Discovery of a Series of Thiazole Derivatives as Novel Inhibitors of Metastatic Cancer Cell Migration and Invasion

Effective inhibitors of cancer cell migration and invasion can potentially lead to clinical applications as a therapy to block tumor metastasis, the primary cause of death in cancer patients. To this end, we have designed and synthesized a series of thiazole derivatives that showed potent efficacy against cell migration and invasion in metastatic cancer cells. The most effective compound, <b>5k</b>, was found to have an IC₅₀ value of 176 nM in the dose-dependent transwell migration assays in MDA-MB-231cells. At a dose of 10 μM, <b>5k</b> also blocked about 80% of migration in HeLa and A549 cells and 60% of invasion of MDA-MB-231 cells. Importantly, the majority of the derivatives exhibited no apparent cytotoxicity in the clonogenic assays. The low to negligible inhibition of cell proliferation is a desirable property of these antimigration derivatives because they hold promise of low toxicity to healthy cells as potential therapeutic agents. Mechanistic studies analyzing the actin cytoskeleton by microscopy demonstrate that compound <b>5k</b> substantially reduced cellular f-actin and prevented localization of fascin to actin-rich membrane protrusions. These results suggest that the antimigration activity may result from impaired actin structures in protrusions that are necessary to drive migration

Structure–Activity Relationship and Pharmacokinetic Studies of 1,5-Diheteroarylpenta-1,4-dien-3-ones: A Class of Promising Curcumin-Based Anticancer Agents

Forty-three 1,5-diheteroaryl-1,4-pentadien-3-ones were designed as potential curcumin mimics, structurally featuring a central five-carbon dienone linker and two identical nitrogen-containing aromatic rings. They were synthesized using a Horner–Wadsworth–Emmons reaction as the critical step and evaluated for their cytotoxicity and antiproliferative activities toward both androgen-insensitive and androgen-sensitive prostate cancer cell lines and an aggressive cervical cancer cell line. Most of the synthesized compounds showed distinctly better in vitro potency than curcumin in the four cancer cell lines. The structure–activity data acquired from the study validated (1<i>E</i>,4<i>E</i>)-1,5-dihereroaryl-1,4-pentadien-3-ones as an excellent scaffold for in-depth development for clinical treatment of prostate and cervical cancers. 1-Alkyl-1<i>H</i>-imidazol-2-yl, ortho pyridyl, 1-alkyl-1<i>H</i>-benzo­[<i>d</i>]­imidazole-2-yl, 4-bromo-1-methyl-1<i>H</i>-pyrazol-3-yl, thiazol-2-yl, and 2-methyl-4-(trifluoromethyl)­thiazol-5-yl were identified as optimal heteroaromatic rings for the promising in vitro potency. (1<i>E</i>,4<i>E</i>)-1,5-Bis­(2-methyl-4-(trifluoromethyl)­thiazol-5-yl)­penta-1,4-dien-3-one, featuring thiazole rings and trifluoromethyl groups, was established as the optimal lead compound because of its good in vitro potency and attractive in vivo pharmacokinetic profiles

Design, Synthesis, and Osteogenic Activity of Daidzein Analogs on Human Mesenchymal Stem Cells

Osteoporosis is caused by an overstimulation of osteoclast activity and the destruction of the bone extracellular matrix. Without the normal architecture, osteoblast cells are unable to rebuild phenotypically normal bone. Hormone replacement therapy with estrogen has been effective in increasing osteoblast activity but also has resulted in the increased incidence of breast and uterine cancer. In this study we designed and synthesized a series of daidzein analogs to investigate their osteogenic induction potentials. Human bone marrow derived mesenchymal stem cells (MSCs) from three different donors were treated with daidzein analogs and demonstrated enhanced osteogenesis when compared to daidzein treatment. The enhanced osteogenic potential of these daidzein analogs resulted in increased osterix (Sp7), alkaline phosphatase (ALP), osteopontin (OPN), and insulin-like growth factor 1 (IGF-1), which are osteogenic transcription factors that regulate the maturation of osteogenic progenitor cells into mature osteoblast cells

Rational Design of a Boron-Modified Triphenylethylene (GLL398) as an Oral Selective Estrogen Receptor Downregulator

Development of orally bioavailable nonsteroidal selective estrogen receptor downregulators (SERDs) provides clinical opportunities for the long-term treatment and adjuvant therapy of breast cancer at all stages. We describe the design, synthesis, and identification of a boron-modified GW7604 derivative (GLL398, <b>9</b>), a SERD candidate, in which a boronic acid functional group replaces the phenolic hydroxyl group of GW7604. Compound <b>9</b> strongly binds to ERα in a fluorescence resonance energy transfer binding assay (IC₅₀ = 1.14 nM) and potently degrades ERα in MCF-7 breast cancer cells (IC₅₀ = 0.21 μM). Most importantly, the introduction of the boronic acid group confers superior oral bioavailability of <b>9</b> (AUC = 36.9 μg·h/mL) in rats as compared to GW7604 (AUC = 3.35 μg·h/mL). The strikingly favorable pharmacokinetic property of <b>9</b> makes it a promising oral SERD suitable for clinical evaluation

