Design, synthesis, biological assessment, and in-Silico studies of 1,2,4-triazolo[1,5-a]pyrimidine derivatives as tubulin polymerization inhibitors

Mohamed, Heba S.; Amin, Noha H.; El‐Saadi, Mohammed T.; Abdel‐Rahman, Hamdy M.

doi:10.1016/j.bioorg.2022.105687

Cited by 24 publications

(13 citation statements)

References 63 publications

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“…Mechanism studies indicate that 4 exerts antiproliferative effects by inhibition of tubulin assembly, with 3-fold greater potency than CA-4, and these data, together with data obtained with compound 5 recently identified by Mohamed et al [64], confirm that the 3 ,4 ,5 -trimethoxyphenyl ring located at the 7-position of the triazolopyrimidine system contributes to maximal activity. This latter derivative, as an analogue of 4 where the aryl ring was moved from the 2-to the 5-position of the 7-(3 ,4 ,5 -trimethoxyphenyl) triazolopyrimidine scaffold and replaced by an amino group, exhibits significant antiproliferative activity (IC 50 : 0.53 µM) against the HCT-116 cancer cell line, with four-fold less activity than CA-4 as a tubulin polymerization inhibitor (IC 50 : 3.84 and 1.1 µM, respectively) [64].…”

Section: Introductionsupporting

confidence: 71%

“…The [1,2,4]triazolo [1,5-a]pyrimidine scaffold incorporating the 1,2,4-triazole nucleus (Figure 1) was previously identified by us and others as a promising nucleus for the design of new microtubule-destabilizing agents [61][62][63][64][65]. Two different series of compounds that retain the 3,4,5-trimethoxyphenyl ring at the 7-position of the triazolopyrimidine core variably functionalized at its 2-position were evaluated for their antitumor activity [62][63][64].…”

Section: Introductionmentioning

confidence: 99%

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Design, Synthesis and Biological Investigation of 2-Anilino Triazolopyrimidines as Tubulin Polymerization Inhibitors with Anticancer Activities

et al. 2022

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A further investigation aiming to generate new potential antitumor agents led us to synthesize a new series of twenty-two compounds characterized by the presence of the 7-(3′,4′,5′-trimethoxyphenyl)-[1,2,4]triazolo[1,5-a]pyrimidine pharmacophore modified at its 2-position. Among the synthesized compounds, three were significantly more active than the others. These bore the substituents p-toluidino (3d), p-ethylanilino (3h) and 3′,4′-dimethylanilino (3f), and these compounds had IC50 values of 30–43, 160–240 and 67–160 nM, respectively, on HeLa, A549 and HT-29 cancer cells. The p-toluidino derivative 3d was the most potent inhibitor of tubulin polymerization (IC50: 0.45 µM) and strongly inhibited the binding of colchicine to tubulin (72% inhibition), with antiproliferative activity superior to CA-4 against A549 and HeLa cancer cell lines. In vitro investigation showed that compound 3d was able to block treated cells in the G2/M phase of the cell cycle and to induce apoptosis following the intrinsic pathway, further confirmed by mitochondrial depolarization and caspase-9 activation. In vivo experiments conducted on the zebrafish model showed good activity of 3d in reducing the mass of a HeLa cell xenograft. These effects occurred at nontoxic concentrations to the animal, indicating that 3d merits further developmental studies.

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Section: Introductionsupporting

confidence: 71%

Section: Introductionmentioning

confidence: 99%

Design, Synthesis and Biological Investigation of 2-Anilino Triazolopyrimidines as Tubulin Polymerization Inhibitors with Anticancer Activities

et al. 2022

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“…In the last decade, many trimethoxyphenyl-based structures were designed, developed, and synthesized as promising anticancer agents that could target tubulin protein, and some of these compounds reached clinical trials, or were approved by the FDA for cancer treatment [ 123 , 124 , 125 ]. Starting with CA-4P ( Figure 1 ), which was approved for thyroid cancer, many other trimethoxyphenyl-based compounds entered the clinical trials for specific cancer types including St.56 (BNC-105p; Figure 11 ), which was found to have considerable potency and an inhibitory effect against the growth of different kinds of cancer cell lines with a broader therapeutic index than CA-4P in vivo.…”

Section: Trimethoxy Phenyl Analogsmentioning

confidence: 99%

Recent Advances of Tubulin Inhibitors Targeting the Colchicine Binding Site for Cancer Therapy

Hawash

2022

Biomolecules

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Cancer accounts for numerous deaths each year, and it is one of the most common causes of death worldwide, despite many breakthroughs in the discovery of novel anticancer candidates. Each new year the FDA approves the use of new drugs for cancer treatments. In the last years, the biological targets of anticancer agents have started to be clearer and one of these main targets is tubulin protein; this protein plays an essential role in cell division, as well as in intracellular transportation. The inhibition of microtubule formation by targeting tubulin protein induces cell death by apoptosis. In the last years, numerous novel structures were designed and synthesized to target tubulin, and this can be achieved by inhibiting the polymerization or depolymerization of the microtubules. In this review article, recent novel compounds that have antiproliferation activities against a panel of cancer cell lines that target tubulin are explored in detail. This review article emphasizes the recent developments of tubulin inhibitors, with insights into their antiproliferative and anti-tubulin activities. A full literature review shows that tubulin inhibitors are associated with properties in the inhibition of cancer cell line viability, inducing apoptosis, and good binding interaction with the colchicine binding site of tubulin. Furthermore, some drugs, such as cabazitaxel and fosbretabulin, have been approved by FDA in the last three years as tubulin inhibitors. The design and development of efficient tubulin inhibitors is progressively becoming a credible solution in treating many species of cancers.

