An approach to the structural requirements of hydroxycoumarins to induce apoptosis in U-937 cells

VAZQUEZ, RAMIRO

Buenos Aires

Workshop; Strategies For The delopment Of New Drugs; 2008

Facultad de Farmacia y Bioquímica, UBA y la CSIR, Sudáfrica

It has been reported that some coumarins can cause significant changes on cell growth and differentiation in several kinds of malignant neoplasm depending on their pattern of substitute groups in the aromatic ring. Many of these studies describe the necessity of the aromatic ring to be substituted at least by a polar chemical group. In the present work, structurally related hydroxycoumarins were studied in order to elucidate the key structural requirements to induce apoptosis in U-937 promonocytic cells. We identified a set of hydroxycoumarins, among them 7,8-dihydroxy-coumarin and esculetin, which have shown pro-apoptotic activity inducing DNA fragmentation, characteristic morphological changes of programmed cell death as well as increase in the activity of Caspase-3. Moreover we demonstrated that dihydroxylated coumarins failed to induce apoptosis in normal cells as mature human monocytes or human umbilical vein endothelial cells (HUVEC). In an effort to relate the biological activity and the structural requirements of these compounds, we carried out a Structure Activity Relationship (SAR) assay. Our findings indicated that the presence of two adjacent phenolic hydroxyl groups was the most important factor in terms of SAR, whereas the position of the o-dihydroxyl groups in the aromatic nucleus had little effect and others structural characteristics of coumarins also influenced their pro-apoptotic activity. Based on these results and knowing the needs of alternative chemotherapeutic strategies, hydroxycoumarins might be applied in the treatment of hematological malignancies.