Synthesis of 2,6-Diamino-Substituted Purine Derivatives and Evaluation of Cell Cycle Arrest in Breast and Colorectal Cancer Cells

Abstract

Reversine is a potent antitumor 2,6-diamino-substituted purine acting as an Aurora kinases inhibitor and interfering with cancer cell cycle progression. In this study we describe three reversine-related molecules, designed by docking calculation, that present structural modifications in the diamino units at positions 2 and 6. We investigated the conformations of the most stable prototropic tautomers of one of these molecules, the N6-cyclohexyl-N6-methyl-N2-phenyl-7H-purine-2,6-diamine (3), by Density Functional Theory (DFT) calculation in the gas phase, water and chloroform, the last solvent considered to give insights into the detection of broad signals in NMR analysis. In all cases the HN(9) tautomer resulted more stable than the HN(7) form, but the most stable conformations changed in different solvents. Molecules 1–3 were evaluated on MCF-7 breast and HCT116 colorectal cancer cell lines showing that, while being less cytotoxic than reversine, they still caused cell cycle arrest in G2/M phase and polyploidy. Unlike reversine, which produced a pronounced cell cycle arrest in G2/M phase in all the cell lines used, similar concentrations of 1–3 were effective only in cells where p53 was deleted or down-regulated. Therefore, our findings support a potential selective role of these structurally simplified, reversine-related molecules in p53-defective cancer cells.

Reversine induces cell cycle arrest and apoptosis via upregulation of the Fas and DR5 signaling pathways in human colorectal cancer cells

“…CDK, cyclin-dependent kinase; PI, propidium iodide. thyroid cancer (10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23). Thus, the impact of reversine on tumor cell behavior and its association with intracellular signaling pathways in human colorectal cancer cells were investigated.…”

“…The Aurora kinases, a family of mitotic serine/threonine kinases, serve a critical role in regulating cell-cycle progression, and aberrant expression of these kinases has been reported in a broad range of human cancer types, including breast, ovarian and gastric cancer (7)(8)(9). Numerous studies demonstrated that reversine possesses anticancer properties, causing cell growth arrest, cell cycle arrest, apoptosis, polyploidy and autophagy via the inhibition of Aurora kinases in various human cancer cell lines, including breast, thyroid, kidney, cervix, lung and colon cancer (10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23). Additionally, reversine inhibits tumor growth, as observed from xenograft mice model experiments (22,23).…”

Heterocycles in Medicinal Chemistry

“…Synthesis of 2,6-diamino-substituted purine derivatives as analogues of reversine and their screening against breast and colorectal cancer cells and affecting the cell cycle was described by Bosco et al The compounds caused a cycle arrest in the G2/M phase. It should be noted that the compounds were effective only in cells, where p53 was deleted or down-regulated [14].…”

Role of Bcl‑2 on drug resistance in breast cancer polyploidy‑induced spindle poisons

“…At present, paclitaxel, vincristine and other spindle poisons are the first-line chemotherapy options for the majority of solid tumors, such as breast and ovarian cancer (17,18). These drugs affect the structure and function of spindles during the process of mitosis in tumor cells, destroying the kinetochore and affecting the adhesion of the tube and the integrity of the mitotic apparatus to prevent normal splitting of the chromosome centromere, which is originally placed in the center of the equatorial plate (19,20). Consequently, the chromosome cohort cannot be normally separated from the two poles of the spindle, and the spindle assembly checkpoint is activated.…”