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).