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 ... -  《-》

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 biological evaluation of novel 2,3-Di-O-Aryl/Alkyl sulfonate derivatives of l-ascorbic acid: Efficient access to novel anticancer agents via in vitro screening, tubulin polymerization inhibition, molecular docking study and ADME pre

A series of novel l-ascorbic acid derivatives bearing aryl and alkyl sulfonate substituents were synthesized and characterized. In vitro anticancer evaluation against MCF-7 (breast) and A-549 (lung) cancer cell lines revealed potent activity for most of the compounds, with 2b being equipotent to the standard drug colchicine against MCF-7 (IC50 = 0.04 μM). Notably, compound 2b displayed 89-fold selectivity for MCF-7 breast cancer over MCF-10A normal breast cells. Derivatives with two sulfonate groups (2a-g, 3a-g) exhibited superior potency over those with one sulfonate (4a-c,5g, 6b). Compounds 2b and 2c potently inhibited tubulin polymerization in A-549 cancer cells (73.12 % and 62.09 % inhibition, respectively), substantiating their anticancer potential through microtubule disruption. Molecular docking studies showed higher binding scores and affinities for these compounds at the colchicine-binding site of α, β-tubulin compared to colchicine itself. In-silico ADMET predictions indicated favourable drug-like properties, with 2b exhibiting the highest binding affinity. These sulfonate derivatives of l-ascorbic acid represents promising lead scaffolds for anticancer drug development.

Deshmukh SR ，Nalkar AS ，Sarkate AP ，Tiwari SV ，Lokwani DK ，Thopate SR ... -  《-》

Design, Synthesis and Biological Evaluation of 2-Phenyl Indole Analogues of OXi8006 as Colchicine Site Inhibitors of Tubulin Polymerization and Vascular Disrupting Agents.

Inhibitors of tubulin polymerization represent a promising therapeutic approach for the treatment of solid tumors. Molecules that bind to the colchicine site are of interest as they can function with a dual mechanism of action as both potent antiproliferative agents and tumor-selective vascular disrupting agents (VDAs). One such example is a 2-aryl-3-aroyl-indole molecule (OXi8006) from our laboratory that demonstrates potent inhibition of tubulin polymerization and strong antiproliferative activity (cytotoxicity) against a variety of human cancer cell lines. A water-soluble prodrug OXi8007, synthesized from OXi8006, demonstrates in vivo disruption of tumor-associated microvessels in several tumor types (mouse models). The molecular framework of OXi8006 inspired a series of fourteen new 2-aryl-3-aroyl-indole analogues that incorporated various functional group modifications on both the indole core and the aroyl ring. Electron withdrawing and donating groups at the mono-substituted 3' position and the di-substituted 3',5' positions were all accommodated while maintaining inhibition of tubulin polymerization (IC50 < 5 μM), with several analogues demonstrating activity comparable to OXi8006 and the benchmark natural product combretastatin A-4 (CA4). Preliminary structure-activity relationship (SAR) studies were further enhanced by molecular docking to predict possible colchicine site interactions. Two analogues (KGP366 and KGP369) previously synthesized in our laboratory were re-synthesized using a somewhat modified route to increase synthetic efficiency and were subsequently converted to their corresponding water-soluble phosphate prodrug salts to evaluate their efficacy as VDAs. Administration of the prodrug salt (KGP415) of KGP369 caused significant reduction in bioluminescence signal from an orthotopic kidney tumor (RENCA-luc) in BALB/c mice, indicative of VDA activity. Collectively, these new functionalized indole-based analogues have extended SAR knowledge related to the colchicine binding site, and the most biologically active analogues hold promise for continued development as pre-clinical candidates for cancer therapy.

Vairin R ，Tamminga C ，Shi Z ，Borchardt C ，Jambulapati J ，Bai R ，Wanniarachchi H ，Bueno L ，Hamel E ，Mason RP ，Trawick ML ，Pinney KG ... -  《-》

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 ... -  《-》