Stilbenoid derivatives as potent inhibitors of HIF-1α-centric cancer metabolism under hypoxia.

Hypoxia-inducible factor (HIF)-1α is a crucial transcription factor associated with cancer metabolism and is regarded as a potent anticancer therapeutic strategy within the hypoxic microenvironment of cancer. In this study, stilbenoid derivatives were designed, synthesized, and assessed for their capacity to inhibit HIF-1α-associated cancer metabolism and evaluated for inhibition of cancer cell viability and HIF activation. Through the structure-activity relationship studies, compound 28e was identified as the most potent derivative. Specifically, under the hypoxic condition, 28e reduced the accumulation of HIF-1α protein and the expression of its target genes related to glucose metabolism without affecting the expression of HIF-1α mRNA. Furthermore, 28e inhibited glucose uptake, glycolytic metabolism, and mitochondrial respiration, decreasing cellular ATP production under hypoxic conditions. In addition, 28e displayed significant anti-tumor effects and effectively suppressed the accumulation of HIF-1α protein in tumor tissue in vivo xenograft model. These findings suggest that our stilbenoid derivatives exert their anticancer effects by targeting HIF-1α-centered cancer metabolism under hypoxic conditions.

Ca(II)-Catalyzed Cascade Reaction of Tryptamines with Propargylic Alcohols: Temperature-Driven Ring Opening and Closing via the Allene Migration Pathway for the Synthesis of Pyrrolo[1,2-a]indoles.

A temperature-dependent cascade of reactions between tryptamines and propargylic alcohols was developed to achieve selective formation of pyrroloindoline and pyrrolo[1,2-a]indole heterocycles by Ca(II) catalysis. The cascade consists of electrophilic addition of allene at the C3 carbon of indole followed by intramolecular cyclization at 60 °C to yield pyrroloindolines. Furthermore, simultaneous 1,2-allene migration and pyrrolidine ring opening were followed by intramolecular cyclization via C-N bond formation at reflux temperature to obtain pyrrolo[1,2-a]indole scaffolds. A wide range of substrates, a clean reaction profile, scalability, and good to excellent yields are the advantages of this protocol.

Natural products as IL-6 inhibitors for inflammatory diseases: Synthetic and SAR perspective.

Interleukin-6 (IL-6), a pleiotropic cytokine, plays a pivotal role in the pathophysiology of various diseases including diabetes, atherosclerosis, Alzheimer's disease, multiple myeloma, rheumatoid arthritis, and prostate cancer. The signaling pathways associated with IL-6 offer promising targets for therapeutic interventions in inflammatory diseases and IL-6-dependent tumors. Although certain anti-IL-6 monoclonal antibodies are currently employed clinically, their usage is hampered by drawbacks such as high cost and potential immunogenicity, limiting their application. Thus, the imperative arises to develop novel small non-peptide molecules acting as IL-6 inhibitors. Various natural products derived from diverse sources have been investigated for their potential to inhibit IL-6 activity. Nevertheless, these natural products remain inadequately explored in terms of their structure-activity relationships. In response, our review aims to provide syntheses and structure activity perspective of natural IL-6 inhibitors. The comprehensive amalgamation of information presented in this review holds the potential to serve as a foundation for forthcoming research endeavors by medicinal chemists, facilitating the design of innovative IL-6 inhibitors to address the complexities of inflammatory diseases.

Integration of Hybridization Strategies in Pyridine-Urea Scaffolds for Novel Anticancer Agents: Design, Synthesis, and Mechanistic Insights.

Annually, millions of new cancer cases are reported, leading to millions of deaths worldwide. Among the newly reported cases, breast and colon cancers prevail as the most frequently detected variations. To effectively counteract this rapid increase, the development of innovative therapies is crucial. Small molecules possessing pyridine and urea moieties have been reported in many of the currently available anticancer agents, especially VEGFR2 inhibitors. With this in mind, a rational design approach was employed to create hybrid small molecules combining urea and pyridine. These synthesized compounds underwent in vitro testing against breast and colon cancer cell lines, revealing potent submicromolar anticancer activity. Compound 8a, specifically, exhibited an impressive GI50 value of 0.06 µM against the MCF7 cancer cell line, while compound 8h displayed the highest cytotoxic activity against the HCT116 cell line, with a GI50 of 0.33 ± 0.042 µM. Notably, compounds 8a, 8h, and 8i demonstrated excellent safety profiles when tested on normal cells. Molecular docking, dynamic studies, and free energy calculations were employed to validate the affinity of these compounds as VEGFR2 inhibitors.

Small Molecule c-KIT Inhibitors for the Treatment of Gastrointestinal Stromal Tumors: A Review on Synthesis, Design Strategies, and Structure-Activity Relationship (SAR).

