Licochalcone A-Inspired Chalcones: Synthesis and Their Antiproliferative Potential in Prostate Cancer Cells.

Prostate cancer remains a significant global health concern, prompting ongoing exploration of novel therapeutic agents. Licochalcone A, a natural product in the chalcone family isolated from licorice root, is characterized by its enone structure and demonstrates antiproliferative activity in the micromolar range across various cell lines, including prostate cancer. Building on our prior success in enhancing curcumin's antiproliferative potency by replacing the substituted phenol with a 1-alkyl-1H-imizadol-2-yl moiety, we applied a similar approach to design a new class of licochalcone A-inspired chalcones.

Discovery of Oral Degraders of the ROS1 Fusion Protein with Potent Activity against Secondary Resistance Mutations.

The development of therapeutic resistance in the majority of patients limits the long-term benefit of ROS1 inhibitor treatment. On-target mutations of the ROS1 kinase domain confer resistance to crizotinib and lorlatinib in more than one-third of acquired resistance cases with no current effective treatment option. As an alternative to stoichiometric inhibition, proteolytic degradation of ROS1 could provide an effective tool to combat resistance generated by these mutations.

Novel Anti-Cancer Stem Cell Compounds: A Comprehensive Review.

Cancer stem cells (CSCs) possess a significant ability to renew themselves, which gives them a strong capacity to form tumors and expand to encompass additional body areas. In addition, they possess inherent resistance to chemotherapy and radiation therapies used to treat many forms of cancer. Scientists have focused on investigating the signaling pathways that are highly linked to the ability of CSCs to renew themselves and maintain their stem cell properties.

Synthesis of organic-inorganic hybrid nanocomposites modified by catalase-like catalytic sites for the controlling of kiwifruit bacterial canker.

Kiwifruit bacterial canker, caused by pv. (), is one of the most important diseases in kiwifruit, creating huge economic losses to kiwifruit-growing countries around the world. Metal-based nanomaterials offer a promising alternative strategy to combat plant diseases induced by bacterial infection.

Discordant interactions between YAP1 and polycomb group protein SCML2 determine cell fate.

The Polycomb group protein SCML2 and the transcriptional cofactor YAP1 regulate diverse cellular biology, including stem cell maintenance, developmental processes, and gene regulation in mammals and flies. However, their molecular and functional interactions are unknown. Here, we show that SCML2 interacts with YAP1, as revealed by immunological assays and mass spectroscopy.

Discovery of Novel Pentacyclic Triterpene Acid Amide Derivatives as Excellent Antimicrobial Agents Dependent on Generation of Reactive Oxygen Species.

Developing new agricultural bactericides is a feasible strategy for stopping the increase in the resistance of plant pathogenic bacteria. Some pentacyclic triterpene acid derivatives were elaborately designed and synthesized. In particular, compound A exhibited the best antimicrobial activity against pv.

Tricyclic Diterpenoids Selectively Suppress Androgen Receptor-Positive Prostate Cancer Cells.

Androgen receptor (AR) is a viable therapeutic target for lethal castration-resistant prostate cancer (CRPC), because the continued progression of CRPC is mainly driven by the reactivation of AR transcriptional activity. The current FDA-approved AR antagonists binding to ligand binding domain (LBD) become ineffective in CRPC with AR gene amplification, LBD mutation, and the evolution of LBD-truncated AR splice variants. Encouraged by the fact that tricyclic aromatic diterpenoid QW07 has recently been established as a potential -terminal AR antagonist, this study aims to explore the structure-activity relationship of tricyclic diterpenoids and their potential to suppress AR-positive cell proliferation.

Discovery of berberine analogs as potent and highly selective p300/CBP HAT inhibitors.

The protein p300 is a positive regulator of cancer progression and is related to many human pathological conditions. To find effective p300/CBP HAT inhibitors, we screened an internal compound library and identified berberine as a lead compound. Next, we designed, synthesized, and screened a series of novel berberine analogs, and discovered that analog 5d was a potent and highly selective p300/CBP HAT inhibitor with IC values of 0.

Design, Synthesis, and Evaluation of Niclosamide Analogs as Therapeutic Agents for Enzalutamide-Resistant Prostate Cancer.

Niclosamide effectively downregulates androgen receptor variants (AR-Vs) for treating enzalutamide and abiraterone-resistant prostate cancer. However, the poor pharmaceutical properties of niclosamide due to its solubility and metabolic instability have limited its clinical utility as a systemic treatment for cancer. A novel series of niclosamide analogs was prepared to systematically explore the structure-activity relationship and identify active AR-Vs inhibitors with improved pharmaceutical properties based on the backbone chemical structure of niclosamide.

A Predictive Model of Adaptive Resistance to BRAF/MEK Inhibitors in Melanoma.

