Triazole-based hybrid molecules in anticancer drug discovery: structural classes and mechanistic insights, 2014–2025

• Meena Bhandari,
• Akshi Goyal and
• Deepak Yadav

Beilstein J. Org. Chem. 2026, 22, 1168–1195, doi:10.3762/bjoc.22.94

• and lay the groundwork for designing future anticancer drug candidates. Keywords: anticancer agents; cancer cells; cytotoxicity; hybrids; 1,2,3-triazole; 1,2,4-triazole; Introduction Annually, almost 9 million individuals pass away from cancer-related causes [1]. Different types of carcinomas can

• counteract cancer cells' susceptibility to medications [37]. These hybrid molecules offer multiple advantages over conventional anticancer agents. They can improve pharmacokinetic, pharmacodynamic, and physicochemical properties, minimize drug–drug interactions, and potentially overcome drug resistance [38

• towards different cancer cells. These compounds demonstrated promising growth inhibition with IC50 values ranging from 14.6–33.4 µM (Paca-2), 4.1–65.1 µM (MeI-501), 12.5–51.3 µM (PC-3), 9.9–14.5 µM (A-375) and 20.4–70.2 µM (Caco-2). Notably, compounds 31a and 31c are more effective against Paca-2 cells

Synthesis and acaricidal activity against Varroa destructor of α- and γ-costic acid dimers

• Alessandro Santarsiere,
• Ernesto Santoro,
• Maria Letizia Ciavatta,
• Marianna Carbone,
• Sonia Ganassi,
• Cosimo Tedino,
• Antonio De Cristofaro,
• Antonio Evidente and
• Stefano Superchi

Beilstein J. Org. Chem. 2026, 22, 1088–1096, doi:10.3762/bjoc.22.87

• activity with respect to their parent compounds shifting potencies from two-digit to single-digit micromolar levels against apoptosis-resistant cancer cells [20]. Similar increases in anticancer activity have been also reported for dimers of other natural bioactive compounds [20]. Consequently, it was of

The trans-influence in gold chemistry from a catalytic perspective

• Manfred Bochmann

Beilstein J. Org. Chem. 2026, 22, 838–856, doi:10.3762/bjoc.22.66

• increased take-up into oestrogen-receptor positive (ER+) breast cancer cells for improved anticancer activity [33]. Similar chelate and pincer gold(III) complexes are potential anticancer therapy targets [34][35][36]. In their assessment of the trans-influence of the C^N^C pincer in comparison with the C^C

• -complexes stabilised by C^N^C and C^N chelate ligands [28][29][30][31][32] and an example of a gold(III) complex targeting oestrogen-receptor positive (ER+) breast cancer cells [11][33][34][35][36]. Gold(III) C^C chelate complexes. Gold hydride complexes supported by tridentate pincer ligands and

Anti-invasive and cytotoxic evaluation of a (+)-pinoresinol-based semisynthetic library against glioblastoma

• Chen Zhang,
• Kah Yean Lum,
• Jonathan M. White,
• Paul I. Forster,
• Nicholas Booth,
• Sunita A. Ramesh and
• Rohan A. Davis

Beilstein J. Org. Chem. 2026, 22, 691–704, doi:10.3762/bjoc.22.54

• cancer cells from moving. In this study, a unique plant-derived lignan‑based library was screened against glioblastoma (brain cancer) cell lines to evaluate anti-invasive and cytotoxicity effects. Results and Discussion The air-dried and ground seeds of E. maculata were sequentially extracted with CH2Cl2

• (MIC = 25 µM), and Malassezia furfur (MIC = 12.5 µM) [20]; antioxidant activity with the inhibition of CuSO4-induced peroxidation of low-density lipoprotein in a concentration-dependent manner from 0.1−10 µM [21], and anti-invasiveness activity on HT115 human colon cancer cells at a concentration

• migration of proliferating cancer cells [23][29], all compounds were tested against two human glioblastoma cell lines, U251MG and KNS42 [23][24]. Glioblastoma, which is also known as glioblastoma multiforme (GBM), is a grade IV glioma and one of the deadliest human cancers [30]. Following cytotoxicity

