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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.

Rice productivity improvement is an urgent priority to secure food availability in Indonesia, and polyploid induction using antimitotic compounds provides a promising strategy. This study evaluated agronomic responses of four rice genotypes (Cibogo, F4 Sb × Cb, F4 Sb × Ch, and Ciherang) following in vivo seed soaking with natural antimitotic extracts from Gloriosa superba, Catharanthus roseus, and Elephantopus scaber at varying concentrations. Seeds were treated with standardized antimitotic solutions and key traits-tiller number, plant height, panicle production, leaf number, panicle weight, and stomatal characteristics-were assessed. The results revealed clear genotype-specific and dose-dependent responses. The 10% G. superba treatment consistently enhanced tiller formation, plant height, and panicle production across most genotypes, and produced \"giant rice\" phenotypes in F4 Sb × Cb. Cibogo showed the heaviest panicles under 10% E. scaber and 15% G. superba, while Ciherang performed best at lower doses, particularly 5% C. roseus and 5-10% G. superba. In contrast, stomatal density and size remained relatively stable, indicating that stomatal traits are not reliable standalone markers of polyploidization. Collectively, these findings highlight the agronomic potential of G. superba-particularly at ~10%-as a candidate natural antimitotic extract to improve yield-related traits. However, because direct cytological verification (e.g., flow cytometry and/or chromosome counting) was not performed in this study, the observed responses should be interpreted as polyploid-like or putative outcomes that require validation in future work.

Objective: The aim of this study was to screen plant extracts for antimitotic activity using Vigna radiata germination inhibition assay, followed by Allium cepa root tip assay and evaluation of their cytotoxic potential on colon carcinoma (HCT-116) cell lines. Subjects and Methods: Aqueous extracts of Aconitum heterophyllum, Terminalia bellirica, Bauhinia variegata, Vanda roxburghii, and Cassia angustifolia were prepared by maceration method, and preliminary screening studies to check their antimitotic activity were done by V. radiata germination inhibition assay, followed by A. cepa root tip assay. Furthermore, cytotoxic actions were evaluated by cell proliferation assay. Effect of T. bellirica aqueous extract was analyzed to induce morphological changes, cell death, lactate dehydrogenase release, and cell survival of HCT-116 cells. Statistical Analysis Used: The data represented were analyzed by Student's t-test using SigmaStat 2.0 statistical analysis software. The normality of data was tested by the Shapiro-Wilk test before the Student's t-test. P values *P ≤ 0.05, **P ≤ 0.01, and ***P ≤ 0.001 were considered as statistically significant. Results: All the plant extracts showed promising antimitotic activity. Out of all, T. bellirica was highly effective on HCT-116 cells and promising effect on cell proliferation assay and Annexin-propidium iodide staining revealed that T. bellirica efficiently induces apoptosis. Conclusions: T. bellirica inhibits cancer cell growth and induces apoptotic cell death. Collectively, it may hold potential for cancer therapeutics.

Plant ploidy manipulation is often required for breeding purposes. However, there is no comprehensive review covering genome doubling in vegetable crops despite the abundance of data for a large number of vegetable species. Similar to other species, genome doubling is required in vegetable crops to obtain doubled haploids (DHs). It is also utilized for the production of polyploids to overcome interspecific hybrid sterility and improve agricultural traits. Spontaneous haploid genome duplication (SHGD) occurs in many Apiaceae, Brassicaceae, Cucurbitaceae, and Solanaceae crops, allowing for the laborious treatment with antimitotic agents to be bypassed. SHGD mechanisms are not fully understood, but existing data suggest that SHGD can occur via nuclear fusion, endoreduplication, or other mechanisms during microspore or ovule early embryogenic development. Other studies show that SHGD can occur at later developmental stages during extended plant growth in vitro or ex vitro, possibly due to the presence of phytohormones in the medium and/or diploid cell competitive advantage. For unresponsive accessions and species with rare SHGD, such as onion (Allium cepa L.) and beet cultivars (Beta vulgaris subsp. vulgaris L.), antimitotic agent treatment has to be applied. Antimitotic agent application efficiency depends on the treatment conditions, especially the agent concentration and exposure time. Also, plant developmental stage is critical for agent accessibility and plant survival. The existing methods can be used to further improve genome doubling methodology for major vegetable crops and other species.

Taxanes form a large family of compounds, the most famous of which is paclitaxel, an effective antitumor drug currently used against various cancers. First approved for the treatment of ovarian and breast cancer, it was subsequently endorsed for the treatment of many other cancer pathologies. Originally extracted from the bark of Taxus brevifolia, it has also been found in other Taxus species. Most of the drug for clinical use is currently produced by semi-synthesis, starting from a natural precursor, 10-deacetylbaccatin III recovered from the needles of Taxus baccata. The yield of paclitaxel and its precursors from yew is very low, and is not sufficient to satisfy the commercial requirements. Many attempts have been made to explore new paclitaxel-producing species including microorganisms. However, the availability of paclitaxel and related compounds is still low. The discovery of taxanes in differentiated and undifferentiated tissue of Corylus avellana suggested that the production of these compounds is not a peculiarity of the genus Taxus, giving hope for the future availability of these compounds. Here we review works aimed at exploring new paclitaxel-producing organisms with different ecology to Taxus plants. Particular focus has been placed on highlighting the discovery of taxanes in angiosperm plants. Thus, it is conceivable that, by developing appropriate methodologies, new plant species could be employed for the commercial production of paclitaxel and other antineoplastic compounds.

