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Molecules. 2018 Jun 12;23(6). pii: E1420. doi: 10.3390/molecules23061420.

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.

Author information

1
Chemistry Department, Faculty of Sciences, University of Sharjah, Sharjah 27272, UAE. m5elnaggar@yahoo.com.
2
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh 33516, Egypt. wagdy2000@gmail.com.
3
Chemistry Research Laboratory, Department of Chemistry, University of Oxford, 12 Mansfield Road, OX1 3TA Oxford, UK. hadia.almahli@yahoo.com.
4
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Egyptian Russian University, Badr City, Cairo 11829, Egypt. hadia.almahli@yahoo.com.
5
Department of Pharmacology and Toxicology, Faculty of Pharmacy, Egyptian Russian University, Badr City, Cairo 11829, Egypt. amro_elgez@yahoo.com.
6
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Egyptian Russian University, Badr City, Cairo 11829, Egypt. ph.fares@yahoo.com.
7
School of Chemistry, University of Wollongong, Wollongong 2522, New South Wales, Australia. ph.fares@yahoo.com.
8
The Regional Center for Mycology and Biotechnology, Al-Azhar University, Cairo 11759, Egypt. mmelaasser@hotmail.com.
9
Department of Applied Organic Chemistry, National Research Center, Dokki, Cairo 12622, Egypt. hatem_741@yahoo.com.

Abstract

In connection with our research program on the development of new isatin-based anticancer candidates, herein we report the synthesis of two novel series of thiazolidinone-isatin conjugates (4an) and thiazolo[3,2-a]benzimidazolone-isatin conjugates (7ad), and in vitro evaluation of their antiproliferative activity towards two breast cancer cell lines; triple negative MDA-MB-231, and MCF-7. Compounds 4m and 7b emerged as the most active congeners against MDA-MB-231 cells (IC50 = 7.6 ± 0.5 and 13.2 ± 1.1 µM, respectively). Compounds 4m and 7b were able to provoke apoptosis in MDA-MB-231 cells, evidenced by the up-regulation of Bax and down-regulation of Bcl-2, besides boosting caspase-3 levels. Hybrid 4m induced a fourfold increase in the percentage of cells at Sub-G₁, with concurrent arrest in G₂-M phase by 2.5-folds. Furthermore, hybrid 4m resulted in a sixfold increase in the percentage of annexin V-FITC positive apoptotic MDA-MB-231 cells as compared with the control. Moreover, the cytotoxic activities of the active conjugates were assessed towards two nontumorigenic cell lines (breast MCF-10A and lung WI-38) where both conjugates 4m and 7b displayed mean tumor selectivity index: 9.6 and 13.9, respectively. Finally, several ADME descriptors were predicted for the active conjugates via a theoretical kinetic study.

KEYWORDS:

QSAR; anticancer; apoptosis; isatin-thiazolidinone hybrids; triple-negative breast cancer

PMID:
29895744
PMCID:
PMC6099623
DOI:
10.3390/molecules23061420
[Indexed for MEDLINE]
Free PMC Article

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