Advantages of PROTACs in achieving selective degradation of homologous protein families

• Luxi Yang,
• Xinfei Mao,
• Jingyi Zhang,
• Jing Shu,
• Wenhai Huang,
• Xiaowu Dong,
• Yinqiao Chen and
• Mingfei Wu

Beilstein J. Org. Chem. 2026, 22, 628–661, doi:10.3762/bjoc.22.49

• more conducive to the selective degradation of CDK6. In addition to CDK4/6, CDK9 is another family member that is getting a lot of attention. Many studies have shown that CDK9 is closely related to many types of cancer and it is crucial to cancer cells’ maintenance, growth, metastasis, and chemical

• molecular selectivity (Figure 10). As for the “amide series”, the authors discovered that in MDA-MB-231 human breast cancer cells, the 10-atom and 11-atom linker PROTACs (SJF-6693 (26) and SJF-6690 (27)) were not selective and degraded both p38α and p38δ nonspecifically with DC50 < 100 nM (Figure 11

• : Serum-glucocorticoid-induced protein kinase (SGK) plays a key role in mediating resistance to phosphoinositide 3-kinase (PI3K)/Akt inhibition in breast cancer cells [132]. It has been reported that different ATP competitive inhibitors have similar affinity for all SGK isoforms [133][134]. Due to the

Design and synthesis of an erdafitinib-based selective FGFR2 degrader

• Yumeng Jin,
• Shidong Wang,
• Sihan Pan,
• Shuqi Huang,
• Weichen Zhou,
• Xiaohao Huang,
• Lei Zheng and
• Lingfeng Chen

Beilstein J. Org. Chem. 2026, 22, 583–591, doi:10.3762/bjoc.22.44

• gastric cancer cells. Although LC-JD-5, which is the homoisomer of LC-JD-6, is still lacking compared to LC-JD-6. To further verify the potency, LC-JD-6 was prescribed at an extensive concentration range (0.4–10,00 nM) in KATO III cells after 6 hours, with the DC50 of 121.4 nM and a maximal degradation

• -JD-6 could directly degrade FGFR2 from the plasma membrane. KATO III gastric cancer cells were incubated with 500 nM LC-JD-6 for 12 hours, followed by flow cytometric quantification of cell surface FGFR2 expression. As shown in Figure 4b and Figure 4c, LC-JD-6 treatment led to a marked decrease in

Modern synthetic pathways towards eribulin and its subunits

• Sebastian Dominik Graf

Beilstein J. Org. Chem. 2026, 22, 495–526, doi:10.3762/bjoc.22.37

• within their isolation study on halichondrin B, in 1986, Hirata and Uemura showed its promising activity against murine cancer cells [6], which led to a great interest in the pharmaceutical society [7][8][9][10][11][12][13][14][15][16][17][18][19][20]. Only 6 years later, Kishi and co-workers first

Recent advances in the stereoselective synthesis of distal biaxially chiral molecules

• Fanxing Zhou,
• Chen Zhang,
• Lingyu Sun,
• Yiyun Fang,
• Siming Zheng,
• Lina Hu,
• Mengyang Shen,
• Zhen Zhao,
• Wei Xu,
• Yunqiang Sun and
• Zi-Qiang Rong

Beilstein J. Org. Chem. 2026, 22, 461–479, doi:10.3762/bjoc.22.34

• (Scheme 11) [52]. A preliminary biological evaluation revealed inhibitory activity of selected products against MV4-11 cancer cells, highlighting their potential in pharmaceutical research. At the same time, efficient synthetic routes to uracils bearing a single C–N axis were also achieved in yields

Structural reassignment of compound 968, an allosteric glutaminase inhibitor

• Lindsey A. Albertelli,
• Sainabou Jallow,
• Chun Li and
• Scott M. Ulrich

Beilstein J. Org. Chem. 2026, 22, 455–460, doi:10.3762/bjoc.22.33

• Lindsey A. Albertelli Sainabou Jallow Chun Li Scott M. Ulrich Department of Chemistry, Ithaca College, Ithaca, NY 14850, USA 10.3762/bjoc.22.33 Abstract Many cancer cells require extracellular glutamine to meet the energetic, biosynthetic, and redox demands of the proliferative state

