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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 [3H-indole-3,2′-pyrrolidin]-2(1H)-ones p53-MDM2 inhibitors, while installing a pyrrole ring via 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 2a and 2b were preliminarily tested for cytotoxic activities against normal cells, MDA-MB 231, HepG-2, and Caco-2 via MTT assay. 2b was superior to 5-fluorouracil. Mechanistically, 2b 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.

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Highly divergent complexity molecules, having spirooxindole core structure, possess excellent bioactivities. The 1,3-dipolar cycloaddition reaction is one of the most efficient approach for the rapid synthesis of spirooxindole analogues. Herein, we report the synthesis of a series of spirooxindolone analogues via multicomponent reaction of chalcone, based on cyclohexanone, substituted isatin (isatin, 5-Cl-isatin, and 5-Br-isatin), and secondary amine of the amino acids (L-Proline and Thioproline). The included activities of the resulting spirooxazolines, including anti-inflammatory, anti-leishmanial, and cytotoxic activity against 3T3 and HeLa cell lines. Among series of nine diphenyl substituted derivatives of spiro fused benzylidine thioazol indolines (IVa-IVi), compounds IVb (IC 50 = 5.8 � 0.9 μM), IVc (IC 50 = 2.4 � 1.3 μM), IVd (IC 50 = 5.0 � 0.6 μM), and IVg (IC 50 = 10.4 � 4.6 μM) have shown potent anti-inflammatory activity, several fold more active than the standard drug, ibuprofen (IC 50 = 11.2 � 1.9 μM). Whereas, compounds IVa (IC 50 = 18.0 � 1.1 μM), and IVh (IC 50 = 26.0 � 3.4 μM) exhibited a significant anti-inflammatory potential. All other compounds (IVe and IVf) were found to be inactive. Two meta flouro substituted phenyl rings containing compound IVc (IC 50 = 2.4 � 1.3 μM) was the most potent member of the series. In order to rationalize the observed biological activities of the spirooxindole-pyrrolothiazole derivatives, in silico studies were also performed. The results of present study identify a new series of potent anti-inflammatory agents, deserve to be further investigated as leads.[a] G. Lotfy, Dr. Y. M. A. Aziz, Prof. M. M. Said have shown a significant anti-inflammatory potential. All other compounds (VId and VIe) were found to be inactive. Two ortho, meta dichloro substituted phenyl rings containing compound VIc (IC 50 = 4.2 � 1.8 μM) was found to be the most active Scheme 1. Synthesis of target thioazol/pyrrol indolines analogues IVa-i and VIa-h.