Multimechanistic Conjugates Based on Melampomagnolide B and 10-HCPT/SN-38: Novel Antitumor Agents for Colorectal Cancer Therapy

The design of multimechanistic conjugates based on 10-hydroxycamptothecin ( 10-HCPT ) offers a promising approach to reduce toxicity and enhance antitumor efficacy. We designed and synthesized a novel series of conjugates by linking melampomagnolide B ( MMB ) to 10-HCPT/SN-38 via diverse linkers. Among them, 6i1/6i2 exhibited remarkable anticolorectal cancer potency and minimal cytotoxicity toward normal THLE-2 cells. Mechanistic studies indicated that 6i1/6i2 could inhibit IκB kinase β (IKKβ), leading to the inhibition of p65 and IκBα phosphorylation, suppression of p65 nuclear translocation, and subsequent regulation of genes controlled by nuclear factor kappa-B (NF-κB). Additionally, they targeted topoisomerase I (Topo I), inducing DNA damage, reactive oxygen species (ROS) accumulation, mitochondrial membrane potential loss, and S-phase arrest. In a CT-26 xenograft model, 6i1 and 6i2 (5 mg/kg) potently suppressed tumor growth, achieving TGI rates of 89.9% and 95.4% without observable toxicity.