• . Glutaminases catalyze the hydrolysis of glutamine to glutamate, which supports the biosynthesis of amino acids, lipids, and glutathione and can also be oxidatively deaminated to α-ketoglutarate and enter the citric acid cycle. The “glutamine addiction” of cancer cells has made glutaminase an attractive

• anticancer drug target. Compound 968 is a glutaminase inhibitor that is widely used to probe cancer cells’ dependence on glutaminase activity. Here, we show by NMR spectroscopy and X-ray crystallography that the reported benzo[c]phenanthridine structure of compound 968 is incorrect; its true structure is the

Synthesis and anti-cancer activity of naphthalimide–organylselanyl conjugates

• Rajkumar Ravi and
• Selvakumar Karuthapandi

Beilstein J. Org. Chem. 2026, 22, 416–435, doi:10.3762/bjoc.22.29

• -231 breast cancer cells were seeded into 96-well plates containing culture medium composed of 10% protein and 90% media (DMEM supplemented with fetal bovine serum, FBS) to a final volume of 100 μL per well. The cells were incubated for 48 h at 37 °C in a 5% CO₂ atmosphere. Test compounds were

Design, synthesis and biological evaluation of 2,5-diaryloxazolo[4,5-d]pyrimidin-7-ylamines as selective cytotoxic agents against HeLa cells

• Maryna V. Kachaeva,
• Agnieszka B. Olejniczak,
• Marta Denel-Bobrowska,
• Victor V. Zhirnov,
• Yevheniia S. Velihina,
• Stepan G. Pilyo and
• Volodymyr S. Brovarets

Beilstein J. Org. Chem. 2026, 22, 390–398, doi:10.3762/bjoc.22.27

• lines such as HepG2 (liver), HeLa (cervix), A549 (lung), and glioblastoma models rely on enhanced nucleotide metabolism to sustain rapid DNA/RNA synthesis. Oxazolopyrimidines can inhibit these overactive enzymes in cancer cells, while normal cells (with lower demand) are less affected. This explains why

• breast cancer cells (MCF-7 – IC50 1.18–11.81 µM) by increasing intracellular accumulation [7]. A significant number of studies has been published on the anticancer activity of oxazolo[5,4-d]pyrimidines, showing their significant activity as agonists and antagonists of signaling pathways involved in the

• cytotoxicity results (CC50, µM) for the investigated compounds and the calculated selectivity index values are presented in Table 1. The compounds 2, 6, and 8 were found to be non-toxic towards all the cancer and non-cancer cell lines investigated (CC50 > 1000 µM). In general, cancer cells form the following

Spirobarbiturates with a pyrrolizidine moiety: synthesis, structure and biological evaluation

• Arthur A. Puzyrkov,
• Andrew S. Drachuk,
• Ekaterina A. Popova,
• Alexander V. Stepakov and
• Vitali M. Boitsov

Beilstein J. Org. Chem. 2026, 22, 274–288, doi:10.3762/bjoc.22.20

• potential in the brain with regard to bioavailability in the CNS. Antiproliferative activity study. Cancer cells are favorable in vitro models that are widely used in cancer research and drug discovery. In this study, the MTS assay was applied to evaluate the antiproliferative activity of the synthesized

• compounds. The results of antiproliferative activity study showed that generally spiro-adducts have limited effect on the tested cancer cells, while they caused significant changes of Sk-mel-2 cells’ actin cytoskeleton structure leading to the disappearance of stress fibers (granular actin was distributed

Synthesis and characterization of a isothiouronium-calix[4]arene derivative: self-assembly and anticancer activity

• Giuseppe Granata,
• Loredana Ferreri,
• Claudia Giovanna Leotta,
• Giovanni Mario Pitari and
• Grazia Maria Letizia Consoli

