Novel Piperazine-based Compounds Inhibit Microtubule Dynamics and Sensitize Colon Cancer Cells to Tumor Necrosis Factor-induced Apoptosis

Chitti

Journal of Heterocyclic Chem

et al. 2018

A series of 28 novel 2‐(4‐aminophenyl)benzothiazole analogues have been synthesized and characterized using various analytical techniques like 1H NMR, 13C NMR, electrospray ionization mass spectrometry, and IR and bioevaluated for their antiproliferative activity over a group of three human cancer cell lines, namely, lung cancer (A549), cervical cancer (HeLa), and breast cancer (MDA‐MB‐231), using sulforhodamine B assay method. Few synthesized molecules (5a, 5c, 5d, 5f, 7b, and 7j) displayed effective growth inhibition (GI50) activity against the tested human cancer cell lines at lower micromolar concentration (GI50) values in the range 0.2–1.7 μM. Noticeably, compound 7b exhibited reasonable activity in all three cancer cell lines in the GI50 range 0.55–1.2 μM. Further, when 7b was screened for tubulin polymerization inhibition, it exhibited more than 55% inhibition at concentration of 5.0 μM. The molecular docking simulations supported the molecular interactions of the derivatives with the targeted receptor. These derivatives may serve as lead structures for development of potential anticancer drug candidates, and 7b might act as a potential microtubule polymerization inhibitor.

Section: Introductionmentioning

confidence: 99%

Design, Synthesis, and Biological Evaluation of 2‐(4‐Aminophenyl)benzothiazole Analogues as Antiproliferative Agents

Chitti

Journal of Heterocyclic Chem

et al. 2018

Medicinal Research Reviews

“…AK301, a colchicine binding site tubulin inhibitor, was found to cause treated cells to express elevated levels of TNF receptor 1 (TNFR1) on the cell surface and increase caspases‐8, ‐9, and ‐3 activations in the presence of TNF‐α. It also induced Fas‐ and tumor necrosis ligand–dependent apoptosis . Interestingly, it caused greater TNF‐α sensitization than other tubulin binding agents, including, colchicine, nocodazole, and vincristine, though it achieved a lower degree of tubulin polymerization inhibition from tubulin binding assays.…”

Section: Mt‐targeting Agents’ Potentiation Of Immune Response and Impmentioning

confidence: 97%

“…Cell death imposed by an immune response can be from cell killing by cytotoxic T cells and natural killer cells, and can also be stimulated by apoptotic ligands, such as TNF‐α. There have been reports on MT‐targeting agents sensitizing cells to TNF‐α and other inflammatory apoptotic ligands . AK301, a colchicine binding site tubulin inhibitor, was found to cause treated cells to express elevated levels of TNF receptor 1 (TNFR1) on the cell surface and increase caspases‐8, ‐9, and ‐3 activations in the presence of TNF‐α.…”

Section: Mt‐targeting Agents’ Potentiation Of Immune Response and Impmentioning

confidence: 99%

“…There have been reports on MT-targeting agents sensitizing cells to TNF-α and other inflammatory apoptotic ligands. 205,206 AK301, a colchicine binding site tubulin inhibitor, was found to cause treated cells to express elevated levels of TNF receptor 1 (TNFR1) on the cell surface and increase caspases-8, -9, and -3 activations in the presence of TNF-α. It also induced Fas-and tumor necrosis ligand-dependent apoptosis.…”

Section: Inflammationmentioning

confidence: 99%

See 1 more Smart Citation

Current advances of tubulin inhibitors as dual acting small molecules for cancer therapy

Arnst

Banerjee

Chen

et al. 2019

122

107

Microtubule (MT)‐targeting agents are highly successful drugs as chemotherapeutic agents, and this is attributed to their ability to target MT dynamics and interfere with critical cellular functions, including, mitosis, cell signaling, intracellular trafficking, and angiogenesis. Because MT dynamics vary in the different stages of the cell cycle, these drugs tend to be the most effective against mitotic cells. While this class of drug has proven to be effective against many cancer types, significant hurdles still exist and include overcoming aspects such as dose limited toxicities and the development of resistance. Newer generations of developed drugs attack these problems and alternative approaches such as the development of dual tubulin and kinase inhibitors are being investigated. This approach offers the potential to show increased efficacy and lower toxicities. This review covers different categories of MT‐targeting agents, recent advances in dual inhibitors, and current challenges for this drug target.

“…35 DiOC 6 is a mitochondria membrane potential-sensitive dye, while PI is able to penetrate the membranes of dead and apoptotic cells. 36 However, the inhibition of microtubule assembly inevitably results in late stage apoptosis. After 48 h of incubation the rate of apoptosis in 10c culture was comparable with the control one ( Figure 5 A and B), while both 10d and 9a induced significant apoptosis.…”

Section: Effects Of Compound 10c On Apoptosis Inductionmentioning

confidence: 99%

Synthesis and Biological Evaluation of Furanoallocolchicinoids

et al. 2014

A series of conformationally flexible furan-derived allocolchicinoids was prepared from commercially available colchicine in good to excellent yields using a three-step reaction sequence. Cytotoxicity studies indicated the potent activity of two compounds against human epithelial and lymphoid cell lines (AsPC-1, HEK293, and Jurkat) as well as against Wnt-1 related murine epithelial cell line W1308. The results of in vitro experiments demonstrated that the major effect of these compounds was the induction of cell cycle arrest in the G2/M phase as a direct consequence of effective tubulin binding. In vivo testing of the most potent furanoallocolchicinoid 10c using C57BL/6 mice inoculated with Wnt-1 tumor cells indicated significant inhibition of the tumor growth.