Design and Synthesis of Novel Imatinib Analogs as Antitumor Multi-target Kinase Inhibitors
Iten Mamdouh Fawzy Abd El-Moteleb;
Abstract
Cancer is a life-threatening disease and a leading cause of death. Although a range of therapies based on chemotherapy, surgery, and radiotherapy are available, yet they are of limited efficacy. Moreover, current anticancer regimens are associated with significant levels of toxicity and serious adverse side-effects. Hence, many research projects have been focused on developing new chemotherapies with minimal side-effects on mammalian cells. Targeted therapies became one of the eminent principles of drug design and development nowadays to combat cancer.
Imatinib (Gleevec, STI571) became one of the most popular targeted drugs which was approved by FDA for the treatment of chronic myeloid leukemia (CML) as well as various types of cancer. It was proved that imatinib had a potential role in the treatment of non-small cell lung cancer. Additionally, imatinib showed effective inhibition to all epithelial colon cancer cell lines. In fact, imatinib possess loads of proposed mechanisms to fight cancer, the foremost of which is that it acts as tyrosine kinase inhibitor especially against Bcr-Abl. Surprisingly, imatinib anti-tumor activity expressed another evolved mechanism; it had the ability to suppress CrKl phosphorylation level. Moreover, it arrested cell cycle at Go/G1 of K562 cells and dramatically activated caspase-3 together with downstream substrates PARP thus it induced apoptosis.
Unfortunately, imatinib faced resistance in CML patients, due to a point mutation in the kinase domain of Bcr-Abl which leads to disruption in the binding site of imatinib on the tyrosine kinase. Consequently, extensive research had led to the production of second generation of tyrosine kinase inhibitors (TKIs) as dasatnib, nilotinib, bosutinib and ponatinib which showed less resistance and less intolerance than imatinib. Although many new potent (TKIs) are in market, imatinib still represents the front-line therapy for cancer treatment.
The current study aimed to design “two series” of analogs to act as anti-tumor agents.
Imatinib (Gleevec, STI571) became one of the most popular targeted drugs which was approved by FDA for the treatment of chronic myeloid leukemia (CML) as well as various types of cancer. It was proved that imatinib had a potential role in the treatment of non-small cell lung cancer. Additionally, imatinib showed effective inhibition to all epithelial colon cancer cell lines. In fact, imatinib possess loads of proposed mechanisms to fight cancer, the foremost of which is that it acts as tyrosine kinase inhibitor especially against Bcr-Abl. Surprisingly, imatinib anti-tumor activity expressed another evolved mechanism; it had the ability to suppress CrKl phosphorylation level. Moreover, it arrested cell cycle at Go/G1 of K562 cells and dramatically activated caspase-3 together with downstream substrates PARP thus it induced apoptosis.
Unfortunately, imatinib faced resistance in CML patients, due to a point mutation in the kinase domain of Bcr-Abl which leads to disruption in the binding site of imatinib on the tyrosine kinase. Consequently, extensive research had led to the production of second generation of tyrosine kinase inhibitors (TKIs) as dasatnib, nilotinib, bosutinib and ponatinib which showed less resistance and less intolerance than imatinib. Although many new potent (TKIs) are in market, imatinib still represents the front-line therapy for cancer treatment.
The current study aimed to design “two series” of analogs to act as anti-tumor agents.
Other data
| Title | Design and Synthesis of Novel Imatinib Analogs as Antitumor Multi-target Kinase Inhibitors | Other Titles | تصميم وتشييد نظائر جديدة لدواء الإيماتينيب ذات نشاط ضد السرطان كمثبطات لعدد من إنزيمات الكيناز | Authors | Iten Mamdouh Fawzy Abd El-Moteleb | Issue Date | 2018 |
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