Design and development of new substituted pyrimidine hybrids with imidazole and triazole: Exploring utility as an anticancer agent via human topoisomerase-II and tubulin inhibition.

In the present research, we developed pyrimidine-based hybridized molecules with either imidazole or triazole to find effective anticancer drugs. The reaction was accomplished using a multicomponent reaction pathway. The synthetics were explored for their utility as an anticancer agent via human topoisomerase-II and tubulin inhibition. Among the synthetics, compounds 1B4, 1B5, and 1B6 were potent anticancer agents tested in five cancer cell lines compared to colchicine and etoposide employed as positive controls. These synthetics were found further devoid of any significant cytotoxicity towards normal cells, thus proving their selective anticancer nature. Further, these compounds inhibited both the tubulin and hTopoII as indicated by in vitro-based assay. The mechanistic insights were corroborated using molecular docking studies. Besides this, the molecules were found to portray their secondary anticancer cell death mechanism via apoptosis. They decreased the oxidative stress, induced apoptosis, and arrested the cell cycle arrest at the G2/M phase in cancer cells.

Yadav UP ，Yaseen M ，Singh S ，Babu MA ，Bhat MA ，Kumar R ，Tyagi Y ，Ullah I ，Huang Y ... -  《-》

Development of 1,2,3-triazole hybrids as multi-faced anticancer agents co-targeting EGFR/mTOR pathway and tubulin depolymerization.

Novel 1,2,3-triazole hybrids bearing various substituents have been synthesized as potential anticancer agents. Ligand-based approach has been adopted to design these compounds relying on the hybridization of 1,2,3-triazole with α,β-unsaturated carbonyl, 5- and 6-membered heterocyclic scaffolds. All synthesized members were investigated for their cytotoxic potency against nine types comprising 60 panels of human cancerous cells by the US National Cancer Institute: Development Therapeutic Program (US_NCI_DTP). Among the tested members, 4b, 4e, and 4h showed prominent cytotoxic effects (> 80 % growth inhibition: GI) on a wide panel of tested cancer cell lines, mainly melanoma and colorectal cancer redeeming their selection for five dose testing. Presenting low nanomolar GI50 concentrations, two representative potent anticancer compounds 4b and 4e were subjected to cytotoxicity testing on colon normal cell (FHC) to investigate their safety window and they showed less toxicity to normal cells at the concentration required to produce anticancer effect. Furthermore, 4b and 4e were exposed to additional mechanistic studies in colorectal cancer cell HCT-116 suggesting multifaceted mechanisms of action. A study into the effects of cytotoxic chemicals 4b and 4e on cell cycle progression regulation showed triggered the arrest of cell cycles during the G1 and S phases. Moreover, 4b and 4e caused cell death mainly through apoptosis the thing that has been reinforced by the elevated Bax: Bcl2 ratio, as well as concentrations of caspases 3 and 9 within HCT-116. Further, both compounds showed prominent inhibition profiles against tubulin polymerization as well as EGFR catalytic activity reaching down to low-digit micromolar and sub-micromolar concentrations, respectively, as compared to positive reference controls. Compounds' impacts on gene expression of cancer-associated and EGFR-downstream signaling markers including TNFα, IL-6, and mTOR, were explored in HCT-116 highlighted significant downregulations versus the untreated cells. Docking studies demonstrated the specific fit of 4b and 4e into EGFR and the colchicine binding site of tubulin.

Shaheen MA ，Darwish KM ，Kishk SM ，El-Sayed MA ，Salama I ... -  《-》

Novel quinazolin-2-yl 1,2,3-triazole hybrids as promising multi-target anticancer agents: Design, synthesis, and molecular docking study.

In our study, a series of quinazoline-1,2,3-triazole hybrids (14a-r) have been designed and synthesized as multi-target EGFR, VEGFR-2, and Topo II inhibitors. All synthesized hybrids were assessed for their anticancer capacity. MTT assay revealed that compounds 14a, 14d, and 14k were the most potent hybrids against four cancer cell lines, HeLa, HePG-2, MCF-7, and HCT-116 at low micromolar range while exhibiting good selectivity against normal cell line WI-38. Sequentially, the three compounds were evaluated for EGFR, VEGFR-2, and Topo II inhibition. Compound 14d was moderate EGFR inhibitor (IC50 0.103 µM) compared to Erlotinib (IC50 0.049 µM), good VEGFR-2 inhibitor (IC50 0.069 µM) compared to Sorafenib (IC50 0.031 µM), and stronger Topo II inhibitor (IC50 19.74 µM) compared to Etoposide (IC50 34.19 µM) by about 1.7 folds. Compounds 14k and 14a represented strong inhibitory activity against Topo II with (IC50 31.02 µM and 56.3 µM) respectively, compared to Etoposide. Additionally, cell cycle analysis and apoptotic induction were performed. Compound 14d arrested the cell cycle on HeLa at G2/M phase by 17.53 % and enhanced apoptosis by 44.08 %. A molecular Docking study was implemented on the three hybrids and showed proper binding interaction with EGFR, VEGFR-2, and Topo II active sites.

