Search

The our previous study synthesized the chrysin-chromene-spirooxindole hybrids 3, and further found compound 3e had good antitumor activity against A549 cells in vitro through multi-target co-regulation of the p53 signalling pathway to inhibit the proliferation of A549 cells. This study was designed to evaluate the antitumor effects of compound 3e on Lewis lung carcinoma of C57BL/6 mice in vivo. Compound 3e significantly inhibited the growth of transplanted tumors in C57BL/6 mice and induced the apoptosis of tumor cells. Further studies showed that compound 3e activates and expands the anti-cancer activity of p53 by inhibiting the expression of MDM2, Akt and 5-Lox proteins, accordingly promotes the expressions Bax and inhibit the Bcl-2 protein, the release of Cyt c as well, which resulted in the activation of apoptotic pathway in tumor cells eventually. Moreover, Compound 3e inhibited tumor metastasis by down-regulating VEGF, ICAM-1 and MMP-2 protein expression and angiogenesis. These results suggested that compound 3e exerts an effective antitumor activity in vivo through activating the p53 signaling pathway, which could be exploited as a promising candidate for the development of new anti-tumour drugs., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

The first example of Ca(OH) 2 -activated p-regioselective synthesis of chrysin-fused chromene was reported through a cascade Michael/cyclization of chrysin and arylidenemalononitrile. The newly synthesized structurally diverse 2-amino 3-cyano chromene-chrysin hybrids 3 were evaluated for their in vitro anticancer activity, and some of the compounds showed stronger anti-proliferative activity against K562, PC-3, A549 and NCI-H1299 than parent compound chrysin, and demonstrated equipotent potency compared with the reference drug of cisplatin. In particular, compound 3h had the highest cytotoxicity towards K562 cells (IC 50  = 6.41 µM). Furthermore, compound 3h induced apoptosis of K562 cells in a concentration-dependent manner, as well as induced the apoptosis possibly through promoting the formation of apoptotic DNA of cancer cell via the intrinsic apoptotic pathway. Thus, our results provide in vitro evidence that compound 3h may be a potential candidate for the development of new anti-tumour drugs., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

A series of structurally diverse chrysin-chromene-spirooxindole hybrids were designed, synthesized via a Knoevenagel/Michael/cyclization of chrysin and isatylidene malononitrile derivatives through utilizing a hybrid pharmacophore approach. The newly synthesized compounds were evaluated for their in vitro anticancer activity, and most of the compounds showed stronger anti-proliferative activity than parent compound chrysin. In particular, compound 3e had the highest cytotoxicity towards A549 cells (IC 50  = 3.15 ± 0.51 μM), and had better selectivity in A549 cells and normal MRC-5 cells. Furthermore, compound 3e could significantly inhibit the proliferation and migration of A549 cells in a dose-dependent manner, as well as induce the apoptosis possibly through mitochondria-mediated caspase-3/8/9 activation and multi-target co-regulation of the p53 signaling pathway. Thus, our results provide in vitro evidence that compound 3e may be a potential candidate for the development of new anti-tumour drugs., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Two series of 1,4-naphthoquinone-chromone hybrids 4a (4aa–4ao) and 4b (4ba–4bq) were designed, synthesized and evaluated as antitumor agents. Most of the compounds exhibited moderate to excellent cytotoxicity to tumor cells (K562 and A549), especially the 4a series compounds that showed equal or stronger antiproliferative activity compared to positive control cisplatin on two different types of cells (except for 4al and 4an). Among them, compound 4ac showed significant inhibitory activity on A549 cells with an IC50 value of 2.93 μM, and was 5.2 times more active than cisplatin (IC50 = 15.32 ± 2.64 μM). Meanwhile, AO/EB staining, flow cytometry, cell morphology, and ultrastructural analysis revealed that compound 4ac could induce A549 cell apoptosis and arrest at the G1 phase. Further mechanism studies speculated that compound 4ac may regulate the p53-MDM2 pathway, alter the Bax/Bcl-2 ratio to release Cyt c, activate the mitochondrial apoptosis pathway to induce cell apoptosis, and inhibit A549 cell proliferation through cycle arrest. Collectively, compound 4ac could be used as a potential candidate compound for anti-lung cancer drugs. [ABSTRACT FROM AUTHOR]

Developed herein is a diversity-oriented one-pot multicomponent synthesis of polycyclic 3,3′- pyrrolidinyl-dispirooxindoles 3 via a multicomponent 1,3-dipolar cycloaddition event of 3-methyl-4-nitro-5-isatylidenyl-isoxazoles 2 with azomethine ylides (thermally generated in situ from isatins and proline or thioproline). Products bearing four consecutive stereocenters consist of two oxindole moieties and a polycyclic pyrrolidinyl core, including vicinal spiroquaternary stereocenters fused in one ring structure were smoothly obtained in high yields (up to 85% yield) with good diastereoselectivity (up to >20:1). Valuable features of this method were application of 3-methyl-4-nitro-5-isatylidenyl-isoxazoles as 1,3-dipolarophiles and the design of new hybrid architectures for biological screenings through the adequate fusion of these sub-units of isoxazole and 3,3′-pyrrolidinyl-dispirooxindole, generating drug-like molecules. [ABSTRACT FROM AUTHOR]

Developed herein is a facile and efficient methodology toward the synthesis of novel turmerone motif-fused spiropyrrolidine oxindoles via a multicomponent 1,3-dipolar cycloaddition event of dienones 2 with azomethine ylides (thermally generated in situ from isatin derivatives and sarcosine). Products bearing adjacent quaternary–tertiary centers were smoothly obtained in high yields (up to 93% yield) with good diastereoselectivity (up to >20:1). In addition, their biological activity has been preliminarily demonstrated by in vitro evaluation against human lung cancer cells A549 and human leukemia cells K562 by the MTT-based assays, using the commercially available standard drug of Cisplatin as a positive control. The results also demonstrated that most of the compounds showed considerable cytotoxicities to these two cell lines of K562 and A549, showed comparably potent or even more potent than the positive control of Cisplatin (up to 5.1 times), and indicated that novel turmerone motif-fused spiropyrrolidine oxindoles may be potential leads for further biological screenings and may generate drug-like molecules. [ABSTRACT FROM AUTHOR]

Facile and efficient methodology for the synthesis of novel turmerone motif-fused spiropyrrolidine oxindoles via a multicomponent 1,3-dipolar cycloaddition reaction of dienones with azomethine ylides is reported. [ABSTRACT FROM AUTHOR]