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Antimitotic agents such as the clinically approved vinca alkaloids, taxanes and epothilone can arrest cell growth during interphase and are therefore among the most important drugs available for treating cancer. These agents suppress microtubule dynamics and thus interfere with intracellular transport, inhibit cell proliferation and promote cell death. Because these drugs target biological processes that are essential to all cells, they face an additional challenge when compared to most other drug classes. General toxicity can limit the applicable dose and therefore reduce therapeutic benefits. Photopharmacology aims to avoid these side-effects by introducing compounds that can be applied globally to cells in their inactive form, then be selectively induced to bioactivity in targeted cells or tissue during a defined time window. This review discusses photoswitchable analogues of antimitotic agents that have been developed by combining different photoswitchable motifs with microtubule-stabilizing or microtubule-destabilizing agents.

Tubulin is a heterodimeric protein composed of α- and β-subunits, which polymerize to form the cell’s microtubules. The latter are key components in mitotic spindle formation and essential targets in anticancer therapy. Compounds such as paclitaxel, tubulysins, dolastatins and synthetic analogues of these latter compounds, including cemadotin, exert their cytotoxic effects by disrupting microtubule dynamics. Previously, we reported the production and anticancer activity of a library of cemadotin analogues featuring a C-terminal tertiary amide functionalized with a variety of N-substituents, thus resulting in compounds occurring as a mixture of amide rotamers. Here we describe a comprehensive NMR and conformational study that provides new insights into the effect of the conformational equilibrium on the binding mode of the novel cemadotin analogues to the tubulin target. The conformational behavior of the isomer equilibrium of cemadotin’s terminal amide bond was investigated by TOCSY and ROESY NMR experiments, which allowed the identification and quantification of individual rotamer populations. A slow interconversion between the s-cis and s-trans amide rotamers was observed under standard NMR conditions (25 °C), indicating a significant energy barrier and conformational rigidity. Molecular docking and saturation transfer difference (STD) NMR experiments were performed with a representative analogue and tubulin to assess the binding mode. The results revealed that the s-trans rotamer is the predominant conformer in solution and exhibits a more favorable interaction with tubulin compared to the s-cis isomer, thus helping to understand the conformational requirements for an improved tubulin binding and the inhibition of the polymerization process.

Circular RNAs (circRNAs), a class of endogenous RNAs, have emerged as an enigmatic class of genes. However, little is known about their value in the progression and chemoresistance of cancers. The present study sought to determine the expression profiles and potential modulatory role of circRNAs on breast cancer cell viability and monastrol resistance. Monastrol-resistant cell lines were established by exposing breast cancer cells to increasing concentrations of monastrol. A human circRNA microarray was used to search for dysregulated circRNAs in monastrol-resistant cells, then circRNA-MTO1 (hsa-circRNA-007874) was validated as a circRNA that exhibited elevated expression levels in monastrol-resistant cells. Mechanistic investigations suggested that upregulation of circRNA-MTO1 suppressed cell viability, promoted monastrol-induced cell cytotoxicity and reversed monastrol resistance. Subsequently, Eg5 was identified as the functional target of circRNA-MTO1, and MTO1 inhibited Eg5 protein level but not mRNA level. By treating with protein synthesis inhibitor cycloheximide (CHX), it was revealed that MTO1 did not affect the protein stability of Eg5. RNA-pull down experiments followed by mass spectrometry revealed that MTO1 interacted with tumor necrosis factor receptor associated factor 4 (TRAF4), and sequester TRAF4 from activating Eg5 translation, thereby inhibiting the Eg5 protein level. Taken together, the data reveal a regulatory mechanism by circRNA-MTO1 to control cell viability and monastrol resistance in breast cancer cells.

Despite decades of research, cancer continues to be a disease of great concern to millions of people around the world. It has been responsible for a total of 609,820 deaths in the U.S. alone in 2023. Over the years, many drugs have been developed to remove or reduce the disease’s impact, all with varying mechanisms of action and side effects. One class of these drugs is small-molecule mitotic inhibitors. These drugs inhibit cancer cell mitosis or self-replication, impeding cell proliferation and eventually leading to cell death. In this paper, small-molecule mitotic inhibitors are discussed and classified through their discovery, underlying chemistry, and mechanism(s) of action. The binding/inhibition of microtubule-related proteins, DNA damage through the inhibition of Checkpoint Kinase 1 protein, and the inhibition of mitotic kinase proteins are discussed in terms of their anticancer activity to provide an overview of a variety of mitotic inhibitors currently commercially available or under investigation, including those in ongoing clinical trial. Clinical trials for anti-mitotic agents are discussed to track research progress, gauge current understanding, and identify possible future prospects. Additionally, antibody–drug conjugates that use mitotic inhibitors as cytotoxic payloads are discussed as possible ways of administering effective anticancer treatments with minimal toxicity.

Unique ecozones, such as those in Canada, play an important role in the production of distinct natural product chemicals that help plants survive highly variable abiotic conditions and herbivory. Extracts prepared from Hook. (heartleaf arnica), a North American species related to the European medicinal plant L., induce mitotic arrest in human cancer cell lines with a mitotic spindle morphology distinct from other mitotic inhibitors isolated from prairie plant species. This study aimed to identify the anti-mitotic compound(s) of . The cytotoxic and anti-mitotic activities of extracts and their active compounds on human cancer cells were characterized by MTT assays, light microscopy, flow cytometry, and immunofluorescence microscopy. The active compounds were isolated by bioassay-guided HPLC fractionation and identified by NMR. Five anti-mitotic sesquiterpene lactones were isolated from : three previously unidentified structures, and the known compounds aromaticin and pulchellin-2α- -isovalerate. These compounds induced rounded cells positive for the mitotic marker phospho-histone H3 at concentrations of 5 µM, yet had distinct effects on mitotic spindle morphology. Furthermore, aromaticin treatment induced ubiquitin foci in cells, indicating that it may target the ubiquitin-proteasome pathway. This is the first report of mitotic inhibitors from . Of these five compounds, three have previously undescribed chemical structures, whereas new anti-mitotic activities have been identified for aromaticin and pulchellin-2α- -isovalerate. Differences in their biological activities suggest that they possess distinct cellular targets. These findings support continued exploration of Canadian botanical species as sources of structurally diverse bioactive compounds.