The proto-oncogenic protein, c-KIT, plays a crucial role in regulating cellular transformation and differentiation processes, such as proliferation, survival, adhesion, and chemotaxis. The overexpression of, and mutations, in c-KIT can lead to its dysregulation and promote various human cancers, particularly gastrointestinal stromal tumors (GISTs); approximately 80-85% of cases are associated with oncogenic mutations in the KIT gene. Inhibition of c-KIT has emerged as a promising therapeutic target for GISTs. However, the currently approved drugs are associated with resistance and significant side effects, highlighting the urgent need to develop highly selective c-KIT inhibitors that are not affected by these mutations for GISTs. Herein, the recent research efforts in medicinal chemistry aimed at developing potent small-molecule c-KIT inhibitors with high kinase selectivity for GISTs are discussed from a structure-activity relationship perspective. Moreover, the synthetic pathways, pharmacokinetic properties, and binding patterns of the inhibitors are also discussed to facilitate future development of more potent and pharmacokinetically stable small-molecule c-KIT inhibitors.

Design, Synthesis and Biological Evaluation of Novel MDH Inhibitors Targeting Tumor Microenvironment.

MDH1 and MDH2 enzymes play an important role in the survival of lung cancer. In this study, a novel series of dual MDH1/2 inhibitors for lung cancer was rationally designed and synthesized, and their SAR was carefully investigated. Among the tested compounds, compound 50 containing a piperidine ring displayed an improved growth inhibition of A549 and H460 lung cancer cell lines compared with LW1497. Compound 50 reduced the total ATP content in A549 cells in a dose-dependent manner; it also significantly suppressed the accumulation of hypoxia-inducible factor 1-alpha (HIF-1α) and the expression of HIF-1α target genes such as GLUT1 and pyruvate dehydrogenase kinase 1 (PDK1) in a dose-dependent manner. Furthermore, compound 50 inhibited HIF-1α-regulated CD73 expression under hypoxia in A549 lung cancer cells. Collectively, these results indicate that compound 50 may pave the way for the development of next-generation dual MDH1/2 inhibitors to target lung cancer.

Discovery and optimization of natural-based nanomolar c-Kit inhibitors via in silico and in vitro studies.

c-Kit is a receptor tyrosine kinase which is involved in intracellular signaling and mutations of c-Kit have been associated with various types of cancers. Investigations have shown that inhibition of c-Kit, using tyrosine kinase inhibitors, yielded promising results in cancer treatment marking it as a promising target for cancer therapy. However, the emerging resistance for the current therapy necessitates the development of more potent inhibitors which are not affected by these mutations. Herein, virtual screening of a library of natural-based compounds yielded three hits (2, 5 and 6) which possessed nanomolar inhibitory (2.02, 4.33 and 2.80 nM, respectively) activity when tested in vitro against c-Kit. Single point mutation docking studies showed the hits to be unaffected by the most common resistance mutation in imatinib-resistant cells, mutation of Val654. Although, the top hits exhibited around 3000 higher inhibitory potency toward c-Kit when compared to imatinib (5.4 µM), previous studies have shown that they are metabolically unstable. Fragment-based drug design approaches were then employed to enhance binding affinity of the top hit and make it more metabolically stable. Screening of the generated fragments yielded a new derivative, F1, which demonstrated stronger binding affinity, stability and binding free energy when compared to the hit compound 2.Communicated by Ramaswamy H. Sarma.

Placental transfer and mammary excretion of a novel angiotensin receptor blocker fimasartan in rats.

BACKGROUND: Fimasartan (FMS) is a potent angiotensin receptor blocker for the treatment of mild to moderate hypertension. This study aimed to evaluate the transfer of FMS to fetus and breast milk in rats. METHODS: In order to study the transfer to the fetus and nursing pup, pregnant and nursing maternal rats were administered with FMS by a constant intravenous infusion to reach target plasma concentrations of 200 ng/mL and 100 ng/mL. The concentrations of FMS in plasma, placenta, amniotic fluid, fetus, and milk were determined by a validated LC-MS/MS assay. RESULTS: Upon constant intravenous infusion, the plasma FMS concentration reached the target steady state concentrations (Css = 200 ng/mL and 100 ng/mL) in 24 h. The tissue-to-plasma partition coefficients (Kp) for placenta, amniotic fluid, and milk were obtained based on the observed FMS concentrations in the tissues and Css. The Kp values for all tissues were not different between high (Css = 200 ng/mL) and low (Css = 100 ng/mL) dose groups. While the mean Kp of the placenta was 44.6-59.0 %, the mean Kp was 1.3-1.7 % for the amniotic fluid and 14.9-17.0 % for fetus. The mean Kp of milk was 10.4-15.2 %. CONCLUSIONS: Placental transfer and milk excretion of FMS was relatively lower compared to other angiotensin receptor blockers.

