Replacing the tropolonic methoxyl group of colchicine with methylamino increases tubulin binding affinity with improved therapeutic index and overcomes paclitaxel cross-resistance

Discovery of Novel Isoquinoline Analogues as Dual Tubulin Polymerization/V-ATPase Inhibitors with Immunogenic Cell Death Induction

“…1,2 Microtubule-targeting agents (MTAs) play an important role in cancer treatment. 3,4 MTAs, including microtubule-stabilizing agents (MSAs) and microtubule-destabilizing agents (MDAs), 5,6 are often described as cytotoxic agents that kill tumor cells primarily by regulating apoptosis. 7−9 Previously, apoptosis is often considered as an immunologically silent or even tolerogenic death modality.…”

“…Microtubules are composed of α-tubulin and β-tubulin and play an extremely important role in various cellular processes. , Microtubule-targeting agents (MTAs) play an important role in cancer treatment. , MTAs, including microtubule-stabilizing agents (MSAs) and microtubule-destabilizing agents (MDAs), , are often described as cytotoxic agents that kill tumor cells primarily by regulating apoptosis. − Previously, apoptosis is often considered as an immunologically silent or even tolerogenic death modality . However, with the increasing attention to tumor immunotherapy, numerous studies have shown that some but not all MTA-induced apoptosis regimens can induce effective immunogenic cell death (ICD). , Since both 2D cell cultures and mouse tumor models exhibit higher cell division rates than human tumors, current studies tend to overestimate the efficacy of MTAs. , The failure of the vast majority of MTAs also reinforces the idea that MTAs also have capabilities independent of their ability to delay the completion of mitosis. , In fact, many human cancers have low proliferation rates and it is not clear how drugs that kill only dividing cells can promote tumor regression .…”

“…Tubulin colchicine-binding site inhibitors (CBSIs, a class of microtubule destabilizers), such as colchicine, nocodazole, and SIX2G, have been reported to be effective in triggering ICD (Figure A). In addition, some CBSIs have been found to have immunomodulatory effects (Figure A). − Meanwhile, considering the advantages of CBSIs such as significant antiproliferative activity, simple structure, and overcoming drug resistance, it is extremely attractive to develop novel CBSIs with ICD induction ability.…”

“…In addition, some CBSIs have been found to have immunomodulatory effects (Figure 1A). 29−31 Meanwhile, considering the advantages of CBSIs such as significant antiproliferative activity, 32 simple structure, 33 and overcoming drug resistance, 3 it is extremely attractive to develop novel CBSIs with ICD induction ability.…”

Design, synthesis and antiproliferative screening of newly synthesized acrylate derivatives as potential anticancer agents

“…[7][8][9] Several natural products, such as colchicine, paclitaxel, and the vinca alkaloids, inhibit tubulin polymerization by binding to tubulin at their respective binding sites. 10,11 In the case of tubulin polymerization inhibition at the colchicine binding site, combretastatin A-4 (CA-4) is a cis-stilbenoid molecule that elicited remarkable b-tubulin polymerization suppression activity acting at the colchicine site. [12][13][14] CA-4 is the lead antimitotic molecule within the combretastatin family which exerts outstanding antitumor activity on various cancer cells due to b-tubulin polymerization suppression activity and anti-vascular effect.…”