Discovery of hydrazide-based pyridazino[4,5- b ]indole scaffold as a new phosphoinositide 3-kinase (PI3K) inhibitor for breast cancer therapy.
Ahmed A M SarhanAhmed T A BoraeiAssem BarakatMohamed S NafiePublished in: RSC advances (2020)
Herein, the mono and dialkylation of pyridazino[4,5- b ]indole were achieved with a set of alkylating agents, including amyl bromide, allyl bromide, benzyl bromide and ethyl chloroacetate in the presence of K 2 CO 3 /acetone or KOH/DMSO. The hydrazinolysis of mono and di-esters 10 and 11 gave the target hydrazides 12 and 13, which displayed promising, potent, and significant cytotoxic activity against the MCF-7 cell line with IC 50 values of 4.25 and 5.35 μm compared to that of the standard drug 5-FU (IC 50 6.98 μm), respectively. RT-PCR analysis of the most active compound 12 was performed to determine its mode of action through the up-regulation of pro-apoptotic genes and inhibition of anti-apoptotic and PI3K/AKT/mTOR genes. The findings were consistent with the proposed mechanism illustrated in the in silico study. Further, the in vivo analysis exhibited its potent anti-cancer activity through the prolongation of survival parameters, and inhibition of ascetic fluid parameters in EAC-bearing mice.
Keyphrases
- anti inflammatory
- cancer therapy
- cell death
- genome wide
- small molecule
- drug delivery
- genome wide identification
- drug induced
- high throughput
- breast cancer cells
- dna methylation
- ionic liquid
- emergency department
- protein kinase
- adipose tissue
- skeletal muscle
- free survival
- escherichia coli
- genome wide analysis
- staphylococcus aureus
- candida albicans