Format

Send to

Choose Destination
J Enzyme Inhib Med Chem. 2017 Dec;32(1):600-613. doi: 10.1080/14756366.2017.1279155.

Synthesis and in vitro anti-proliferative activity of some novel isatins conjugated with quinazoline/phthalazine hydrazines against triple-negative breast cancer MDA-MB-231 cells as apoptosis-inducing agents.

Author information

1
a Department of Pharmaceutical Chemistry, Faculty of Pharmacy , Egyptian Russian University , Badr City, Cairo , Egypt.
2
b Department of Chemistry, Faculty of Pharmacy , University of Oxford , Oxford , UK.
3
c Department of Pharmaceutical Chemistry, Faculty of Pharmacy , Ain Shams University , Cairo , Abbassia , Egypt.
4
d Department of Pharmaceutical Chemistry, College of Pharmacy , King Saud University , Riyadh , Saudi Arabia.
5
e Department of Pharmacology and Toxicology, Faculty of Pharmacy , British University in Egypt , Cairo , Egypt.
6
f Department of Biology , The American University in Cairo , New Cairo , Egypt.
7
g Department of Biochemistry, Faculty of Pharmacy , Egyptian Russian University , Badr City, Cairo , Egypt.
8
h Stem Cell & Tissue Re-Engineering Program, Research Center , King Faisal Specialized Hospital & Research Center , Riyadh , Saudi Arabia.
9
i Department of Applied Organic Chemistry , National Research Center, Dokki , Giza , Egypt.

Abstract

Treatment of patients with triple-negative breast cancer (TNBC) is challenging due to the absence of well- defined molecular targets and the heterogeneity of such disease. In our endeavor to develop potent isatin-based anti-proliferative agents, we utilized the hybrid-pharmacophore approach to synthesize three series of novel isatin-based hybrids 5a-h, 10a-h and 13a-c, with the prime goal of developing potent anti-proliferative agents toward TNBC MDA-MB-231 cell line. In particular, compounds 5e and 10g were the most active hybrids against MDA-MB-231 cells (IC50 = 12.35 ± 0.12 and 12.00 ± 0.13 μM), with 2.37- and 2.44-fold increased activity than 5-fluorouracil (5-FU) (IC50 = 29.38 ± 1.24 μM). Compounds 5e and 10g induced the intrinsic apoptotic mitochondrial pathway in MDA-MB-231; evidenced by the reduced expression of the anti-apoptotic protein Bcl-2, the enhanced expression of the pro-apoptotic protein Bax and the up-regulated active caspase-9 and caspase-3 levels. Furthermore, 10g showed significant increase in the percent of annexin V-FITC positive apoptotic cells from 3.88 to 31.21% (8.4 folds compared to control).

KEYWORDS:

Isatin; phthalazine; quinazoline; synthesis; triple-negative breast cancer

PMID:
28173708
PMCID:
PMC6010087
DOI:
10.1080/14756366.2017.1279155
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Taylor & Francis Icon for PubMed Central
Loading ...
Support Center