4 years ago

Mild C(sp3)–H functionalization of dihydrosanguinarine and dihydrochelerythrine for development of highly cytotoxic derivatives

Mild C(sp3)–H functionalization of dihydrosanguinarine and dihydrochelerythrine for development of highly cytotoxic derivatives
A series of C(6)–substituted dihydrobenzo[c]phenanthridines were synthesized by mild copper-catalyzed C(sp 3 )–H functionalization of dihydrosanguinarine (2) and dihydrochelerythrine (3) with certain nucleophiles selected to enhance cytotoxicity against human breast, colorectal, and prostate cancer cell lines. We also investigated the cytotoxicity of our previously reported C(6)–functionalized N-methyl-5,6-dihydrobenzo[c]phenanthridines 1a1e to perform structure-activity relationship (SAR) studies. Among the target compounds, five β–aminomalonates (1a, 1b, 2a, 2b, and 3b), one α-aminophosphonate (2c), and one nitroalkyl derivative (2h) exhibited half maximal inhibitory concentration (IC50) values in the range of 0.6–8.2 μM. Derivatives 1b, 2b and 2h showed the lowest IC50 values, with 2b being the most potent with values comparable to those of the positive control doxorubicin. On the basis of their IC50 values, derivatives 1a, 1b, 2a, 2b, 2h, and 3b were selected to evaluate the apoptotic PC-3 cell death at 10 μM by flow cytometry using propidium iodide and fluorescein isothiocyanate-conjugated Annexin V dual staining. The results indicated that the cytotoxic activity of the tested compounds in PC-3 cells is due to the induction of apoptosis, with 1a and 2h being the most active (55% of early apoptosis induction). Our preliminary SAR study showed that the incorporation of specific malonic esters, dialkyl phosphites and nitro alkanes on scaffolds 13 significantly enhanced their cytotoxic properties. Moreover, it appears that the electron donating 7,8-methylenedioxy group allowed derivatives of 2 to exhibit higher cytotoxicity than derivatives of 1 and 3. The present results suggest that derivatives 2b and 2h may be considered as potential lead compounds for the development of new anticancer agents.

Publisher URL: www.sciencedirect.com/science

DOI: S0223523417304671

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