Novel 9-Benzylaminoacridine Derivatives as Dual Inhibitors of Phosphodiesterase 5 and Topoisomerase II for the Treatment of Colon Cancer

Abstract

It has been shown that phosphodiesterase 5 (PDE5) inhibitors have anticancer effects in a variety of malignancies in both in vivo and in vitro experiments. The role of cGMP elevation in colorectal carcinoma (CRC) has been extensively studied. Additionally, DNA topoisomerase II (Topo II) inhibition is a well-established mechanism of action that mediates the effects of several approved anticancer drugs such as doxorubicin and mitoxantrone. Herein, we present 9-benzylaminoacridine derivatives as dual inhibitors of the PDE5 and Topo II enzymes. We synthesized 31 derivatives and evaluated them against PDE5, whereby 22 compounds showed micromolar or sub-micromolar inhibition. The anticancer activity of the compounds was evaluated with the NCI 60-cell line testing. Moreover, the effects of the compounds on HCT-116 colorectal carcinoma (CRC) were extensively studied, and potent compounds against HCT-116 cells were studied for their effects on Topo II, cell cycle progression, and apoptosis. In addition to exhibiting significant growth inhibition against HCT116 cells, compounds 11, 12, and 28 also exhibited the most superior Topo II inhibitory activity and low micromolar PDE5 inhibition and affected cell cycle progression. Knowing that compounds that combat cancer through multiple mechanisms are among the best candidates for effective therapy, we believe that the current class of compounds merits further optimization and investigation to unleash their full therapeutic potential.

Advancements in Phosphodiesterase 5 Inhibitors: Unveiling Present and Future Perspectives

“…The most potent PDE5 inhibitor of the series 61 ( exhibited lower growth inhibitory activity against colorectal cells (HCT-116 hand, the three most potent topoisomerase two inhibitors, 62, 63 and 64, sh cromolar PDE5 inhibitory activity and significant growth inhibitory effects 116 cells. However, 64 was shown to have less selective anticancer act showed a relatively high growth inhibition against the non-malignant de CCD-966SK cells (IC50 = 4.67 µM) [272]. Abadi and co. tried to combine the anticancer properties of PDE5 and Topoisomerase II inhibitors in a single molecule through the synthesis of several 9-benzylaminoacridine derivatives.…”

“…On the other hand, the three most potent topoisomerase two inhibitors, 62, 63 and 64, showed low micromolar PDE5 inhibitory activity and significant growth inhibitory effects against HCT-116 cells. However, 64 was shown to have less selective anticancer activity, where it showed a relatively high growth inhibition against the non-malignant dermal fibroblast CCD-966SK cells (IC 50 = 4.67 µM) [272]. acting NO donor and PDE5 inhibitor, having wound healing effects in both normal mice and mice with diabetes mellitus [271].…”