Novel Thiazolidinone/Thiazolo[3,2-a]Benzimidazolone-Isatin Conjugates as Apoptotic Anti-proliferative Agents Towards Breast Cancer: One-Pot Synthesis and In Vitro Biological Evaluation

El‐Naggar, Mohamed; Eldehna, Wagdy M.; Almahli, Hadia; Elgez, Amr; Farès, Mohamed; Elaasser, Mahmoud M.; Abdel‐Aziz, Hatem A.

doi:10.3390/molecules23061420

Cited by 57 publications

(33 citation statements)

References 53 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Apoptosis study. The levels of the apoptotic markers caspase-3, caspase-9, p53 and Bax, as well as the anti-apoptotic marker Bcl-2 were evaluated by the use of ELISA colorimetric kits per the manufacturer's instructions, as reported earlier 28,29 . Furthermore, the pro-apoptotic potential of spirooxindole 6a towards HepG2 cells was assessed using FITC Annexin V Apoptosis Detection Kit by flow cytometry, according to the manufacturer's protocol and referring to the reported procedures 30,31 .…”

Section: Biological Evaluationmentioning

confidence: 99%

“…Furthermore, spirooxindoles 6 h, 6k and 6n-6p displayed moderate antiradical activity with IC 50 values of 46. 29 Ferric reducing antioxidant power (FRAP). FRAP assay is a widely used antioxidant assay that uses antioxidant substances as reducing agents in a redox-linked colorimetric reaction, wherein Fe 3þ is reduced to Fe 2þ at acidic pH that results in a formation of a coloured ferrous-probe complex from a colourless ferric-probe complex 35 .…”

Section: Biological Evaluationmentioning

confidence: 99%

See 1 more Smart Citation

Antitumor properties of certain spirooxindoles towards hepatocellular carcinoma endowed with antioxidant activity

Al-Rashood

Hamed

Hassan

et al. 2020

Journal of Enzyme Inhibition and Medicinal Chemistry

View full text Add to dashboard Cite

In the current medical era, spirooxindole motif stands out as a privileged heterospirocyclic scaffold that represents the core for a wide range of bioactive naturally isolated products (such as Strychnofoline and spirotryprostatins A and B) and synthetic compounds. Interestingly, no much attention has been paid to develop spirooxindole derivatives with dual antioxidant and anticancer activities. In this context, a series of spirooxindoles 6a-p was examined for their anticancer effect towards HepG2 hepatocellular carcinoma and PC-3 prostate cancer cell lines. Spirooxindole 6a was found to be an efficient anti-proliferative agent towards both HepG2 and PC-3 cells (IC50 ¼ 6.9 and 11.8 mM, respectively). Afterwards, spirooxindole 6a was assessed for its apoptosis induction potential in HepG2 cells, where its pro-apoptotic impact was approved via the significant elevation in the Bax/Bcl-2 ratio and the expression levels of caspase-3, ARTICLE HISTORY

show abstract

Section: Biological Evaluationmentioning

confidence: 99%

Section: Biological Evaluationmentioning

confidence: 99%

Antitumor properties of certain spirooxindoles towards hepatocellular carcinoma endowed with antioxidant activity

Al-Rashood

Hamed

Hassan

et al. 2020

Journal of Enzyme Inhibition and Medicinal Chemistry

View full text Add to dashboard Cite

show abstract

“…The influence of bis-indoles 7e and 9a on cell cycle progression was examined in breast cancer MCF-7 cells, after 24 h of treatment, through DNA flow cytometric assay by the use of BD FACS Caliber flow cytometer, as described previously [27]. The cell cycle distributions were calculated using CellQuest software (Becton Dickinson).…”

Section: Cell Cycle Analysismentioning

confidence: 99%

“…The apoptotic action of bis-indoles 7e and 9a was further explored through the investigation of their effect on the phosphatidylserine externalization in breast cancer MCF-7 cells, using Annexin-V-FITC Apoptosis Detection Kit according to manufacturer's protocol, as reported earlier [27].…”

Section: Annexin V-fitc/pi Apoptosis Assaymentioning

confidence: 99%

Marine-Inspired Bis-indoles Possessing Antiproliferative Activity against Breast Cancer; Design, Synthesis, and Biological Evaluation

et al. 2020

View full text Add to dashboard Cite

Diverse indoles and bis-indoles extracted from marine sources have been identified as promising anticancer leads. Herein, we designed and synthesized novel bis-indole series 7a–f and 9a–h as Topsentin and Nortopsentin analogs. Our design is based on replacing the heterocyclic spacer in the natural leads by a more flexible hydrazide linker while sparing the two peripheral indole rings. All the synthesized bis-indoles were examined for their antiproliferative action against human breast cancer (MCF-7 and MDA-MB-231) cell lines. The most potent congeners 7e and 9a against MCF-7 cells (IC50 = 0.44 ± 0.01 and 1.28 ± 0.04 μM, respectively) induced apoptosis in MCF-7 cells (23.7-, and 16.8-fold increase in the total apoptosis percentage) as evident by the externalization of plasma membrane phosphatidylserine detected by Annexin V-FITC/PI assay. This evidence was supported by the Bax/Bcl-2 ratio augmentation (18.65- and 11.1-fold compared to control) with a concomitant increase in the level of caspase-3 (11.7- and 9.5-fold) and p53 (15.4- and 11.75-fold). Both compounds arrested the cell cycle mainly in the G2/M phase. Furthermore, 7e and 9a displayed good selectivity toward tumor cells (S.I. = 38.7 and 18.3), upon testing of their cytotoxicity toward non-tumorigenic breast MCF-10A cells. Finally, compounds 7a, 7b, 7d, 7e, and 9a were examined for their plausible CDK2 inhibitory action. The obtained results (% inhibition range: 16%–58%) unveiled incompetence of the target bis-indoles to inhibit CDK2 significantly. Collectively, these results suggested that herein reported bis-indoles are good lead compounds for further optimization and development as potential efficient anti-breast cancer drugs.

show abstract

“…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

View full text Add to dashboard Cite

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.

show abstract

Novel Thiazolidinone/Thiazolo[3,2-a]Benzimidazolone-Isatin Conjugates as Apoptotic Anti-proliferative Agents Towards Breast Cancer: One-Pot Synthesis and In Vitro Biological Evaluation

Cited by 57 publications

References 53 publications

Antitumor properties of certain spirooxindoles towards hepatocellular carcinoma endowed with antioxidant activity

Antitumor properties of certain spirooxindoles towards hepatocellular carcinoma endowed with antioxidant activity

Marine-Inspired Bis-indoles Possessing Antiproliferative Activity against Breast Cancer; Design, Synthesis, and Biological Evaluation

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

Contact Info

Product

Resources

About