Tricholomenyn B, an antimitotic geranylcyclohexenone originally discovered from a basidiomycete Tricholoma acerbum , was isolated as a bitter and antibacterial constituent from fruiting bodies of T . japonicum . Careful comparison of NMR, MS, and other physicochemical properties of the isolated substance with the literature values revised a previously proposed macrolide structure 1 to a macrodiolide 2 . Compound 2 was perceived bitter at a minimum dose of 37.5 μg, showed weak antimicrobial activity against Kocuria rhizophila and Staphylococcus aureus , and was marginally cytotoxic (IC 50 2.6 µM) against P388 murine leukemia cells.

In our continuing study on a survey of biologically active natural products from heartwood of Santalum album (Southwest Indian origin), we newly found potent fish toxic activity of an n-hexane soluble extract upon primary screening using killifish (medaka) and characterized α-santalol and β-santalol as the active components. The toxicity (median tolerance limit (TLm) after 24 h at 1.9 ppm) of α-santalol was comparable with that of a positive control, inulavosin (TLm after 24 h at 1.3 ppm). These fish toxic compounds including inulavosin were also found to show a significant antifungal effect against a dermatophytic fungus, Trichophyton rubrum. Based on a similarity of the morphological change of the immobilized Trichophyton hyphae in scanning electron micrographs between treatments with α-santalol and griseofulvin (used as the positive control), inhibitory effect of α-santalol on mitosis (the antifungal mechanism proposed for griseofulvin) was assessed using sea urchin embryos. As a result, α-santalol was revealed to be a potent antimitotic agent induced by interference with microtubule assembly. These data suggested that α-santalol or sandalwood oil would be promising to further practically investigate as therapeutic agent for cancers as well as fungal skin infections.

Colchicine, a pseudoalkaloid isolated from Colchicum autumnale, has been identified as a potent anticancer agent because of its strong antimitotic activity. It was shown that colchicine modifications by regioselective demethylation affected its biological properties. For demethylated colchicine analogs, 10-demethylcolchicine (colchiceine, 1) and 1-demethylthiocolchicine (3), a series of 12 colchicine derivatives including 5 novel esters (2b–c and 4b–d) and 4 carbonates (2e–f and 4e–f) were synthesized. The antiproliferative activity assay, together with in silico evaluation of physicochemical properties, confirmed attractive biological profiles for all obtained compounds. The substitutions of H-donor and H-acceptor sites at C1 in thiocolchicine position provide an efficient control of the hydration affinity and solubility, as demonstrated for anhydrate 3, hemihydrate 4e and monohydrate 4a.

14,15-Dihydroclerodin, or dihydroclerodin-I (DCLR), is a natural product that can also be synthesized through catalytic hydrogenation of clerodin. In this study, dihydroclerodin, purified from Clerodendrum viscosum leaves, was evaluated for its cell cycle arrest and cytotoxic effects in Allium cepa root tip cells and compared with colchicine-induced antimitotic activity. Treatments with dihydroclerodin at concentrations of 100, 200, and 300 µg mL −1 , and colchicine at 150 µg mL −1 (as a positive control), were administered for 2, 4, and 4 + 16 h (4-hour treatment followed by 16 h of recovery). The highest frequency of metaphase cells was observed with dihydroclerodin (300 µg mL −1 ) and colchicine (150 µg mL −1 ) at 4 h, with values of 75.09 ± 0.93% and 78.31 ± 0.49%, respectively. Both treatments significantly increased the percentages of aberrant cells, chromosomal aberrations (CA), micronuclei (MN), C-metaphases (C-Met), and polyploid (PP) cells. These findings suggest that dihydroclerodin exhibits strong antimitotic effects, warranting further investigation of its potential in cancer chemotherapy due to its ability to induce cell cycle delay and cytotoxicity.

Noscapine is a phthalide isoquinoline alkaloid that easily traverses the blood brain barrier and has been used for years as an antitussive agent with high safety. Despite binding opioid receptors, noscapine lacks significant hypnotic and euphoric effects rendering it safe in terms of addictive potential. In 1954, Hans Lettré first described noscapine as a mitotic poison. The drug was later tested for cancer treatment in the early 1960's, yet no effect was observed likely as a result of its short biological half-life and limited water solubility. Since 1998, it has regained interest thanks to studies from Emory University, which showed its anticancer activity in animal models with negligible toxicity. In contrast to other microtubule-inhibitors, noscapine does not affect the total intracellular tubulin polymer mass. Instead, it forces the microtubules to spend an increased amount of time in a paused state leading to arrest in mitosis and subsequently inducing mitotic slippage/mitotic catastrophe/apoptosis. In experimental models, noscapine does not induce peripheral neuropathy, which is common with other microtubule inhibitors. Noscapine also inhibits tumor growth and enhances cancer chemosensitivity via selective blockage of NF-κB, an important transcription factor in glioblastoma pathogenesis. Due to their anticancer activities and high penetration through the blood–brain barrier, noscapine analogues strongly deserve further study in various animal models of glioblastoma as potential candidates for future patient therapy.