Department of Organic Chemistry, Faculty of Pharmacy, "Carol Davila" University of Medicine and Pharmacy, 6 Traian Vuia Street, 020956 Bucharest, Romania.
Center of Immunology, "Stefan S. Nicolau" Institute of Virology, Romanian Academy, 285 Mihai Bravu Ave., 030304 Bucharest, Romania.
Int J Mol Sci. 2023 Jul 19;24(14):11642. doi: 10.3390/ijms241411642.
New pyrrolo[1,2-]pyridazines were synthesized by 3 + 2 cycloaddition reaction between mesoionic oxazolo-pyridazinones and methyl/ethyl propiolate. The mesoionic compounds were generated in situ by action of acetic anhydride on 3(2)pyridazinone acids obtained from corresponding esters by alkaline hydrolysis followed by acidification. The structures of the compounds were confirmed by elemental analyses and IR, H-NMR, C-NMR, and X-ray diffraction data. The regioselectivity of cycloaddition was evidenced by NMR spectroscopy and confirmed by X-ray analysis. The compounds were evaluated for their cytotoxicity on plant cells ( L.) and crustacean animal cells ( Kellogg and Straus). The results indicated that the tested compounds exhibited low toxicity on the plant cell (IC values higher than 200 µM), while on Artemia nauplii no lethality was observed. Daphnia magna assay showed that pyrrolo[1,2-]pyridazines and could exhibit toxic effects, whereas, for the other compounds, toxicity was low to moderate. Also, the cytotoxic effects of the compounds were tested on three human adenocarcinoma-derived adherent cell lines (colon LoVo, ovary SK-OV-3, breast MCF-7). The in vitro compound-mediated cytotoxicity assays, performed by the MTS technique, demonstrated dose- and time-dependent cytotoxic activity for several compounds, the highest anti-tumor activity being observed for , and , especially against colon cancer cells.
新的吡咯并[1,2-]哒嗪是通过中氧杂唑并哒嗪酮和甲基/乙基丙炔酸酯之间的 3 + 2 环加成反应合成的。中氧杂化合物是通过醋酸酐作用于 3(2)哒嗪酮酸原位生成的，3(2)哒嗪酮酸是通过相应酯的碱性水解和酸化得到的。化合物的结构通过元素分析和 IR、H-NMR、C-NMR 和 X 射线衍射数据得到确认。NMR 光谱证实了环加成的区域选择性，并通过 X 射线分析得到了证实。通过植物细胞（L.）和甲壳动物细胞（Kellogg 和Straus）评估了化合物的细胞毒性。结果表明，测试的化合物对植物细胞的毒性较低（IC 值高于 200 µM），而对卤虫无致死作用。水蚤试验表明，吡咯并[1,2-]哒嗪和可以表现出毒性作用，而其他化合物的毒性则较低至中等。此外，还测试了化合物对三种人腺癌细胞系（结肠 LoVo、卵巢 SK-OV-3、乳腺 MCF-7）的细胞毒性。通过 MTS 技术进行的体外化合物介导的细胞毒性测定表明，几种化合物具有剂量和时间依赖性的细胞毒性活性，其中化合物、和表现出最高的抗肿瘤活性，尤其是对结肠癌细胞。
