millepachine and Neoplasms

Conjugated α,β-unsaturated ketones are very useful compounds associated with diverse medicinal properties. This review outlines α,β-unsaturated ketones as candidate cytotoxic agents which affect mitochondrial function. Both naturally occurring compounds and synthetic chemicals have been discussed which exert their cytotoxic effects, at least in part, by acting on mitochondria. Biochemical differences between tumour mitochondria and this organelle in non-malignant cells have been exploited to investigate various compounds that can cause greater toxicity to neoplasms than normal cells. On a number of instances, correlations between the structures of various α,β-unsaturated ketones and cytotoxic potencies have been observed. The aspiration is that this review will assist drug designers to create compounds which are significantly more toxic to neoplasms than normal tissues.

Topics: Animals; Humans; Ketones; Mitochondria; Neoplasms

Microtubule targeting agents (MTAs) are used as clinically effective chemotherapies for cancer treatment but might be limited by the acquired or intrinsic resistance of cancer cells to apoptosis. The vulnerability of therapy-resistant cancers to ferroptosis provides an alternative way to overcome drug resistance. In this study, on the basis of the MTAs obtained in our previous studies, a series of MTAs were synthesized, and detailed structure-activity relationships were obtained through extensive molecular dynamics studies. Among them, a diphenylethene derivative, compound

Topics: Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Ferroptosis; Humans; Microtubules; Neoplasms; Stilbenes

A series of amino acid derivatives of millepachine were designed, synthesized, and evaluated for their solubility and antiproliferation ability against tumor. The glycine derivative compound 7a exhibited the best potency and possessed long-term inhibitory capability on cell viability. It was also confirmed that 7a could arrest the cell cycle at G2 /M phase and trigger apoptosis. Furthermore, indirect immunofluorescence staining revealed antitubulin property of 7a, which is consistent with the previously reported derivatives of millepachine. In vivo, 7a suppressed tumor growth in an MDA-MB-231 xenograft tumor model. In summary, the exploit of 7a was a successful approach directed by the concept of generating amino acid prodrugs with increased bioavailability.

Topics: Animals; Antineoplastic Agents; Cell Division; Cell Line, Tumor; Chalcones; Female; G2 Phase; Humans; Mice; Mice, Nude; Neoplasms; Prodrugs; Solubility; Xenograft Model Antitumor Assays

Twenty-five novel pyranochalcone derivatives were synthesized and evaluated for their in vitro and in vivo antiproliferative activities. Among them, compound 10i exhibited superior potent activity against 21 tumor cell lines including multidrug resistant phenotype with the IC50 values ranged from 0.09 to 1.30 μM. In addition, 10i significantly induced cell cycle arrest in G2/M phase, promoted tubulin polymerization into microtubules and caused microtubule stabilization. Further studies confirmed that 10i significantly suppressed the growth of tumor volume in HepG2 xenograft tumor model. Our study demonstrated that 10i could have beneficial antitumor activity as a novel microtubule stabilizing agent.

Topics: Animals; Antineoplastic Agents; Benzopyrans; Cell Line; Cell Proliferation; Chalones; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Female; Hep G2 Cells; Humans; Mice; Mice, Inbred BALB C; Mice, Nude; Microtubules; Molecular Structure; Neoplasms; Structure-Activity Relationship; Tubulin Modulators

A series of novel tubulin polymerization inhibitors (9a-9p) have been synthesized and evaluated for their in vitro and in vivo biological activities. Among these compounds, 9e displayed strong antiproliferative activity against several tumor cell lines (IC50=0.15-0.62μM). Compound 9e was also shown to arrest cells in the G2/M phase of the cell cycle and inhibit the polymerization of tubulin. Molecular docking studies suggested that 9e binds into the colchicine binding site of tubulin. In xenograft experiments, 9e exerted more potent anticancer effect than anticancer drug taxol against the H460 Human lung carcinoma in BALB/c nude mice. In summary, these findings suggest that 9e is a promising new antimitotic compound for the potential treatment of cancer.

Topics: Animals; Antineoplastic Agents; Benzopyrans; Binding Sites; Cell Line, Tumor; Cell Proliferation; Chalcones; Colchicine; Drug Design; Drug Screening Assays, Antitumor; Female; G2 Phase Cell Cycle Checkpoints; Hep G2 Cells; Humans; K562 Cells; M Phase Cell Cycle Checkpoints; Mice; Mice, Inbred BALB C; Mice, Nude; Molecular Docking Simulation; Neoplasms; Protein Binding; Protein Structure, Tertiary; Structure-Activity Relationship; Transplantation, Heterologous; Tubulin; Tubulin Modulators