Beilstein J. Org. Chem. 2025, 21, 2535–2541, doi:10.3762/bjoc.21.195

• chains at the lower rim. The resulting amphiphilic calix[4]arene derivative 3 spontaneously self-assembled into nanoscale aggregates in aqueous medium, as demonstrated by dynamic light scattering analysis. The cytotoxicity of compound 3 towards cancer cells was assessed using human renal carcinoma cells

• (786-O cells) and compared with that in non-malignant fibroblast cells (SW1 cells). Compound 3 showed a significantly greater antiproliferative effect on cancer cells (IC50 37.4 µM) than on normal fibroblasts (517 µM). The importance of the isothiouronium moieties in the observed cytoxic effect was

• to the nanosize, the calixarene-based nanoconstructs could preferentially accumulate in cancer tissues by exploiting the enhanced tumor permeability and retention (EPR) effect [24] or selectively penetrate cancer cells through specific ligand–receptor interactions on the surface of target cells [25

Further elaboration of the stereodivergent approach to chaetominine-type alkaloids: synthesis of the reported structures of aspera chaetominines A and B and revised structure of aspera chaetominine B

• Jin-Fang Lü,
• Jiang-Feng Wu,
• Jian-Liang Ye and
• Pei-Qiang Huang

Beilstein J. Org. Chem. 2025, 21, 2072–2081, doi:10.3762/bjoc.21.162

• ) from marine sponge associated fungus Aspergillus versicolour SCSIO XWS04 F52 [32]. They reported that both the two alkaloids showed cytotoxic activity against leukaemia K562 and colon cancer cells SW1116 with IC50 ranged from 7.5 to 12.5 μM, and significant protection against H1N1 virus-induced

Discovery of cytotoxic indolo[1,2-c]quinazoline derivatives through scaffold-based design

• Daniil V. Khabarov,
• Valeria A. Litvinova,
• Lyubov G. Dezhenkova,
• Dmitry N. Kaluzhny,
• Alexander S. Tikhomirov and
• Andrey E. Shchekotikhin

Beilstein J. Org. Chem. 2025, 21, 2062–2071, doi:10.3762/bjoc.21.161

• biological evaluation of novel indolo[1,2-c]quinazoline derivatives, with a particular focus on their antiproliferative potential against human cancer cells. We introduced structural modifications at positions 5, 6, and 12 of the indolo[1,2-c]quinazoline core to explore the structure–activity relationships

• cytotoxicity and reasonable selectivity toward cancer cells over non-malignant fibroblasts. In contrast, derivatives modified at positions 5 and 6 also demonstrated cytotoxic potential, but without a significant improvement in selectivity. Fluorescence titration assays revealed that only the 12-carboxamide

Synthesis, biological and electrochemical evaluation of glycidyl esters of phosphorus acids as potential anticancer drugs

• Almaz A. Zagidullin,
• Emil R. Bulatov,
• Mikhail N. Khrizanforov,
• Damir R. Davletshin,
• Elvina M. Gilyazova,
• Ivan A. Strelkov and
• Vasily A. Miluykov

Beilstein J. Org. Chem. 2025, 21, 1909–1916, doi:10.3762/bjoc.21.148

• , obtaining products with high purity and moderate to excellent yields. Their cytotoxic potential was evaluated using the MTT assay on human fibroblasts (HSF), prostate cancer (PC-3), and breast cancer (MCF7) cell lines, revealing moderate preferential cytotoxicity toward cancer cells, particularly in the

• . Among the tested compounds, triglycidyl phosphate (3) demonstrated the highest overall cytotoxicity against HSF and PC-3 cell lines, while diglycidyl methylphosphate (2) showed the greatest potency toward MCF7 breast cancer cells. Although the IC50 values for compounds 1 and 2 were somewhat higher in

• normal fibroblasts (HSF) compared to cancer cells, the differences were moderate (less than twofold). These results suggest a modest preferential cytotoxicity toward cancer cells, particularly in the case of compound 2 against MCF7, though further studies are needed to establish meaningful selectivity

Research progress on calixarene/pillararene-based controlled drug release systems