The adaptive acquisition of resistance to BRAF and MEK inhibitor-based therapy is a common feature of melanoma cells and contributes to poor patient treatment outcomes. Leveraging insights from a proteomic study and publicly available transcriptomic data, we evaluated the predictive capacity of a gene panel corresponding to proteins differentially abundant between treatment-sensitive and treatment-resistant cell lines, deciphering predictors of treatment resistance and potential resistance mechanisms to BRAF/MEK inhibitor therapy in patient biopsy samples. From our analysis, a 13-gene signature panel, in both test and validation datasets, could identify treatment-resistant or progressed melanoma cases with an accuracy and sensitivity of over 70%.

Novel roles for HMGA2 isoforms in regulating oxidative stress and sensitizing to RSL3-Induced ferroptosis in prostate cancer cells.

Oxidative stress is increased in several cancers including prostate cancer, and is currently being exploited in cancer therapy to induce ferroptosis, a novel nonapoptotic form of cell death. High mobility group A2 (HMGA2), a non-histone protein up-regulated in several cancers, can be truncated due to chromosomal rearrangement or alternative splicing of HMGA2 gene. The purpose of this study is to investigate the role of wild-type vs.

Core Structure-Activity Relationship Studies of 5,7,20--Trimethylsilybins in Prostate Cancer Cell Models.

Silibinin, also known as silybin, is isolated from milk thistle (). Silibinin has been demonstrated to be a good lead compound due to its potential to prevent and treat prostate cancer. Its moderate potency and poor pharmacokinetic profile hindered it from moving forward to therapeutic use.

A new monocyclic monoterpene derivative from volva of .

A new monoterpene derivative namely dongsunol A () and sixteen known compounds () were isolated from the volva of . All compounds were isolated from this fungus for the first time. Their structures and absolute configurations were determined by nuclear magnetic resonance (NMR), HRESIMS spectral data, and electronic circular dichroism (ECD).

Design and synthesis of a novel ZB716-d6 as a stable isotopically labeled internal standard.

ZB716 is a synthetic, steroidal, orally active anti-estrogen agent that is under clinical development for the treatment of estrogen receptor (ER)-positive metastatic breast cancer. The stable isotope-labeled ZB716 was required for use as an internal standard in LC-MS/MS assays. Therefore, a novel deuterated ZB716 (ZB716-d6) as an isotopically labeled internal standard was designed and synthesized through a newly developed route, which prepared ZB716-d6 in eight steps from the commercially available deuterium-labeled starting material [H]pentafluoropentanol.

Kinetic Promotion Effect of Hydrogen and Dimethyl Disulfide Addition on Propane Dehydrogenation over the Pt-Sn-K/AlO Catalyst.

The kinetic effects of co-feeding of dimethyl disulfide (DMDS) and hydrogen on propane dehydrogenation (PDH) over the Pt-Sn-K/AlO catalyst were investigated by the response surface method. The 3-level Box-Behnken design for 4 factors (reaction temperature, propene, hydrogen, and DMDS flow rate) was used to design the experiment. The initial propane conversion, propene selectivity, and coking amount were chosen as responses and the results were fitted by quadratic models.

Design, synthesis, and antitumor study of a series of novel 1-Oxa-4-azaspironenone derivatives.

A series of 1-oxa-4-azaspiro[4,5]deca-6,9-diene-3,8-dione derivatives containing structural fragments of conjugated dienone have been synthesized previously by our group, however the Michael addition reaction between conjugated dienone and nucleophilic groups in the body may generate harmful and adverse effects. To reduce harmful side effects, the authors started with p-aminophenol to make 1-oxo-4- azaspirodecanedione derivatives, then utilized the Michael addition and cyclopropanation to eliminate α, β unsaturated olefinic bond and lower the Michael reactivity of the compounds in vivo for optimization. At the same time, heteroatoms are put into the molecules in order to improve the hydrophilicity of the molecules and the binding sites of the molecules and the target molecules, establishing the groundwork for improved antitumor activity.

Synthesis and biological evaluation of niclosamide PROTACs.

Roughly 268,000 new cases of prostate cancer and 34,000 deaths from prostate cancer are projected by the American Cancer Society to occur in the United States in 2022. Androgen receptor is a key protein in the proliferation and survival of prostate cancer cells and has been revealed to be overexpressed in 30% to 50% of castration-resistant prostate cancer patients. One promising approach to reducing the level of this protein is Proteolysis Targeting Chimeras (PROTACs) that is an emerging drug discovery technology.

Design, synthesis, and evaluation of a novel series of mono-indolylbenzoquinones derivatives for the potential treatment of breast cancer.

