Isatin-benzoazine molecular hybrids as potential antiproliferative agents: synthesis and in vitro pharmacological profiling

Abdel‐Aziz, Hatem A.; Eldehna, Wagdy M.; Keeton, Adam B.; Piazza, Gary A.; Kadi, Adnan A.; Attwa, Mohamed W.; Attia, Mohamed I.

doi:10.2147/dddt.s140164

Cited by 57 publications

(25 citation statements)

References 45 publications

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“…Isatin (1H-indole-2, 3-dione), a precursor for many pharmacologically active compounds, [2][3][4] is an important medicinal chemistry. 5 Isatin derivatives have extensive biological activities, such as antitumor, anti-HIV, antiinflammatory, anti-convulsion, antidepressant, and antifungal effects, 5 attracting much attention.…”

Section: Introductionmentioning

confidence: 99%

<p>The Acetone Indigo Red Dehydrating Agent IF203 Induces HepG2 Cell Death Through Cell Cycle Arrest, Autophagy and Apoptosis</p>

Shang¹,

Wang²,

Li³

et al. 2020

OTT

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Background: Isatin derivatives have extensive biological activities, such as antitumor. IF203, a novel isatin derivative, has not previously been reported to have antitumor activity. Methods: Acid phosphatase assays (APAs) and Ki-67 immunohistochemistry were used to detect the proliferation of HepG2 cells. Transmission electron microscope (TEM) was applied to detect ultrastructural changes. Flow cytometry (FCM) was used to detect cell cycle, apoptosis, reactive oxygen species (ROS) and mitochondrial membrane potential (MMP) of HepG2 cells in vitro. TUNEL, MMP and ROS immunofluorescence assays were applied to assess apoptosis, MMP, and ROS of HepG2 cells in vivo. Western Blotting was applied to assess the levels of apoptosis-and autophagy-related proteins. Results: In this study, in vivo and in vitro experiments showed that IF203 possesses antitumor activity. The results of APAs and Ki-67 immunohistochemistry demonstrated that IF203 could inhibit the proliferation of HepG2 cells. Cell cycle assays, downregulation of Cyclin B1 and Cdc2, and upregulation of P53 suggested that IF203 could lead to G2/M cell cycle arrest. In addition, ultrastructural changes, apoptosis assays, TUNEL immunofluorescence results, upregulated expression of Bax, and downregulated expression of Bcl-2 suggest that IF203 can induce apoptosis in HepG2 cells. After IF203 treatment, intracellular ROS levels increased, MMP decreased, JC-1 green fluorescence was enhanced, and the levels of Caspase-9, Caspase-3 and Cytochrome C expression were upregulated, suggesting that IF203 could induce apoptosis of HepG2 cells through the mitochondrial apoptosis pathway. Moreover, characteristic apoptotic ultrastructural changes were accompanied by the appearance of many autophagy bubbles and upregulation of Atg5, Atg12, ULK1, Beclin-1 and LC3-II proteins, suggesting that IF203 could induce autophagy in HepG2 cells. Conclusion: This study showed that IF203 leads to the death of HepG2 cells through cell cycle arrest, apoptotic induction, and autophagy promotion.

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Section: Introductionmentioning

confidence: 99%

<p>The Acetone Indigo Red Dehydrating Agent IF203 Induces HepG2 Cell Death Through Cell Cycle Arrest, Autophagy and Apoptosis</p>

Shang¹,

Wang²,

Li³

et al. 2020

OTT

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“…The anticancer SAR of hybrids 56 against HT‐29, ZR‐75, and A549 cancer cell lines revealed that substituent at the C‐5 position of isatin skeleton influenced the activity greatly and halogen atom could improve the activity. [ 117 ] Three of them, 56a–c (IC 50 : 5.31–13.25 μM, MTT assay), were comparable to or better than sunitinib (IC 50 : 5.87–10.14 μM) against HT‐29, ZR‐75, and A549 cancer cell lines, and compound 56b (IC 50 : 9.5 μM) was also active against multidrug‐resistant NCI‐H69AR lung cancer cells. Moreover, this hybrid exhibited an increase in the G1 phase and a decrease in the S and G2/M phases in the cell‐cycle effect assay.…”

