Aziz Yasmine M Abdel, Lotfy Gehad, Said Mohamed M, El Ashry El Sayed H, El Tamany El Sayed H, Soliman Saied M, Abu-Serie Marwa M, Teleb Mohamed, Yousuf Sammer, Dömling Alexander, Domingo Luis R, Barakat Assem
Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Suez Canal University, Ismailia, Egypt.
Department of Chemistry, Faculty of Science, Alexandria University, Alexandria, Egypt.
Front Chem. 2021 Dec 14;9:735236. doi: 10.3389/fchem.2021.735236. eCollection 2021.
The tumor resistance to p53 activators posed a clinical challenge. Combination studies disclosed that concomitant administration of Bcl2 inhibitors can sensitize the tumor cells and induce apoptosis. In this study, we utilized a rapid synthetic route to synthesize two novel hybrid spirooxindole-based p53-MDM2 inhibitors endowed with Bcl2 signaling attenuation. The adducts mimic the thematic features of the chemically stable potent spiro [3-indole-3,2'-pyrrolidin]-2(1)-ones p53-MDM2 inhibitors, while installing a pyrrole ring a carbonyl spacer inspired by the natural marine or synthetic products that efficiently inhibit Bcl2 family functions. A chemical insight into the two synthesized spirooxindoles including single crystal x-ray diffraction analysis unambiguously confirmed their structures. The synthesized spirooxindoles and were preliminarily tested for cytotoxic activities against normal cells, MDA-MB 231, HepG-2, and Caco-2 MTT assay. was superior to 5-fluorouracil. Mechanistically, induced apoptosis-dependent anticancer effect (43%) higher than that of 5-fluorouracil (34.95%) in three studied cancer cell lines, activated p53 (47%), downregulated the Bcl2 gene (1.25-fold), and upregulated p21 (2-fold) in the treated cancer cells. Docking simulations declared the possible binding modes of the synthesized compounds within MDM2.
肿瘤对p53激活剂的耐药性构成了一项临床挑战。联合研究表明，同时给予Bcl2抑制剂可使肿瘤细胞敏感并诱导凋亡。在本研究中，我们采用一种快速合成路线，合成了两种新型的基于螺环氧化吲哚的p53-MDM2抑制剂，它们具有减弱Bcl2信号传导的作用。这些加合物模仿了化学稳定的强效螺[3-吲哚-3,2'-吡咯烷]-2(1)-酮p53-MDM2抑制剂的主题特征，同时引入了一个受天然海洋或合成产物启发的吡咯环和一个羰基间隔基，这些产物能有效抑制Bcl2家族功能。对这两种合成的螺环氧化吲哚进行的化学分析，包括单晶X射线衍射分析，明确证实了它们的结构。通过MTT法对合成的螺环氧化吲哚和 针对正常细胞、MDA-MB 231、HepG-2和Caco-2细胞的细胞毒性活性进行了初步测试。 优于5-氟尿嘧啶。从机制上讲， 在三种研究的癌细胞系中诱导的凋亡依赖性抗癌作用（43%）高于5-氟尿嘧啶（34.95%），激活了p53（47%），下调了Bcl2基因（1.25倍），并上调了处理过的癌细胞中的p21（2倍）。对接模拟揭示了合成化合物在MDM2内可能的结合模式。
