Synthesis and Antileukemia Activity Evaluation of Benzophenanthridine Alkaloid Derivatives

Abstract

Thirty-three benzophenanthridine alkaloid derivatives (1a–1u and 2a–2l) were synthesized, and their cytotoxic activities against two leukemia cell lines (Jurkat Clone E6-1 and THP-1) were evaluated in vitro using a Cell Counting Kit-8 (CCK-8) assay. Nine of these derivatives (1i–l, 2a, and 2i–l) with IC50 values in the range of 0.18–7.94 μM showed significant inhibitory effects on the proliferation of both cancer cell lines. Analysis of the primary structure–activity relationships revealed that different substituent groups at the C-6 position might have an effect on the antileukemia activity of the corresponding compounds. In addition, the groups at the C-7 and C-8 positions could influence the antileukemia activity. Among these compounds, 2j showed the strongest in vitro antiproliferative activity against Jurkat Clone E6-1 and THP-1 cells with good IC50 values (0.52 ± 0.03 μM and 0.48 ± 0.03 μM, respectively), slightly induced apoptosis, and arrested the cell-cycle, all of which suggests that compound 2j may represent a potentially useful start point to undergo further optimization toward a lead compound.

Insights on Antitumor Activity and Mechanism of Natural Benzophenanthridine Alkaloids

“…The compounds chelerythrine (2), structurally modified to yield compounds 13-16, sanguinarine (1), and derivatives 8-12, exhibit potent activity against Jurkat clone e6-1 and THP-1 leukemia cell lines, with IC 50 values from 0.18 to 7.94 µM. Notably, most of the activities of the above compounds are higher than those of chelerythrine (2) and sanguinarine (1)'s original activities, in which the IC 50 values of compound 12 against the above two leukemia cell lines reach 0.53 ± 0.05 and 0.18 ± 0.03 µM, respectively [46]. Sanguinarine (1), chelerythrine (2), sanguilutine (3), sanguirubine (4), chelirubine (5), and macarpine (7) (Figure 1) exhibit antitumor activity against various cancer cell lines, Sanguinarine (1), chelerythrine (2), sanguilutine (3), sanguirubine (4), chelirubine (5), and macarpine (7) (Figure 1) exhibit antitumor activity against various cancer cell lines, Sanguinarine (1), chelerythrine (2), sanguilutine (3), sanguirubine (4), chelirubine (5), and macarpine (7) (Figure 1) exhibit antitumor activity against various cancer cell lines, 0.91 ± 0.04 1.17 ± 0.13…”

“…The compounds chelerythrine (2), structurally modified to yield compounds 13-16, sanguinarine (1), and derivatives 8-12, exhibit potent activity against Jurkat clone e6-1 and THP-1 leukemia cell lines, with IC50 values from 0.18 to 7.94 µM. Notably, most of the activities of the above compounds are higher than those of chelerythrine (2) and sanguinarine (1)'s original activities, in which the IC50 values of compound 12 against the above two leukemia cell lines reach 0.53 ± 0.05 and 0.18 ± 0.03 µM, respectively [46]. The compounds chelerythrine (2), structurally modified to yield compounds 13-16, sanguinarine (1), and derivatives 8-12, exhibit potent activity against Jurkat clone e6-1 and THP-1 leukemia cell lines, with IC 50 values from 0.18 to 7.94 µM.…”

“…The compounds chelerythrine ( 2 ), structurally modified to yield compounds 13 – 16 , sanguinarine ( 1 ), and derivatives 8 – 12 , exhibit potent activity against Jurkat clone e6-1 and THP-1 leukemia cell lines, with IC 50 values from 0.18 to 7.94 μM. Notably, most of the activities of the above compounds are higher than those of chelerythrine ( 2 ) and sanguinarine ( 1 )’s original activities, in which the IC 50 values of compound 12 against the above two leukemia cell lines reach 0.53 ± 0.05 and 0.18 ± 0.03 μM, respectively [ 46 ].…”

Cytostatic Activity of Sanguinarine and a Cyanide Derivative in Human Erythroleukemia Cells Is Mediated by Suppression of c-MET/MAPK Signaling

“…According to previous research, 1 exerts its cytostatic effects mainly by inducing the apoptosis of tumor cells through regulatory proteins and signaling pathways, including the mitogen-activated protein kinase (MAPK) [11], PI3K/AKT [12], JAK2/STAT3, and P53 pathways [13,14]. However, it is not clear how these signaling pathways and proteins are To improve the cytostatic activity of 1 and reduce its toxic effects on normal cells, in our previous work we carried out structural modification and assessed the anti-leukemia activities of its derivatives [9]. We found that the activity of 1 was mainly dependent on the following structural features: the fusion of the B/C ring, hydroxylation patterns, N-methyl substitutions, and planar configuration [10].…”