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.
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).
a Department of Pharmaceutical Chemistry, Faculty of Pharmacy , Egyptian Russian University , Badr City, Cairo , Egypt.
Wagdy M
WM
Eldehna
a Department of Pharmaceutical Chemistry, Faculty of Pharmacy , Egyptian Russian University , Badr City, Cairo , Egypt.|b Department of Chemistry, Faculty of Pharmacy , University of Oxford , Oxford , UK.
Hadia
H
Almahli
c Department of Pharmaceutical Chemistry, Faculty of Pharmacy , Ain Shams University , Cairo , Abbassia , Egypt.
Ghada H
GH
Al-Ansary
d Department of Pharmaceutical Chemistry, College of Pharmacy , King Saud University , Riyadh , Saudi Arabia.
Hazem A
HA
Ghabbour
e Department of Pharmacology and Toxicology, Faculty of Pharmacy , British University in Egypt , Cairo , Egypt.|f Department of Biology , The American University in Cairo , New Cairo , Egypt.
Mohamed H
MH
Aly
g Department of Biochemistry, Faculty of Pharmacy , Egyptian Russian University , Badr City, Cairo , Egypt.
Omnia E
OE
Ismael
h Stem Cell & Tissue Re-Engineering Program, Research Center , King Faisal Specialized Hospital & Research Center , Riyadh , Saudi Arabia.
Abdullah
A
Al-Dhfyan
i Department of Applied Organic Chemistry , National Research Center, Dokki , Giza , Egypt.
Hatem A
HA
Abdel-Aziz
D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D005260:Female; D006801:Humans; D006834:Hydrazines / Q000494:pharmacology*; D066298:In Vitro Techniques; D007510:Isatin / Q000494:pharmacology*; D010793:Phthalazines / Q000494:pharmacology*; D064726:Triple Negative Breast Neoplasms / Q000473:pathology*
D006834:Hydrazines; D010793:Phthalazines; D007510:Isatin
Isatin; phthalazine; quinazoline; synthesis; triple-negative breast cancer