Design, synthesis, and biological evaluation of benzenesulfonyl chloride-substituted berberine derivatives as potential PGAM1 inhibitors

Berberine, an isoquinoline alkaloid isolated from the Chinese herb
Coptis chinensis
and other Berberis plants, exhibits a broad spectrum of pharmacological properties. It can inhibit the proliferation of various cancer cell types and impede invasion and metastasis. Benzenesulfonyl chloride or compounds containing the structure of benzenesulfonyl chloride have shown some potential in the development of anticancer drugs. In this study, a series of berberine benzenesulfonyl chloride couplings (compounds
4-59
) was designed and synthesized based on berberine. Cell activity assays identified compounds
18
and
46
containing six methyl groups, as exhibiting significant anti-proliferative activity against lung cancer cell line H460 (compound
18
: 4.50 μM, compound
46
: 10.82 μM). Further assessment of the enzyme activity of these compounds against phosphoglycerate mutase 1 (PGAM1) demonstrated that compound
18
has an IC
50
of 0.081 μM, compound
22
has an IC
50
of 0.076 μM, and compound
35
has an IC
50
of 0.087 μM. The enzymatic activity of these three compounds is comparable to that of the positive control PGMI-004A, which has an IC
50
of 0.052 μM. These findings suggest that these compounds have potential as PGAM1 inhibitors. Compounds
18
and
46
were found to induce apoptosis, block the cell cycle at the G2/M stage, cause reactive oxygen species (ROS) to burst, and induce mitochondrial dysfunction. Importantly, compounds
18
and
46
down-regulated the expression of PGAM1 and up-regulated ACTA2 and P53 in the Western blot analyses. In conclusion, this study further provides a robust scientific foundation for the structural modification of berberine and the development of anti-lung cancer agents.