Breast cancer is one of the most common cancers in the world, and pro-apototic drugs activating the apoptotic pathway are a strategy for anticancer therapy. To explore new antineoplastic agents, a series of novel mono-indolylbenzoquinone derivatives have been designed and synthesized. Compared with the lead bis-indolylbenzoquinones, most of the novel mono-indolylbenzoquinone derivatives have significantly increased their activity against A549, HeLa, and especially, MDA-MB-231 cell lines.

Design, synthesis, and antitumor activity evaluation of novel acyl sulfonamide spirodienones.

Based on the promising results of benzenesulfonamide spirodienones as antineoplastic agents, we have designed and synthesized a series of novel acyl sulfonamides spirodienone for antineoplastic evaluation. Of these, compound 4a exhibited remarkable in vitro antiproliferative activity by arresting the cell cycle and inducing apoptosis of MDA-MB-231 cells. Acute toxicity study has demonstrated 4a at 100 mg/kg dose caused no obvious toxicity to the major organs of mice.

3--Carbamoyl-5,7,20--trimethylsilybins: Synthesis and Preliminary Antiproliferative Evaluation.

To search for novel androgen receptor (AR) modulators for the potential treatment of castration-resistant prostate cancer (CRPC), naturally occurring silibinin was sought after as a lead compound because it possesses a moderate potency towards AR-positive prostate cancer cells and its chemical scaffold is dissimilar to all currently marketed AR antagonists. On the basis of the structure-activity relationships that we have explored, this study aims to incorporate carbamoyl groups to the alcoholic hydroxyl groups of silibinin to improve its capability in selectively suppressing AR-positive prostate cancer cell proliferation together with water solubility. To this end, a feasible approach was developed to regioselectively introduce a carbamoyl group to the secondary alcoholic hydroxyl group at C-3 without causing the undesired oxidation at C2-C3, providing an avenue for achieving 3--carbamoyl-5,7,20--trimethylsilybins.

Fulvestrant-3-Boronic Acid (ZB716) Demonstrates Oral Bioavailability and Favorable Pharmacokinetic Profile in Preclinical ADME Studies.

Fulvestrant-3-boronic acid (ZB716), an oral selective estrogen receptor degrader (SERD) under clinical development, has been investigated in ADME studies to characterize its absorption, metabolism, and pharmacokinetics. ZB716 was found to have high plasma protein binding in human and animal plasma, and low intestinal mucosal permeability. ZB716 had high clearance in hepatocytes of all species tested.

From Pure Antagonists to Pure Degraders of the Estrogen Receptor: Evolving Strategies for the Same Target.

Pure antiestrogens, or selective estrogen receptor degraders (SERDs), have proven to be effective in treating breast cancer that has progressed on tamoxifen and/or aromatase inhibitors. However, the only FDA-approved pure antiestrogen, fulvestrant, is limited in efficacy by its low bioavailability. The search for orally bioavailable SERDs has continued for nearly as long as the clinical history of the injection-only fulvestrant.

An amide mimic of desTHPdactylolide: Total synthesis and antiproliferative evaluation.

(-)-Zampanolide is a unique microtubule stabilizing agent (MSA) with covalent-binding mechanism and low nanomolar anitproliferative potency towards multi-drug resistant cancer cells. MSAs have a special connection with prostate cancer by inhibiting androgen receptor nuclear translocation. Zampanolide and the structurally related dactylolide have thus been sought after by us as lead compounds for development of anti-prostate cancer agents.

Acquisition of Letrozole Resistance Through Activation of the p38/MAPK Signaling Cascade.

Background/aim: Previous reports identified a global proteomic signature of estrogen-independent letrozole resistant breast cancer cells, however, it remains unclear how letrozole-resistance is impacted when cells remain estrogen receptor positive (ER+).

Materials And Methods: To capture the protein expression profile associated with ER+ Aromatase inhibitor (AI) resistance, a global proteomic analysis was conducted using the letrozole-sensitive (T47Darom cells) and letrozole-resistant cells (T47DaromLR cells). To examine the molecular features associated with this phenotype Kaplan- Meier analysis, phospho-antibody arrays, proliferation and apoptosis assays were conducted.

Synthesis and anticancer activity evaluation of naphthalene-substituted triazole spirodienones.

Building on our previous work that discovered 1,2,4-triazole-spirodienone as a promising pharmacophore for anticancer activity, we have further diversified 1,2,4-triazole- spirodienone derivatives and synthesized a series of novel naphthalene-substituted triazole spirodienones to explore their antineoplastic activity. Of these, compound 6a possesses remarkable in vitro cytotoxic activity by arresting cell cycle and inducing apoptosis in MDA-MB-231 cells. Subsequently, acute toxicity assay showed that 6a at 20 mg/kg has no apparent toxicity to the major organ in mice.