivatives as robust and feasible candidates deserving to be further developed in the search for novel potent antiproliferative microtubule-targeting agents.
设计并合成了一系列新型 3,4-二氢苯并[4,5]咪唑并[1,2-a][1,3,5]三嗪（BIT）衍生物。对两种人结肠直肠腺癌细胞系（CaCo-2 和 HT-29）和一种人真皮微血管内皮细胞系（HMVEC-d）进行了体外抗增殖活性检测。最具活性的化合物，即 2-4 和 8，进一步进行了研究，以阐明其生物活性背后的机制。通过免疫荧光测定，我们确定这些分子的靶标是微管细胞骨架，随后形成密集的微管聚集，特别是在紫杉醇处理的细胞中观察到的癌细胞周围。总的来说，这些结果强调了 BIT 衍生物作为强大且可行的候选物，值得进一步开发，以寻找新型有效的微管靶向抗增殖剂。
