新型酰胺基双噻唑类 Bcl-2 抑制剂的合成、 及 研究及其作为抗结直肠癌药物的应用。
Novel -amide-based bis-thiazoles as Anti-colorectal Cancer Agents Through Bcl-2 Inhibition: Synthesis, , and studies.
机构信息
Department of Chemistry, Faculty of Science, Cairo University, Giza, 12613, Egypt.
Department of Chemistry, Faculty of Science, Aswan University, Aswan, Egypt.
出版信息
Anticancer Agents Med Chem. 2023;23(3):328-345. doi: 10.2174/1871520622666220615140239.
BACKGROUND
Some heterocycles having bisamide linkage are receiving much interest due to their remarkable biological potencies and they are naturally occurring. Some bisamides and thiazole derivatives were found to inhibit the protein levels of Bcl-2 significantly. This prompted us to synthesize new bis(heterocyclic) derivatives having bisamide function to explore their anti-cancer activities.
METHODS
Novel bis-amide-based bis-thiazoles and thiadiazoles were synthesized by reaction of a new bisthiosemicarbazone with a variety of hydrazonoyl chlorides, a-chloroacetylacetone and haloacetic acid derivatives. Most of the synthesized derivatives were tested for colorectal (HCT-116) and breast (MCF-7) cell lines using the MTT assay, with the apoptotic investigation through flow cytometric and RT-PCR analyses.
RESULTS
Some derivatives were found to be highly cytotoxic against HCT-116 cells with an IC range of (10.44-13.76 μM) compared to 5-fluorouracil (5-FU) (IC = 11.78 μM). One product significantly stimulated apoptotic colorectal cancer cell death by 27.24-fold (50.13% compared to control 1.84%) by arresting the cell cycle at the G2/M phase. The obtained results revealed that compound 7f was more cytotoxic against HCT-116 cells than 5-FU. Compound 7f remarkably enhanced apoptotic colorectal cancer cell death and upregulated the propapoptotic genes (P53, BAX and Capases-3,-8,-9) and downregulated the anti-apoptotic gene, B-cell lymphoma 2 (Bcl-2). In vivo study exhibited that 7f-treatment caused tumor inhibition ratio (TIR%) of 50.45% compared to 54.86% in the 5-FU treatment, with a significant reduction in tumor mass and volume. The anti-tumor activity of compound 7f was accompanied by ameliorated hematological and biochemical analyses, histopathological improvement in treated liver tissues, and the immunohistochemical staining revealed Bcl-2 inhibition in agreement with the in vitro results.
CONCLUSION
Compound 7f is an interesting candidate for further development as a chemotherapeutic anti-cancer agent.
背景
由于具有显著的生物学效力并且是天然存在的，一些含有双酰胺键的杂环化合物受到了广泛关注。一些双酰胺和噻唑衍生物被发现能显著抑制 Bcl-2 蛋白水平。这促使我们合成具有双酰胺功能的新型双（杂环）衍生物，以探索它们的抗癌活性。
方法
通过新的双硫代半缩肼与各种腙酰氯、α-氯代乙酰丙酮和卤代乙酸衍生物的反应，合成了新型双酰胺基双噻唑和噻二唑衍生物。大多数合成的衍生物都通过 MTT 法在结肠直肠（HCT-116）和乳腺（MCF-7）细胞系中进行了测试，并通过流式细胞术和 RT-PCR 分析进行了凋亡研究。
结果
与 5-氟尿嘧啶（5-FU）（IC=11.78 μM）相比，一些衍生物对 HCT-116 细胞具有高细胞毒性，IC 范围为（10.44-13.76 μM）。一种产物通过将细胞周期阻滞在 G2/M 期，使结肠直肠癌细胞凋亡增加 27.24 倍（与对照相比为 50.13%，为 1.84%）。结果表明，化合物 7f 对 HCT-116 细胞的细胞毒性比 5-FU 更强。化合物 7f 显著增强了结肠直肠癌细胞的凋亡死亡，并上调了促凋亡基因（P53、BAX 和 Capases-3、-8、-9），下调了抗凋亡基因 B 细胞淋巴瘤 2（Bcl-2）。体内研究表明，与 5-FU 治疗组的 54.86%相比，7f 治疗组的肿瘤抑制率（TIR%）为 50.45%，肿瘤质量和体积显著减小。化合物 7f 的抗肿瘤活性伴随着血液学和生化学分析的改善、治疗肝组织的组织病理学改善以及免疫组织化学染色显示 Bcl-2 抑制，与体外结果一致。
结论
化合物 7f 是进一步开发为化疗抗癌药物的有前途的候选药物。
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