Section: Isatin–coumarin Hybridsmentioning

confidence: 99%

Recent advances in isatin hybrids as potential anticancer agents

Ding

Zhou

Zeng

2020

Archiv der Pharmazie

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The isatin framework is a useful template for the development of novel anticancer agents. This is exemplified by the fact that several isatin‐based anticancer agents, such as semaxanib, sunitinib, nintedanib, and hesperadin, are already in use or under clinical trials for the treatment of diverse kinds of cancers. Isatin‐based hybrids could be obtained by incorporating other anticancer pharmacophores into the isatin skeleton and they have the potential to overcome drug resistance with reduced side effects. Thus, isatin‐based hybrids may provide attractive scaffolds for the development of novel anticancer agents. This review covers the recent advances of isatin‐based hybrids with anticancer activity, covering articles published between 2001 and 2019. The anticancer activities of these molecules and the structure–activity relationships are also discussed. The purpose of this review article is to set up the direction for the design and development of isatin‐based hybrids with high efficacy and low toxicity.

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“…It is thought that conjugating two or more pharmacophoric subunits from different biologically active molecules in the molecular architecture of a single hybrid compound might reduce the risk of drug-drug interactions, overcome the drug resistance, and enhance the biological activity via the potential interaction with two targets as one single entity [31]. In this field, our research group has reported many studies concerning the development of efficient oxindole-based anticancer hybrids (hybrids I-III [32][33][34], Figure 1) that exhibited different enzymatic and cellular targets such as apoptosis induction in different human cancer cell lines [35,36], inhibition of cancer-related carbonic anhydrase IX isoform [37,38], in addition to inhibition of tyrosine kinases [39,40].…”

Section: Introductionmentioning

confidence: 99%

Synthesis, Biological Evaluation and In Silico Studies of Certain Oxindole–Indole Conjugates as Anticancer CDK Inhibitors

Al-Warhi,

El Kerdawy,

Aljaeed

et al. 2020

Molecules

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On account of their overexpression in a wide range of human malignancies, cyclin-dependent kinases (CDKs) are among the most validated cancer targets, and their inhibition has been featured as a valuable strategy for anticancer drug discovery. In this study, a hybrid pharmacophore approach was adopted to develop two series of oxindole–indole conjugates (6a–i and 9a–f) and carbocycle–indole conjugates (11a,b) as efficient antitumor agents with potential inhibitory action toward CDK4. All oxindole–indole conjugates, except 6i, 9b, and 9c efficiently affected the growth of the human breast cancer MCF-7 (IC50: 0.39 ± 0.05–21.40 ± 1.58 μM) and/or MDA-MB-231 (IC50: 1.03 ± 0.04–22.54 ± 1.67 μM) cell lines, whereas bioisosteric replacement of the oxindole nucleus with indane or tetralin rings (compounds 11a,b) diminished the anti-proliferative activity. In addition, hybrids 6e and 6f displayed effective cell cycle disturbance and proapoptotic capabilities in MCF-7 cells. Furthermore, the efficient anti-proliferative agents towards MCF-7 and/or MDA-MB-231 cell lines (6a–h, 9a, and 9e) were investigated for their potential inhibitory action toward CDK4. Hybrids 6a and 6e displayed good CDK4 inhibitory activity with IC50s equal 1.82 and 1.26 µM, respectively. The molecular docking study revealed that oxindole moiety is implicated in two H-bonding interactions via both (NH) and (C=O) groups with the key amino acids Glu94 and Val96, respectively, whereas the indole framework is stably accommodated in a hydrophobic sub-pocket establishing hydrophobic interactions with the amino acid residues of Ile12, Val20, and Gln98 lining this sub-pocket. Collectively, these results highlighted hybrids 6a and 6e as good leads for further optimization as promising antitumor drugs toward breast malignancy and CDK inhibitors.

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Isatin-benzoazine molecular hybrids as potential antiproliferative agents: synthesis and in vitro pharmacological profiling

Cited by 57 publications

References 45 publications

<p>The Acetone Indigo Red Dehydrating Agent IF203 Induces HepG2 Cell Death Through Cell Cycle Arrest, Autophagy and Apoptosis</p>

<p>The Acetone Indigo Red Dehydrating Agent IF203 Induces HepG2 Cell Death Through Cell Cycle Arrest, Autophagy and Apoptosis</p>

Recent advances in isatin hybrids as potential anticancer agents

Synthesis, Biological Evaluation and In Silico Studies of Certain Oxindole–Indole Conjugates as Anticancer CDK Inhibitors

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