Next Article in Journal
A New Tetradentate Mixed Aza-Thioether Macrocycle and Its Complexation Behavior towards Fe(II), Ni(II) and Cu(II) Ions
Next Article in Special Issue
Structure-Based Design of Biologically Active Compounds
Previous Article in Journal
Beneficial Impact of Semicarbazide-Sensitive Amine Oxidase Inhibition on the Potential Cytotoxicity of Creatine Supplementation in Type 2 Diabetes Mellitus
Previous Article in Special Issue
Targeting Trypanothione Reductase, a Key Enzyme in the Redox Trypanosomatid Metabolism, to Develop New Drugs against Leishmaniasis and Trypanosomiases
 
 
Article

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

1
Department of Chemistry, College of Science, Princess Nourah bint Abdulrahman University, Riyadh 12271, Saudi Arabia
2
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Kasr El-Aini Street, Cairo 11562, Egypt
3
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, New Giza University, Newgiza, km 22 Cairo–Alexandria Desert Road, Cairo 12577, Egypt
4
Department of Biochemistry, Faculty of Pharmacy, Egyptian Russian University, Badr City, Cairo 11829, Egypt
5
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Al-Azhar University, Cairo 11651, Egypt
6
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh 33516, Egypt
7
Department of Applied Organic Chemistry, National Research Center, Dokki, Giza 12622, Egypt
8
Department of Pharmaceutical Chemistry, Pharmacy Program, Batterejee Medical College, Jeddah 6231, Saudi Arabia
9
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Ain Shams University, Abbassia, Cairo 11566, Egypt
*
Authors to whom correspondence should be addressed.
Academic Editor: Sandra Gemma
Molecules 2020, 25(9), 2031; https://doi.org/10.3390/molecules25092031
Received: 3 April 2020 / Revised: 21 April 2020 / Accepted: 23 April 2020 / Published: 27 April 2020
(This article belongs to the Special Issue Structure-Based Design of Biologically Active Compounds)
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. View Full-Text
Keywords: anti-proliferative activity; apoptosis; breast cancer; oxindole; CDK4 inhibitors anti-proliferative activity; apoptosis; breast cancer; oxindole; CDK4 inhibitors
Show Figures

Graphical abstract

MDPI and ACS Style

Al-Warhi, T.; El Kerdawy, A.M.; Aljaeed, N.; Ismael, O.E.; Ayyad, R.R.; Eldehna, W.M.; Abdel-Aziz, H.A.; Al-Ansary, G.H. Synthesis, Biological Evaluation and In Silico Studies of Certain Oxindole–Indole Conjugates as Anticancer CDK Inhibitors. Molecules 2020, 25, 2031. https://doi.org/10.3390/molecules25092031

AMA Style

Al-Warhi T, El Kerdawy AM, Aljaeed N, Ismael OE, Ayyad RR, Eldehna WM, Abdel-Aziz HA, Al-Ansary GH. Synthesis, Biological Evaluation and In Silico Studies of Certain Oxindole–Indole Conjugates as Anticancer CDK Inhibitors. Molecules. 2020; 25(9):2031. https://doi.org/10.3390/molecules25092031

Chicago/Turabian Style

Al-Warhi, Tarfah, Ahmed M. El Kerdawy, Nada Aljaeed, Omnia E. Ismael, Rezk R. Ayyad, Wagdy M. Eldehna, Hatem A. Abdel-Aziz, and Ghada H. Al-Ansary. 2020. "Synthesis, Biological Evaluation and In Silico Studies of Certain Oxindole–Indole Conjugates as Anticancer CDK Inhibitors" Molecules 25, no. 9: 2031. https://doi.org/10.3390/molecules25092031

Find Other Styles
Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

Article Access Map by Country/Region

1
Back to TopTop