El Hamaky NFM ，Hamdi A ，Bayoumi WA ，Elgazar AA ，Nasr MNA ... -  《-》

Design and synthesis of novel imidazole-chalcone derivatives as microtubule protein polymerization inhibitors to treat cervical cancer and reverse cisplatin resistance.

Using the licochalcone moiety as a lead compound scaffold, 16 novel imidazole-chalcone derivatives were designed and synthesized as microtubule protein polymerization inhibitors. The proliferation inhibitory activities of the derivatives against SiHa (human cervical squamous cell carcinoma), C-33A (human cervical cancer), HeLa (human cervical cancer), HeLa/DDP (cisplatin-resistant human cervical cancer), and H8 (human cervical epithelial immortalized) cells were evaluated. Compound 5a exhibited significant anticancer activity with IC50 values ranging from 2.28 to 7.77 μM and a resistance index (RI) of 1.63, while showing minimal toxicity to normal H8 cells. When compound 5a was coadministered with cisplatin, the RI of cisplatin to HeLa/DDP cells decreased from 6.04 to 2.01, while compound 5a enhanced the fluorescence intensity of rhodamine 123 in HeLa/DDP cells. Further studies demonstrated that compound 5a arrested cells at the G2/M phase, induced apoptosis, reduced colony formation, inhibited cell migration, and inhibited cell invasion. Preliminary mechanistic studies revealed that compound 5a decreased the immunofluorescence intensity of α-/β-tubulin in cancer cells, reduced the expression of polymerized α-/β-tubulin, and increased the expression of depolymerized α-/β-tubulin. Additionally, the molecular docking results demonstrate that compound 5a can interact with the tubulin colchicine binding site and generate multiple types of interactions. These results suggested that compound 5a has anticancer effects and significantly reverses cervical cancer resistance to cisplatin, which may be related to its inhibition of microtubule and P-glycoprotein (P-gp) activity.

Liu Z ，Yang Z ，Ablise M 《-》

Design, synthesis and anticancer evaluation of novel 1,3-imidazole-type phenylhistin derivatives: Dual mechanism via P53 induction and microtubulin inhibition.

To enhance biological activity and deepen the understanding of the structure-activity relationship, a systematic study was conducted on the 5-position of the 1,3-imidazol-4-yl group in phenylahistin. The interaction between phenylahistin derivative 16j and the colchicine-binding site was first analyzed in detail, leading to the development of a fragment library to replace the tert-butyl group. A series of 20 novel phenylhistin derivatives were designed, synthesized, and characterized. In vitro activity screening using the NCI-H460 human non-small cell lung cancer line showed strong inhibitory activity for most compounds. Among these, compounds 8 f and 8 g exhibited superior activities, with IC50 values of 10 nM and 2 nM, respectively. Notably, 8 f displayed activity comparable to that of plinabulin, while 8 g was five times more potent. Both compounds 8 f and 8 g were further evaluated across various tumor cell lines showing nanomolar-level potency. Furthermore, detailed biological assays revealed that 8 g and 8 f disrupted microtubule integrity and significantly affected the P53 signaling pathway, strongly inducing G2/M phase arrest, and simultaneously promoting apoptosis in NCI-H460 cells. Molecular docking studies confirmed higher binding scores and stronger affinities for these derivatives at the colchicine-binding site of α, β-tubulin. These findings suggest that the apoptosis-inducing and cytotoxic activities of these derivatives may offer potential clinical value for tumor therapy.

Chen N ，Wang B ，Wang S ，Wang G ，Shen Z ，Wen Y ，Li J ，Zhang B ，FengLi ，Li W ，Yang W ，Xin J ，Ding Z ... -  《-》