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Design, Synthesis, and Photochemical Properties of Clickable Caged Compounds
Published on: October 15, 2019
Controlled microwave-assisted reactions: A facile synthesis of polyfunctionally substituted phthalazines as dual EGFR
Maiiada Hassan Nazmy1, Ramadan Ahmed Mekheimer2, Mai E Shoman3
1Biochemistry Department, Faculty of Pharmacy, Minia University, Minia 61519, Egypt.
Abstract:
Brain tumors are stubborn cancers with poor prognosis and disappointing survival rates. Targeted cancer therapeutics with higher efficacy and lower resistance are highly demanded. An efficient one-pot synthesis of polyfunctionalized phthalazines derivatives was developed by reacting ethyl 1-aryl-5-cyano-1,6-dihydro-4-methyl-6-oxo-3-pyridazine-carboxylates with cinnamonitrile derivatives and the cycloaddition reaction of thieno[3,4-d]pyridazines with activated double or triple bond systems under controlled microwave heating with high yields. The resultant synthesized phthalazines (5a-e, 9 and 13) were tested for their in vitro anti-cancer activities by using in vitro one dose assay at National Cancer institute, USA. Only phthalazine (5b) showed broad spectrum anti-tumor activity against most tested cancer cell lines from all subpanels with mean % GI = 22.61. Interestingly, all tested compounds showed varying growth inhibitory activity against a particular cell line, CNS SNB-75 cell line, but (5b) exhibited the highest growth inhibitory activity against CNS-SNB-75 cell line with (GI% = 108.81) and (IC50 = 3.703 ± 0.2) compared to erlotinib; (IC50 = 12.5 ± 0.68). It caused Pre-G1 apoptosis and growth arrest at S phase. It also increased percentage of the total apoptotic cells in CNS-SNB-75 cell line (39.26%) compared to control cells (2.17%) in the annexin V-FITC experiment. It revealed pronounced EGFR inhibitory activity (IC50 = 47.27 ± 2.41 ng/mL) compared to erlotinib (IC50 = 30.7 ± 1.56 ng/mL). It also inhibited the different PI3K isoforms α, β, γ and δ (with IC50 of 4.39, 13.6, 12.5 and 3.11 μg/mL, respectively compared to LY294002 (with IC50 of 12.7, 8.57, 6.89 and 5.7 μg/mL, respectively). It also caused significant lower protein expression levels of pPI3K, AKT, pAKT and Bcl2 and higher protein expression levels of BAX, Casp3 and Casp9 when compared to untreated cells. Conclusion: Phthalazine (5b) may be an effective, convenient and safe anti-cancer agent acting via proapoptotic and dual EGFR and PI3K kinase inhibitory actions in CNS SNB-75 cell line.
Insights
A novel phthalazine derivative, (5b), demonstrates significant anti-cancer potential against brain tumors. This compound effectively inhibits tumor growth and induces apoptosis, offering a promising new therapeutic avenue for brain cancer treatment.
Area of Science:
- Medicinal Chemistry
- Oncology
- Molecular Biology
Background:
- Brain tumors present a significant challenge in cancer therapy due to poor prognosis and limited treatment options.
- There is a critical need for novel targeted cancer therapeutics with improved efficacy and reduced resistance.
- Phthalazine derivatives are being explored for their potential anti-cancer properties.
Purpose of the Study:
- To synthesize novel polyfunctionalized phthalazine derivatives using an efficient one-pot method.
- To evaluate the in vitro anti-cancer activities of the synthesized phthalazines against various cancer cell lines.
- To investigate the mechanism of action of the most potent phthalazine derivative, specifically its effects on apoptosis and key signaling pathways.
Main Methods:
- One-pot synthesis of phthalazine derivatives via reactions involving pyridazine carboxylates, cinnamonitrile derivatives, and thieno[3,4-d]pyridazines under microwave irradiation.
- In vitro anti-cancer activity assessment using a one-dose assay against a panel of cancer cell lines at the National Cancer Institute.
- Detailed mechanistic studies including cell cycle analysis, apoptosis assays (Annexin V-FITC), EGFR and PI3K kinase inhibition assays, and Western blot analysis of key proteins involved in apoptosis and signaling pathways.
Main Results:
- Phthalazine derivative (5b) exhibited broad-spectrum anti-tumor activity, with significant growth inhibition across multiple cancer cell lines.
- Compound (5b) demonstrated superior growth inhibitory activity and lower IC50 values against the CNS SNB-75 cell line compared to erlotinib.
- Mechanistic studies revealed that (5b) induces Pre-G1 apoptosis and S-phase arrest, significantly increases apoptosis, potently inhibits EGFR and PI3K isoforms, and modulates key apoptotic and signaling proteins (e.g., BAX, Casp3, pPI3K, AKT).
Conclusions:
- Phthalazine derivative (5b) shows significant promise as a novel anti-cancer agent, particularly for CNS tumors.
- The anti-cancer effects of (5b) are mediated through pro-apoptotic mechanisms and dual inhibition of EGFR and PI3K signaling pathways.
- Compound (5b) represents a potential safe and effective therapeutic candidate for brain cancer treatment.
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