Fulvestrant‑3 Boronic Acid (ZB716): An Orally Bioavailable Selective Estrogen Receptor Downregulator (SERD)

Orally bioavailable SERDs may offer greater systemic drug exposure, improved clinical efficacy, and more durable treatment outcome for patients with ER-positive endocrine-resistant breast cancer. We report the design and synthesis of a boronic acid modified fulvestrant (<b>5</b>, ZB716), which binds to ERα competitively (IC₅₀ = 4.1 nM) and effectively downregulates ERα in both tamoxifen-sensitive and tamoxifen-resistant breast cancer cells. Furthermore, It has superior oral bioavailability (AUC = 2547.1 ng·h/mL) in mice, indicating its promising clinical utility as an oral SERD

A Ligand-Based Drug Design. Discovery of 4‑Trifluoromethyl-7,8-pyranocoumarin as a Selective Inhibitor of Human Cytochrome P450 1A2

In humans, cytochrome P450 1A2 is the major enzyme metabolizing environmental arylamines or heterocyclic amines into carcinogens. Since evidence shows that planar triangle-shaped molecules are capable of selectively inhibiting P450 1A2, 16 triangular flavone, and coumarin derivatives were designed and synthesized for these studies. Among these compounds, 7,8-furanoflavone time-dependently inhibits P450 1A2 with a <i>K</i>_I value of 0.44 μM. With a 5 min preincubation in the presence of NADPH, 0.01 μM 7,8-furanoflavone completely inactivates P450 1A2 but does not influence the activities of P450s 1A1 and 1B1. Another target compound, 7,8-pyrano-4-trifluoromethylcoumarin, is found to be a competitive inhibitor, showing high selectivity for the inhibition of P450 1A2 with a <i>K</i>_i of 0.39 μM, 155- and 52-fold lower than its <i>K</i>_i values against P450s 1A1 and 1B1, respectively. In yeast AhR activation assays, 7,8-pyrano-4-trifluoromethyl­coumarin does not activate aryl hydrocarbon receptor when the concentration is lower than 1 μM, suggesting that this compound would not up-regulate AhR-caused P450 enzyme expression. In-cell P450 1A2 inhibition assays show that 7,8-pyrano-4-trifluoromethyl­coumarin decreases the MROD activity in HepG2 cells at concentrations higher than 1 μM. Thus, using 7,8-pyrano-4-trifluoromethyl­coumarin, a selective and specific P450 1A2 action suppression could be achieved, indicating the potential for the development of P450 1A2-targeting cancer preventive agents

A Ligand-Based Drug Design. Discovery of 4‑Trifluoromethyl-7,8-pyranocoumarin as a Selective Inhibitor of Human Cytochrome P450 1A2

In humans, cytochrome P450 1A2 is the major enzyme metabolizing environmental arylamines or heterocyclic amines into carcinogens. Since evidence shows that planar triangle-shaped molecules are capable of selectively inhibiting P450 1A2, 16 triangular flavone, and coumarin derivatives were designed and synthesized for these studies. Among these compounds, 7,8-furanoflavone time-dependently inhibits P450 1A2 with a <i>K</i>_I value of 0.44 μM. With a 5 min preincubation in the presence of NADPH, 0.01 μM 7,8-furanoflavone completely inactivates P450 1A2 but does not influence the activities of P450s 1A1 and 1B1. Another target compound, 7,8-pyrano-4-trifluoromethylcoumarin, is found to be a competitive inhibitor, showing high selectivity for the inhibition of P450 1A2 with a <i>K</i>_i of 0.39 μM, 155- and 52-fold lower than its <i>K</i>_i values against P450s 1A1 and 1B1, respectively. In yeast AhR activation assays, 7,8-pyrano-4-trifluoromethyl­coumarin does not activate aryl hydrocarbon receptor when the concentration is lower than 1 μM, suggesting that this compound would not up-regulate AhR-caused P450 enzyme expression. In-cell P450 1A2 inhibition assays show that 7,8-pyrano-4-trifluoromethyl­coumarin decreases the MROD activity in HepG2 cells at concentrations higher than 1 μM. Thus, using 7,8-pyrano-4-trifluoromethyl­coumarin, a selective and specific P450 1A2 action suppression could be achieved, indicating the potential for the development of P450 1A2-targeting cancer preventive agents