• Liu-Huan Yi,
• Jian Qin,
• Si-Ran Lu,
• Liu-Pan Yang,
• Li-Li Wang and
• Huan Yao

Beilstein J. Org. Chem. 2025, 21, 1757–1785, doi:10.3762/bjoc.21.139

• complex, NMP-BE@SAC5A, that is responsive to dual hypoxia signals (Figure 15) [123]. The azo group in SAC5A endows it with hypoxia responsiveness, allowing it to enhance the accumulation of NMP-BE in tumors under hypoxic conditions in cancer cells. Upon intracellular release in cancer cells, NMP-BE

• exhibited high cytotoxicity against cancer cells but low toxicity to normal cells. They further combined Biotin-SAC4A with DOX and injected it into mice. The experimental results showed that Biotin-SAC4A could firmly bind DOX and promote its release under hypoxic conditions. In 2024, Guo and colleagues

• TANI promote the host–guest interactions between WP5 and TANI, leading to the further formation of supramolecular vesicles by the WP5⊃TANI complex. These vesicles are non-toxic to normal cells but exhibit toxicity towards cancer cells. The WP5⊃TANI supramolecular vesicles can effectively encapsulate

Ambident reactivity of enolizable 5-mercapto-1H-tetrazoles in trapping reactions with in situ-generated thiocarbonyl S-methanides derived from sterically crowded cycloaliphatic thioketones

• Grzegorz Mlostoń,
• Małgorzata Celeda,
• Marcin Palusiak,
• Heinz Heimgartner,
• Marta Denel-Bobrowska and
• Agnieszka B. Olejniczak

Beilstein J. Org. Chem. 2025, 21, 1508–1519, doi:10.3762/bjoc.21.113

• isomeric products was a feasible operation. Cytotoxicity of selected thioaminals 9 and dithioacetals 10 in cancer and non-cancer cells Cytotoxicity investigations represent a pivotal component in the realm of pharmaceutical development and contemporary medicine. In vitro assays constitute a rapid method

• some of them act as potent cytotoxic agents against certain cancer cells. In addition, the newly synthesized, sterically crowded 1,3,4-thiadiazolines 2c,d can be considered as attractive precursors of the corresponding bulky substituted thiiranes 8 and ethylenes derived from the corresponding

Pd-Catalyzed asymmetric allylic amination with isatin using a P,olefin-type chiral ligand with C–N bond axial chirality

• Natsume Akimoto,
• Kaho Takaya,
• Yoshio Kasashima,
• Kohei Watanabe,
• Yasushi Yoshida and
• Takashi Mino

Beilstein J. Org. Chem. 2025, 21, 1018–1023, doi:10.3762/bjoc.21.83

• in medicinal chemistry. For example, racemic compound 1 (Figure 1) was evaluated for its cytotoxicity against human breast cancer cells (MCF7) in comparison to the standard doxorubicin and exhibited excellent activity against the MCF7 cell line [12]. The optically active compound 2 also showed

Photocatalyzed elaboration of antibody-based bioconjugates

• Marine Le Stum,
• Eugénie Romero and
• Gary A. Molander

Beilstein J. Org. Chem. 2025, 21, 616–629, doi:10.3762/bjoc.21.49

• designed in the context of cancer therapy [1], which combines the precision targeting of monoclonal antibodies (mAbs) with the therapeutic effects of cytotoxic drugs [2]. The ADCs are thus designed to deliver potent cytotoxic agents selectively and directly to cancer cells while minimizing damage to

Semisynthetic derivatives of massarilactone D with cytotoxic and nematicidal activities

• Rémy B. Teponno,
• Sara R. Noumeur and
• Marc Stadler

Beilstein J. Org. Chem. 2025, 21, 607–615, doi:10.3762/bjoc.21.48

• human cancer cells and evaluated for their nematicidal activity. Results and Discussion Semisynthesis of massarilactone D derivatives The reaction of massarilactone D with methacryloyl chloride in triethylamine in the presence of catalytic amounts of 4-dimethylaminopyridine afforded compound 2 (11

