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Synthesis and antiproliferative activity of 3-(2-chloroethyl)-5-methyl-6-phenyl-8-(trifluoromethyl)-5,6-dihydropyrazolo[3,4-f][1,2,3,5]tetrazepin-4-(3H)-one
- Source :
- European Journal of Medicinal Chemistry. 96:98-104
- Publication Year :
- 2015
- Publisher :
- Elsevier BV, 2015.
-
Abstract
- Based on the encouraging results found for 3,5-dimethyl-6-phenyl-8-(trifluoromethyl)-5,6-dihydropyrazolo[3,4-f][1,2,3,5]tetrazepin-4-(3H)-one 7 previously tested by us, as well as the consideration that heterocycle fused tetrazepinones bearing the 2-chloroethyl substituent show a better cytotoxic profile than temozolomide and mitozolomide against human cancer cell lines which express the DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT), in this paper we report the multistep synthesis and the biological study of 3-(2-cloroethyl)-5-methyl-6-phenyl-8-(trifluoromethyl)-5,6-dihydropyrazolo[3,4-f][1,2,3,5]tetrazepin-4-(3H)-one 10. Like compound 7, it was active on P-glycoprotein expressing cells (MDR) HL60 and on K562 cell line that are resistant to apoptosis induced by different stimuli, showing GI50 values of 14 and 18 µM respectively. As an antiproliferative agent against the above cells compound 10 was about 2.2 times more active than compound 7. Compound 10 was also tested against WiDR cells which are overexpressing the DNA repair protein MGMT, showing a GI50 value of 2.3 µM. Finally, concerning the effect on cell cycle we observed an evident difference between compounds 7 and 10. In fact, compound 7 induces a block of cell cycle in G0-G1, therefore acting as phase-specific drug, in contrast, compound 10 is a not phase-specific agent. Both the compounds are able to increase the apoptotic sub G0-G1 peak of cell cycle.
- Subjects :
- Methyltransferase
Stereochemistry
HL60
Antineoplastic Agents
Apoptosis
HL-60 Cells
Structure-Activity Relationship
chemistry.chemical_compound
Drug Discovery
Humans
Structure–activity relationship
Cell Proliferation
Pharmacology
Trifluoromethyl
Dose-Response Relationship, Drug
Molecular Structure
Chemistry
Cell growth
Cell Cycle
Organic Chemistry
Azepines
General Medicine
Cell cycle
Settore CHIM/08 - Chimica Farmaceutica
1,2,3,5-Tetrazepinones, pyrazolo[3,4-f][1,2,3,5]-tetrazepinones, drug resistance, apoptosis, antiproliferative activity
Cell culture
Pyrazoles
Drug Screening Assays, Antitumor
K562 Cells
Subjects
Details
- ISSN :
- 02235234
- Volume :
- 96
- Database :
- OpenAIRE
- Journal :
- European Journal of Medicinal Chemistry
- Accession number :
- edsair.doi.dedup.....2dceb43f27808293556ad50c2b1c9fd3