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Synthesis, Antitumor Activity and Molecular Docking Studies on Seven Novel Thiazacridine Derivatives


Marcel Lucas de Almeida, Douglas Viana , Valécia Costa , Flaviana Santos , Michelly Pereira, Maira Pitta , Moacyr Rêgo , Ivan Pitta and Marina Galdino-Pitta *  


Aim and Objective: In the last decades, cancer has become a major problem in public health all around the globe. Chimeric chemical structures have been established as an important trend on medicinal chemistry in the last years. Thiazacridines are hybrid molecules composed of a thiazolidine and acridine nucleus, both pharmacophores that act on important biological targets for cancer. By the fact it is a serious disease, seven new 3-acridin-9-ylmethyl-thiazolidine-2,4-dione derivatives were synthesized, characterized, analyzed by computer simulation and tested in tumor cells. In order to find out if the compounds have therapeutic potential.

Materials and Methods: Seven new 3-acridin-9-ylmethyl-thiazolidine-2,4-dione derivatives were synthesized through Michael addition and Knoevenagel condensation strategies. Characterization was performed by NMR and Infrared spectroscopy techniques. Regarding biological activity, thiazacridines were tested against solid and hematopoietic tumoral cell lines, namely Jurkat (acute T-cell leukemia); HL-60 (acute promyelocytic leukemia); DU 145 (prostate cancer); MOLT-4 (acute lymphoblastic leukemia); RAJI (Burkitt's lymphoma); K562 (chronic myelogenous leukemia) and normal cells PBMC (healthy volunteers). Molecular docking analysis was also performed in order to assess major targets of these new compounds. Cell cycle and clonogenic assay were also performed.

Results: Compound LPSF/AA-62 (9f) exhibited the most potent anticancer activity against HL-60 (IC50 3,7±1,7 µM), MOLT-4 (IC50 5,7±1,1 µM), Jurkat (IC50 18,6 µM), Du-145 (IC50 20±5 µM) and Raji (IC50 52,3±9,2 µM). While the compound LPSF/AA-57 (9b) exhibited anticancer activity against the K562 cell line (IC50 51,8±7,8 µM). Derivative LPSF/AA-62 (9f) did not interfere in the cell cycle phases of the Molt-4 lineage. However, the LPSF/AA-62 (9f) derivative significantly reduced the formation of prostate cancer cell clones. The compound LPSF/AA-62 (9f) has shown strong anchorage stability with enzymes topoisomerases 1 and 2, in particular due the presence of chlorine favored hydrogen bonds with topoisomerase 1.

Conclusion: The 3-(acridin-9-ylmethyl)-5-((10-chloroanthracen-9-yl)methylene)thiazolidine-2,4-dione (LPSF/AA-62) presented the most promising results, showing anti-tumor activity in 5 of the 6 cell types tested, especially inhibiting the formation of colonies of prostate tumor cells (DU-145).


Acridine. thiazolidine. cancer. medicinal chemistry. cytotoxicity. therapeutic innovation.


Universidade Federal de Pernambuco, Núcleo de Pesquisa em Inovação Terapêutica Suely Galdino , Universidade Federal de Pernambuco, NUPIT-SG Department , Universidade Federal de Pernambuco, NUPIT-SG Department , Universidade Federal de Pernambuco, NUPIT-SG Department , UFPE, Pharmacology & Physiology Department , UFPE, Biochemisty Department , UFPE Biochemistry Department , UFPE, NUPIT Department , UFPE, NUPIT Department

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