Abstract
A new series of phenolic glycoside esters, saccharumoside-B and its analogs (9b-9n, 10) have been synthesized by the Koenigs-Knorr reaction. Antiproliferative activities of the compounds (9b-9n, 10) were evaluated on various cancer cell lines including, MCF-7 breast, HL-60 leukemia, MIA PaCa-2 pancreatic, DU145 prostate, HeLa cervical and CaCo-2 colon, as well as normal human MCF10A mammary epithelial and human peripheral blood mononuclear cells (PBMC) by MTT assay. Compounds (9b-9n, 10) exhibited considerable antiproliferative effects against cancer cells with IC50 range of 4.43 ± 0.35 to 49.63 ± 3.59 µM, but they are less cytotoxic on normal cells (IC50 > 100 µM). Among all the compounds, 9f showed substantial antiproliferative activity against MCF-7 and HL-60 cells with IC50 of 6.13 ± 0.64 and 4.43 ± 0.35, respectively. Further mechanistic studies of 9f were carried out on MCF-7 and HL-60 cell lines. 9f caused arrest of cell cycle of MCF-7 and HL-60 cells at G0/G1 phase. Apoptotic population elevation, mitochondrial membrane potential loss, increase of cytosolic cytochrome c and Bax levels, decrease of Bcl-2 levels and enhanced caspases-9 and -3 activities were observed in 9f-treated MCF-7 and HL-60 cells. These results demonstrate anticancer and apoptosis-inducing potentials of 9f in MCF-7 and HL-60 cells via intrinsic pathway.
Highlights
A new series of phenolic glycoside esters, saccharumoside-B and its analogs (9b-9n, 10) have been synthesized by the Koenigs-Knorr reaction
Bax protein levels are dose dependently increased in treated MCF-7 cancer cells compared to untreated cells (Fig. 5, panel F). These results demonstrate the decreasing the ratio of Bcl-2/Bax in 9f-treated MCF-7 cancer cells (Fig. 5)
Compound 9f showed dose dependent inhibition of Bcl-2 and increase in Bax protein levels in treated HL-60 cells as compared to untreated cells (Fig. 6, panel E and F). These results demonstrate the decreasing the ratio of Bcl-2/Bax in 9f-treated HL-60 cancer cells (Fig. 6)
Summary
A new series of phenolic glycoside esters, saccharumoside-B and its analogs (9b-9n, 10) have been synthesized by the Koenigs-Knorr reaction. Mitochondrial membrane potential loss, increase of cytosolic cytochrome c and Bax levels, decrease of Bcl-2 levels and enhanced caspases-9 and -3 activities were observed in 9ftreated MCF-7 and HL-60 cells. Breast cancer is the leading cause of cancer deaths in women with an estimated 1,383,500 new School of Life Sciences, Institute of Science, GITAM University, Visakhapatnam, 530 045, Andhra Pradesh, India. Some of the natural products have been found with moderate bioactivities and poor pharmacokinetic properties[11] To overcome these problems, natural products have been synthesized chemically as in their native form and/or their analogs and explored their utility as drugs[11,12,13]. Discodermolide was synthesized with high yields and used in clinical trials for cancers[14, 15]
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