Design, synthesis and biological evaluation of novel modified dual-target shikonin derivatives for colorectal cancer treatment

[Display omitted] •A novel series of dual-target benzenesulfonyl shikonin derivative has been designed and synthesized.•Z10 could activate activity of PKM2 and inhibit activity against PDK1 by direct intereaction.•Z10 showed significant anticancer activity in colorectal cancer in comparison with shikonin, PKM2 or PDK1 target agent.•Z10 exhibited lower toxicity than shikonin at 4 μM in vitro and at a dosage of 4.2 mg/kg in vivo.•Z10 could significantly induce apoptosis in colorectal cells and in xenograft mice models. Warburg effect provides energy and material essential for tumor proliferation, the reverse of Warburg effect provides insights into the development of a novel anti-cancer strategy. Pyruvate kinase 2 (PKM2) and pyruvate dehydrogenase kinase 1 (PDK1) are two key enzymes in tumor glucose metabolism pathway that not only contribute to the Warburg effect through accelerating aerobic glycolysis, but also serve as druggable target for colorectal cancer (CRC). Considering that targeting PKM2 or PDK1 alone does not seem to be sufficient to remodel abnormal glucose metabolism and achieve significant antitumor activity, a series of novel benzenesulfonyl shikonin derivatives were designed to regulate PKM2 and PDK1 simultaneously. By means of molecular docking and antiproliferative screen, we found that compound Z10 could act as the combination of PKM2 activator and PDK1 inhibitor, thereby significantly inhibited glycolysis that reshaping tumor metabolism. Moreover, Z10 could inhibit proliferation, migration and induce apoptosis in CRC cell HCT-8. Finally, the in vivo anti-tumor activity of Z10 was evaluated in a colorectal cancer cell xenograft model in nude mice and the results demonstrated that Z10 induced tumor cell apoptosis and inhibited tumor cell proliferation with lower toxicity than shikonin. Our findings indicated that it is feasible to alter tumor energy metabolism through multi-target synergies, and the dual-target benzenesulfonyl shikonin derivative Z10 could be a potential anti-CRC agent.