Pyrimidine- and furo[2,3-d]pyrimidine-isoxazole hybrids and their Re(i) tricarbonyl complexes with antiproliferative activity against hematological malignancies
Abstract
Pyrimidine and furo[2,3-d]pyrimidine derivatives have emerged as promising anticancer agents that act through multiple mechanisms, including modulation of downstream signaling pathways such as a JAK2/STAT3 cascade. Herein, we report the synthesis of novel pyrimidine- and furo[2,3-d]pyrimidine-isoxazole hybrids via base-promoted 1,3-dipolar cycloaddition and their evaluation for antiproliferative activity. The compounds were assessed in vitro against five cancer cell lines (CaCo-2, HeLa, HuT-78, THP-1, and CCRF-CEM) and two non-tumor cell lines (MRC-5 and BJ). Within the 5-alkynyl-substituted pyrimidine series, compound 7g′, bearing a 5-chloropentynyl substituent, showed the highest activity against the cutaneous T-cell lymphoma HuT-78 (IC50 = 20.8 μM). Enhanced antiproliferative activity against HuT-78 cells was observed for the furo[2,3-d]pyrimidine isoxazole derivatives 8f′, 9d′, and 9f′, with IC50 values of 20.6, 15.5, 16.9 μM, respectively. Coordination to Re(i) improved activity in selected cases: complex showed strong and selective antiproliferative effects against hematological cancer cell lines (IC50 = 1.5–2.1 μM, SI > 20), whereas demonstrated notable activity against THP-1 cells (IC50 = 2.2 μM, SI > 14). Mechanistic studies in HuT-78 cells revealed that selected derivatives, 8f′, 9f′, and 9g′, induced G0/G1 cell cycle arrest, increasing the G0/G1 population to approximately 57% with a concomitant decrease in the G2/M phase. Collectively, 7g′, 8f′, 9d′, 9f′, and 9g′ were identify as promising lead compounds with potent antiproliferative activity in HuT-78 cells, mediated through G0/G1 cell-cycle arrest, mitochondrial dysfunction, and modulation of the PI3K/AKT and JAK/STAT signaling pathways. In contrast, the complex 7dRe appears to exert its antiproliferative effects through a cell-cycle-independent mechanism that may involve modulation of the autophagic pathway in HuT-78 cells, without triggering classical apoptosis. These results support the potential of these pyrimidine- and furo[2,3-d]pyrimidine-based scaffolds for the development of therapeutic agents targeting T-cell lymphoma and other hematological malignancies.