Highly heterogeneous soil bacterial communities around Terra Nova Bay of Northern Victoria Land, Antarctica.

Given the diminished role of biotic interactions in soils of continental Antarctica, abiotic factors are believed to play a dominant role in structuring of microbial communities. However, many ice-free regions remain unexplored, and it is unclear which environmental gradients are primarily responsible for the variations among bacterial communities. In this study, we investigated the soil bacterial community around Terra Nova Bay of Victoria Land by pyrosequencing and determined which environmental variables govern the bacterial community structure at the local scale. Six bacterial phyla, Actinobacteria, Proteobacteria, Acidobacteria, Chloroflexi, Cyanobacteria, and Bacteroidetes, were dominant, but their relative abundance varied greatly across locations. Bacterial community structures were affected little by spatial distance, but structured more strongly by site, which was in accordance with the soil physicochemical compositions. At both the phylum and species levels, bacterial community structure was explained primarily by pH and water content, while certain earth elements and trace metals also played important roles in shaping community variation. The higher heterogeneity of the bacterial community structure found at this site indicates how soil bacterial communities have adapted to different compositions of edaphic variables under extreme environmental conditions. Taken together, these findings greatly advance our understanding of the adaption of soil bacterial populations to this harsh environment.

Size and aggregation of corticosteroids used for epidural injections.

OBJECTIVE: The purpose of this study was to document particulate size in commonly used corticosteroid preparations. Inadvertent injection of particulate corticosteroids into a vertebral or foraminal artery can cause brain and spinal cord embolic infarcts and the size of the particles could be directly related to the chance that a clinically significant infarct would occur. One might assume that corticosteroids with particles significantly smaller than red blood cells might be safer. DESIGN: The following four types of corticosteroid preparations were used in various solutions and evaluated under light microscopy: dexamethasone sodium phosphate injection, triamcinolone acetonide injectable suspension, betamethasone sodium phosphate and betamethasone acetate injectable suspension, and methylprednisolone acetate injectable suspension. RESULTS: Dexamethasone sodium phosphate particle size was approximately 10 times smaller than red blood cells and the particles did not appear to aggregate; even mixed with 1% lidocaine HCl solution and with contrast dye, the size of the particles were unchanged. Triamcinolone acetonide and betamethasone sodium phosphate showed variable sizes; some particles were larger than red blood cells, and aggregation of particles was evident. Methylprednisolone acetate showed uniformity in size and the majority were smaller than red blood cells which were not aggregated, but the particles were densely packed. CONCLUSIONS: Compared with the particulate steroid solutions, dexamethasone sodium phosphate had particles that were significantly smaller than red blood cells, had the least tendency to aggregation, and had the lowest density. These characteristics should significantly reduce the risk of embolic infarcts or prevent them from occurring after intra-arterial injection. Until shown otherwise in clinical studies, interventionalists might consider using dexamethasone or another corticosteroid preparation with similar high solubility and negligible particle size when performing epidural injections.

Sieving behaviour of nanoscopic pores by hydrated ions.

In this study, for the first time, the anion dependency of Ag-deposition on self-assembled monolayers (SAMs) with alkyl chains long enough to meet the densely packed and well-organized surface is reported. Irrespective of pH, types of terminal groups of the SAMs, and the convective mass transfer condition, SAM structures show the "sieving behaviour" to the Ag deposition by the composition of the electrolytes.

Hair counts from scalp biopsy specimens in Asians.

BACKGROUND: Differences in hair density have been described according to the ethnic background in whites and blacks. Asians are known to have fewer hairs than whites. OBJECTIVE: We performed this study to assess the normal values of hair counts in scalp biopsy specimens from Koreans. METHODS: A total of 35 subjects with clinically normal occipital scalps (13 patients with androgenetic alopecia, 20 with patchy alopecia areata, and 2 healthy volunteers) were included. Horizontal sections of 4-mm punch biopsy specimens from clinically normal occipital scalps were examined at various levels from the papillary dermis to the subcutis, and follicular counts of terminal/vellus hairs and anagen/telogen hairs were obtained. RESULTS: The numbers of total hairs, terminal and vellus hairs, and terminal anagen hairs were significantly lower (P <.05) in Koreans compared with the published data of whites and blacks. Percent ratio of terminal anagen and telogen hairs were similar to whites and blacks. Follicular density was significantly lower (P <.05) in Koreans than in whites and blacks. In Koreans, female subjects had a significantly higher number of terminal hairs than male subjects (P <.05). CONCLUSION: Hair density is significantly lower in Koreans than in whites or blacks. Slight sexual difference exists in follicular counts in Koreans. Our data could be used as a guideline for determining normalcy in interpreting horizontal sections of scalp biopsy specimens from Asians.