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“…[ 1 , 2 , 4 ]Triazolo[1,5- a ]pyrimidine, as an important class of bicyclic N -heteroarenes, exhibits versatile bioactivities, such as antibacterial [ 1 , 2 , 3 ], antiviral [ 4 , 5 , 6 ] and anticancer activities [ 7 , 8 , 9 , 10 , 11 , 12 ]. Recently, [ 1 , 2 , 4 ]triazolo[1,5- a ]pyrimidine derivatives as anticancer agents via acting on different targets, such as tubulin [ 9 , 10 , 11 , 13 , 14 ], LSD1 [ 15 , 16 ] and CDK2 [ 17 ], have aroused remarkable research attention and exhibited potent antitumor activities. 5-Phenyl-[ 1 , 2 , 4 ]triazolo[1,5- a ]pyrimidine 1 as a cytotoxic agent effectively inhibited the growth of MCF-7 cells, with an IC 50 value of 3.91 μM [ 7 ].…”

Section: Introductionmentioning

confidence: 99%

“…5-Phenyl-[ 1 , 2 , 4 ]triazolo[1,5- a ]pyrimidine 1 as a cytotoxic agent effectively inhibited the growth of MCF-7 cells, with an IC 50 value of 3.91 μM [ 7 ]. As a tubulin polymerization inhibitor, compound 2 showed significant antiproliferative activity against HCT-116 cells, with an IC 50 value of 0.53 μM, and compound 2 could induce cell apoptosis and G2/M phase arrest in HCT-116 cells [ 9 ]. Compound 3 could potently inhibit the polymerization of tubulin (IC 50 = 3.84 μM) and display significant inhibitory potency on T47D, HCT29 and A549 cells (IC 50 = 3.49, 0.24 and 6.05 μM, respectively) [ 11 ].…”

Section: Introductionmentioning

confidence: 99%

Design, Synthesis and Biological Evaluation of [1,2,4]Triazolo[1,5-a]pyrimidine Indole Derivatives against Gastric Cancer Cells MGC-803 via the Suppression of ERK Signaling Pathway

Zhang

et al. 2022

Molecules

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[1,2,4]Triazolo[1,5-a]pyrimidine and indole skeletons are widely used to design anticancer agents. Therefore, in this work, a series of [1,2,4]triazolo[1,5-a]pyrimidine indole derivatives were designed and synthesized by the molecular hybridization strategy. The antiproliferative activities of the target compounds H1–H18 against three human cancer cell lines, MGC-803, HCT-116 and MCF-7, were tested. Among them, compound H12 exhibited the most active antiproliferative activities against MGC-803, HCT-116 and MCF-7 cells, with IC50 values of 9.47, 9.58 and 13.1 μM, respectively, which were more potent than that of the positive drug 5-Fu. In addition, compound H12 could dose-dependently inhibit the growth and colony formation of MGC-803 cells. Compound H12 exhibited significant inhibitory effects on the ERK signaling pathway, resulting in the decreased phosphorylation levels of ERK1/2, c-Raf, MEK1/2 and AKT. Furthermore, compound 12 induced cell apoptosis and G2/M phase arrest, and regulated cell cycle-related and apoptosis-related proteins in MGC-803 cells. Taken together, we report here that [1,2,4]triazolo[1,5-a]pyrimidine indole derivatives, used as anticancer agents via the suppression of ERK signaling pathway and the most active compound, H12, might be a valuable hit compound for the development of anticancer agents.

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Design, synthesis, biological assessment, and in-Silico studies of 1,2,4-triazolo[1,5-a]pyrimidine derivatives as tubulin polymerization inhibitors

Cited by 24 publications

References 63 publications

Design, Synthesis and Biological Investigation of 2-Anilino Triazolopyrimidines as Tubulin Polymerization Inhibitors with Anticancer Activities

Design, Synthesis and Biological Investigation of 2-Anilino Triazolopyrimidines as Tubulin Polymerization Inhibitors with Anticancer Activities

Recent Advances of Tubulin Inhibitors Targeting the Colchicine Binding Site for Cancer Therapy

Design, Synthesis and Biological Evaluation of [1,2,4]Triazolo[1,5-a]pyrimidine Indole Derivatives against Gastric Cancer Cells MGC-803 via the Suppression of ERK Signaling Pathway

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