Synthesis, structure, ionochromic and cytotoxic properties of new 2-(indolin-2-yl)-1,3-tropolones

• Yurii A. Sayapin,
• Eugeny A. Gusakov,
• Inna O. Tupaeva,
• Alexander D. Dubonosov,
• Igor V. Dorogan,
• Valery V. Tkachev,
• Anna S. Goncharova,
• Gennady V. Shilov,
• Natalia S. Kuznetsova,
• Svetlana Y. Filippova,
• Tatyana A. Krasnikova,
• Yanis A. Boumber,
• Alexey Y. Maksimov,
• Sergey M. Aldoshin and
• Vladimir I. Minkin

Beilstein J. Org. Chem. 2025, 21, 358–368, doi:10.3762/bjoc.21.26

• MTT assay was used to determine the anticancer activity of compound 7a against these cultures (Figure 6). The viability test is an important method to determine which new compounds are able to target cancer cells. The results of this test (IC50 value ± 95% confidence interval) allow us to evaluate the

Synthesis, characterization, antimicrobial, cytotoxic and carbonic anhydrase inhibition activities of multifunctional pyrazolo-1,2-benzothiazine acetamides

• Ayesha Saeed,
• Shahana Ehsan,
• Muhammad Zia-ur-Rehman,
• Erin M. Marshall,
• Sandra Loesgen,
• Abdus Saleem,
• Simone Giovannuzzi and
• Claudiu T. Supuran

Beilstein J. Org. Chem. 2025, 21, 348–357, doi:10.3762/bjoc.21.25

• prepared in DMSO and cancer cells were treated with 10 μM doses of compounds using the apoptosis inducing standard mensacarcin (10 μM) as a positive control [56]. Only compound 7l decreased cell viability to 63%, while the rest of the compounds showed very low to no significant decrease in cell viability

• experiments. Cytotoxic assays Single-dose MTT assays were performed for compounds 7a–n with the human colon cancer mammalian cell line (HCT-116, ATCC CCL-247) for evaluating the compounds’ inhibitory effects on cell viability [53][54][55][56]. Stock solutions of compounds were prepared in DMSO and cancer

• cells were treated with 10 μM doses of each compound and mensacarcin (10 μM) as a positive control [56]. MTT in 1X PBS was added for a final concentration of 0.5 mg/mL 48 hours post compound addition to each well. Post incubation at 37 °C was carried out for 2 h. After the removal of the growth media

Recent advances in organocatalytic atroposelective reactions

• Henrich Szabados and
• Radovan Šebesta

Beilstein J. Org. Chem. 2025, 21, 55–121, doi:10.3762/bjoc.21.6

• enantiopurity at 130 °C for 48 h in toluene. Investigating the biological activity for a number of compounds, good cytotoxicity was reported for five kinds of cancer cells. The mechanistic study suggests that the indole ring of the substrate is having a crucial role in the reaction mechanism because replacing

N-Glycosides of indigo, indirubin, and isoindigo: blue, red, and yellow sugars and their cancerostatic activity

• Peter Langer

Beilstein J. Org. Chem. 2024, 20, 2840–2869, doi:10.3762/bjoc.20.240

• mitochondria was changed. The presence of β-33b provoked a significant upregulation of the enzyme heme oxygenase-1. In conclusion, mitochondria are attacked by compound β-33b in the context of its cytotoxic activity against skin cancer cells. Aglycon 35 again proved to be inactive in all assays. It was

• carbohydrate moiety is later hydrolytically cleaved in the cell to release the indirubin which then acts as a CDK inhibitor. A synergistic effect of plasma-activated medium (PAM) and β-33b on human skin cancer cells was observed [32][33]. With regard to viability, adhesion capacity, apoptosis and G2/M cell

• cycle arrest, especially in A375 cells, glycoside β-33b alone showed a stronger anticancer effect as compared to oxime 34. PAM significantly increased these effects in skin cancer cells. In contrast, no effect was observed for non-glycosylated thioindirubin 35 alone or in combination with PAM. It is