Synthesis and anticancer activity of podophyllotoxin derivatives with nitrogen-containing heterocycles

Abstract

Three series of podophyllotoxin derivatives with various nitrogen-containing heterocycles were designed and synthesized. The antitumor activity of these podophyllotoxin derivatives was evaluated in vitro against a panel of human tumor cell lines. The results showed that podophyllotoxin-imidazolium salts and podophyllotoxin-1,2,4-triazolium salts a1–a20 exhibited excellent cytotoxic activity. Among them, a6 was the most potent cytotoxic compound with IC50 values of 0.04–0.29 μM. Podophyllotoxin-1,2,3-triazole derivatives b1–b5 displayed medium cytotoxic activity, and podophyllotoxin-amine compounds c1–c3 has good cytotoxic activity with IC50 value of 0.04–0.58 μM. Furthermore, cell cycle and apoptosis experiments of compound a6 were carried out and the results exhibited that a6 could induce G2/M cell cycle arrest and apoptosis in HCT-116 cells.

Podophyllotoxin: Recent Advances in the Development of Hybridization Strategies to Enhance Its Antitumoral Profile

“…On their part, Yin and colleagues have synthesized new podophyllotoxin derivatives bearing nitrogen-containing heterocycles, such as imidazole, methylimidazole, or 1,2,4-triazole [ 105 ]. With the aim of synthesizing these derivatives, they first created a reaction of podophyllotoxin with 2-chloropropionyl chloride ( 61 ) following the procedure described previously in Scheme 1 .…”

“…Among them, compound 66f , bearing a 2-naphthylmethyl substituent at the third position of the imidazole ring, showed the most potent antitumor activity with IC 50 values of 0.07, 0.29, 0.11, and 0.04 against the HepG2, A549, MDA-MB-231, and HCT 116 tumor cell lines, respectively. On another note, compound 66f could also induce apoptosis in the HCT 116 cell line and arrest the cell cycle of this tumor cell line in the G2/M phase [ 105 ].…”

“…In addition, this compound was able to induce apoptosis in the K562/A02 cell line in a time-and concentration-dependent manner, which indicated its potentiality to overcome leukemia cell resistance to apoptosis induced by chemotherapy [104]. On their part, Yin and colleagues have synthesized new podophyllotoxin derivatives bearing nitrogen-containing heterocycles, such as imidazole, methylimidazole, or 1,2,4triazole [105]. With the aim of synthesizing these derivatives, they first created a reaction of podophyllotoxin with 2-chloropropionyl chloride (61) following the procedure described previously in Scheme 1.…”