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Tumor anti-initiating activity of some novel 3,4-dihydropyrimidinones
Hanaa A Tawfik1, Fatma Bassyouni, Amira M Gamal-Eldeen
1Department of Chemistry of Natural Products, Center of Excellence dor Advanced Science, National Research Centre, Dokki 12622, Cairo, Egypt.
Abstract:
Halting the tumor initiation process by targeting the inhibition of the carcinogens metabolic activators (CYP), the induction of the carcinogen detoxification enzymes (glutathione-S-transferases, GSTs), and the induction of antioxidant activity is an effective strategy. Since several dihydropyrimidine derivatives (Biginelli compounds) are therapeutically active, the present study aimed to synthesize some dihydropyrimidines with multifunctional aromatic substitutions and to investigate their effects as anti-initiating agents. Twelve compounds were synthesized and structurally elucidated. The results revealed that compound 10 was a non-cytotoxic inhibitor of cytochrome P 450 1A (Cyp1A) activity, inducer of GST activity, scavenger of OH and inhibitor of DNA fragmentation. Compounds 1 and 9 were radical scavengers of OH and inhibitors of DNA fragmentation. On the other hand, all compounds were not toxic against different tumor cells, except compounds 2, 4, and 5 possessed non specific cytotoxicity against both liver and colon carcinoma cells, while 7 possessed specific cytotoxicity only against colon carcinoma cells. Compound 1 was a non-cytotoxic inducer of GST activity, scavenger of OH and ROO, and inhibitor of DNA fragmentation. The present study proved that compounds 10 and 1 were active and safe tumor anti-initiating and multi-potent blocking agent.
Insights
This study synthesized dihydropyrimidines as potential anti-cancer agents. Compounds 1 and 10 demonstrated significant tumor initiation inhibition and detoxification properties without toxicity.
Area of Science:
- Medicinal Chemistry
- Cancer Research
- Drug Discovery
Background:
- Tumor initiation can be halted by inhibiting carcinogen activators (CYP), inducing detoxification enzymes (GSTs), and boosting antioxidant activity.
- Dihydropyrimidine derivatives, known as Biginelli compounds, exhibit therapeutic potential.
- This research explores novel dihydropyrimidines for their anti-initiating properties.
Purpose of the Study:
- To synthesize multifunctional aromatic-substituted dihydropyrimidines.
- To evaluate their efficacy as tumor anti-initiating agents.
- To assess their cytotoxic effects on various cancer cells.
Main Methods:
- Synthesis and structural elucidation of twelve dihydropyrimidine compounds.
- In vitro assays to measure inhibition of cytochrome P450 1A (Cyp1A) activity.
- Assays to determine glutathione-S-transferases (GSTs) induction, radical scavenging activity (OH, ROO), and DNA fragmentation inhibition.
- Cytotoxicity testing against liver and colon carcinoma cells.
Main Results:
- Compound 10 inhibited Cyp1A, induced GST activity, scavenged OH radicals, and inhibited DNA fragmentation without cytotoxicity.
- Compounds 1 and 9 scavenged OH radicals and inhibited DNA fragmentation.
- Compound 1 showed similar activities to compound 10, including scavenging ROO radicals.
- Most compounds were non-toxic, with specific exceptions exhibiting cytotoxicity against certain cancer cell lines.
Conclusions:
- Compounds 10 and 1 are effective and safe tumor anti-initiating agents.
- These compounds act as multi-potent blocking agents against cancer initiation.
- The study highlights the therapeutic potential of novel dihydropyrimidine derivatives in cancer prevention.
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