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Discovery of hydrazide-based pyridazino[4,5-b]indole scaffold as a new phosphoinositide 3-kinase (PI3K) inhibitor for breast cancer therapy
RSC Advances ( IF 3.9 ) Pub Date : 2020-5-21 , DOI: 10.1039/d0ra02798g Ahmed A M Sarhan 1 , Ahmed T A Boraei 2 , Assem Barakat 3, 4 , Mohamed S Nafie 2
RSC Advances ( IF 3.9 ) Pub Date : 2020-5-21 , DOI: 10.1039/d0ra02798g Ahmed A M Sarhan 1 , Ahmed T A Boraei 2 , Assem Barakat 3, 4 , Mohamed S Nafie 2
Affiliation
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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 K2CO3/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 IC50 values of 4.25 and 5.35 μm compared to that of the standard drug 5-FU (IC50 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.
中文翻译：
发现基于酰肼的哒嗪并[4,5-b]吲哚支架作为用于乳腺癌治疗的新型磷酸肌醇3激酶（PI3K）抑制剂
本文中，哒嗪并[4,5- b ]吲哚的单烷基化和二烷基化反应是在K 2 CO 3 /丙酮或KOH/存在下，用包括戊基溴、烯丙基溴、苄基溴和氯乙酸乙酯在内的一组烷基化剂实现的。二甲基亚砜。单酯和二酯10和11的肼解得到目标酰肼12和13 ，它们对 MCF-7 细胞系表现出有前景的、有效的和显着的细胞毒活性，与标准药物 5-FU (IC 50 6.98 μm) 分别。对最活跃的化合物12进行 RT-PCR 分析，以确定其通过上调促凋亡基因和抑制抗凋亡基因和 PI3K/AKT/mTOR 基因的作用模式。研究结果与计算机研究中阐述的拟议机制一致。此外，体内分析通过延长 EAC 小鼠的生存参数和抑制腹水参数显示出其有效的抗癌活性。
更新日期：2020-05-21
中文翻译：
发现基于酰肼的哒嗪并[4,5-b]吲哚支架作为用于乳腺癌治疗的新型磷酸肌醇3激酶（PI3K）抑制剂
本文中，哒嗪并[4,5- b ]吲哚的单烷基化和二烷基化反应是在K 2 CO 3 /丙酮或KOH/存在下，用包括戊基溴、烯丙基溴、苄基溴和氯乙酸乙酯在内的一组烷基化剂实现的。二甲基亚砜。单酯和二酯10和11的肼解得到目标酰肼12和13 ，它们对 MCF-7 细胞系表现出有前景的、有效的和显着的细胞毒活性，与标准药物 5-FU (IC 50 6.98 μm) 分别。对最活跃的化合物12进行 RT-PCR 分析，以确定其通过上调促凋亡基因和抑制抗凋亡基因和 PI3K/AKT/mTOR 基因的作用模式。研究结果与计算机研究中阐述的拟议机制一致。此外，体内分析通过延长 EAC 小鼠的生存参数和抑制腹水参数显示出其有效的抗癌活性。
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