Recent advances in microtubule-stabilizing agents

Abstract

Highly dynamic mitotic spindle microtubules are superb therapeutic targets for a group of chemically diverse and clinically successful anticancer drugs. Microtubule-targeted drugs disrupt microtubule dynamics in distinct ways, and they are primarily classified into two groups: microtubule destabilizing agents (MDAs), such as vinblastine, colchicine, and combretastatin-A4, and microtubule stabilizing agents (MSAs), such as paclitaxel and epothilones. Systematic discovery and development of new MSAs have been aided by extensive research on paclitaxel, yielding a large number of promising anticancer compounds. This review focuses on the natural sources, structural features, mechanisms of action, structure-activity relationship (SAR) and chemical synthesis of MSAs. These MSAs mainly include paclitaxel, taccalonolides, epothilones, FR182877 (cyclostreptin), dictyostatin, discodermolide, eleutherobin and sarcodictyins, zampanolide, dactylolide, laulimalides, peloruside and ceratamines from natural sources, as well as small molecular microtubule stabilizers obtained via chemical synthesis. Then we discuss the application prospect and development of these anticancer compounds.

Synthesis and Biological Evaluation of New Antitubulin Agents Containing 2-(3′,4′,5′-trimethoxyanilino)-3,6-disubstituted-4,5,6,7-tetrahydrothieno[2,3-c]pyridine Scaffold

“…Although many chemically diverse synthetic tubulin inhibitors have been synthesized, there is still a need to identify novel small molecules that target microtubules [24][25][26][27][28]. Among such compounds, thiophene [29][30][31][32][33][34] and fused thiophenes such as benzo [b]thiophenes [35][36][37][38][39][40], thieno [3,2-d]pyrimidines [41][42][43], and thieno [2,3-b]pyridines [44] were present as molecular skeletons in a significant number of synthetic inhibitors of microtubule polymerization, but there are limited examples of small molecules showing interesting activities in inhibiting both microtubule assembly and cell proliferation based on the 4,5,6,7-tetrahydrothieno [2,3-c]pyridine molecular skeleton as the core structure.…”

Microtubule stabilizer epothilone B as a motor neuron differentiation agent for human endometrial stem cells

“…These doses were at least 10 times higher than the concentrations used in this study for EpoB. In addition, compared with taxol, EpoB has shown to have higher solubility, smaller molecular size, and ability to easily pass through the BBB (Chao et al, 2015; Cao et al, 2018). Another study showed adding 1–3 nM of taxol can increase the neurite growth of mature rat retinal ganglion cells ~40 µm and 10 nM showed a significant reduction of neurite length (Sengottuvel et al, 2011).…”

Emerging roles of allosteric modulators in the regulation of protein‐protein interactions (PPIs): A new paradigm for PPI drug discovery

“…Microtubules, which constitute the cytoskeleton, are major cellular mechanical structures and mediate the cell cycle, cell mechanics, and subcellular transport . These structures resemble hollow cylindrical tubes composed of 13 linear protofilaments built from α‐ and β‐tubulins . PPIs between α‐ and β‐tubulins mediate the dynamics of microtubules (MTs), which are essential to their functions and are involved in oncogenesis .…”

“…194 These structures resemble hollow cylindrical tubes composed of 13 linear protofilaments built from αand β-tubulins. 11,195,196 PPIs between αand β-tubulins mediate the dynamics of microtubules (MTs), which are essential to their functions and are involved in oncogenesis. [197][198][199] Therefore, microtubule-stabilizing agents (MSAs), which stabilize intertubulin PPIs, halt abnormal cell cycles and induce apoptosis, 198,200,201 have become a dynamic field of cancer therapeutics and are now frequently used as anticancer drugs.…”