Purpose GSK923295 is an inhibitor of CENP-E, a key cellular protein important in the alignment of chromosomes during mitosis. This was a Phase I, open-label, first-time-in-human, dose-escalation study, to determine the maximum-tolerated dose (MTD), safety, and pharmacokinetics of GSK923295. Patients and methods Adult patients with previously treated solid tumors were enrolled in successive cohorts at GSK923295 doses ranging from 10 to 250 mg/m 2 . GSK923295 was administered by a 1-h intravenous infusion, once weekly for three consecutive weeks, with treatment cycles repeated every 4 weeks. Results A total of 39 patients were enrolled. The MTD for GSK923295 was determined to be 190 mg/m 2 . Observed dose-limiting toxicities (all grade 3) were as follows: fatigue ( n  = 2, 5%), increased AST ( n  = 1, 2.5%), hypokalemia ( n  = 1, 2.5%), and hypoxia ( n  = 1, 2.5%). Across all doses, fatigue was the most commonly reported drug-related adverse event ( n  = 13; 33%). Gastrointestinal toxicities of diarrhea ( n  = 12, 31%), nausea ( n  = 8, 21%), and vomiting ( n  = 7, 18%) were generally mild. Frequency of neutropenia was low (13%). There were two reports of neuropathy and no reports of mucositis or alopecia. GSK923295 exhibited dose-proportional pharmacokinetics from 10 to 250 mg/m 2 and did not accumulate upon weekly administration. The mean terminal elimination half-life of GSK923295 was 9–11 h. One patient with urothelial carcinoma experienced a durable partial response at the 250 mg/m 2 dose level. Conclusions The novel CENP-E inhibitor, GSK923295, had dose-proportional pharmacokinetics and a low number of grade 3 or 4 adverse events. The observed incidence of myelosuppression and neuropathy was low. Further investigations may provide a more complete understanding of the potential for GSK923295 as an antiproliferative agent.

The antineoplastic drug carmofur is shown to inhibit the SARS-CoV-2 main protease (Mpro). Here, the X-ray crystal structure of Mpro in complex with carmofur reveals that the carbonyl reactive group of carmofur is covalently bound to catalytic Cys145, whereas its fatty acid tail occupies the hydrophobic S2 subsite. Carmofur inhibits viral replication in cells (EC50 = 24.30 μM) and is a promising lead compound to develop new antiviral treatment for COVID-19.A crystal structure of SARS-CoV-2 with inhibitor carmofur reveals the mechanism of action of this compound and opens the way to develop more potent drugs.

Cancer is one of the major healthcare challenges across the globe. Several anticancer drugs are available on the market but they either lack specificity or have poor safety, severe side effects, and suffer from resistance. So, there is a dire need to develop safer and target-specific anticancer drugs. More than 85% of all physiologically active pharmaceuticals are heterocycles or contain at least one heteroatom. Nitrogen heterocycles constituting the most common heterocyclic framework. In this study, we have compiled the FDA approved heterocyclic drugs with nitrogen atoms and their pharmacological properties. Moreover, we have reported nitrogen containing heterocycles, including pyrimidine, quinolone, carbazole, pyridine, imidazole, benzimidazole, triazole, β-lactam, indole, pyrazole, quinazoline, quinoxaline, isatin, pyrrolo-benzodiazepines, and pyrido[2,3-d]pyrimidines, which are used in the treatment of different types of cancer, concurrently covering the biochemical mechanisms of action and cellular targets.

Cancer treatments which include conventional chemotherapy have not proven very successful in curing human malignancies. The failures of these treatment modalities include inherent resistance, systemic toxicity and severe side effects. Out of 50% patients administrated to chemotherapy, only 5% survive. For these reasons, the identification of new drug designs and therapeutic strategies that could target cancer cells while leaving normal cells unaffected still continues to be a challenge. Despite advances that have led to the development of new therapies, treatment options are still limited for many types of cancers. This review provides an overview of platinum, copper and ruthenium metal based anticancer drugs in clinical trials and in vitro/in vivo studies. Presumably, copper and ruthenium complexes have greater potential than Pt(II) complexes, showing reduced toxicity, a new mechanism of action, a different spectrum of activity and the possibility of non-cross-resistance. We focus the discussion towards past, present and future aspects.

Cancer is one of the major deadly diseases globally. The alarming rise in the mortality rate due to this disease attracks attention towards discovering potent anticancer agents to overcome its mortality rate. The discovery of novel and effective anticancer agents from natural sources has been the main point of interest in pharmaceutical research because of attractive natural therapeutic agents with an immense chemical diversity in species of animals, plants, and microorganisms. More than 60% of contemporary anticancer drugs, in one form or another, have originated from natural sources. Plants and microbial species are chosen based on their composition, ecology, phytochemical, and ethnopharmacological properties. Plants and their derivatives have played a significant role in producing effective anticancer agents. Some plant derivatives include vincristine, vinblastine, irinotecan, topotecan, etoposide, podophyllotoxin, and paclitaxel. Based on their particular activity, a number of other plant-derived bioactive compounds are in the clinical development phase against cancer, such as gimatecan, elomotecan, etc. Additionally, the conjugation of natural compounds with anti-cancerous drugs, or some polymeric carriers particularly targeted to epitopes on the site of interest to tumors, can generate effective targeted treatment therapies. Cognizance from such pharmaceutical research studies would yield alternative drug development strategies through natural sources which could be economical, more reliable, and safe to use.