Discovery of oral chemotherapeutic reversal agents for treating multidrug resistance cancer.

The major limitation of cancer treatment is multidrug resistance (MDR), which leads to the inactivation of chemotherapeutic drugs and greater than 90% mortality. To solve this ordeal, we applied ligand-based drug design and bioiosteric replacement strategy from an indazole to a pyrazole ring to discover compounds 27 and 43 with good potential for reversing drug resistance in combination with paclitaxel, and their reversal fold values were 53.2 and 51.0 at 5 µM, respectively, against an MDR cancer cell line (KBvin). Based on the PK profile results, we selected compound 43 with a longer half-life for mechanistic and animal experiments. Combination treatment with compound 43 and paclitaxel-induced apoptosis and enhanced subG1 by decreasing mitochondrial membrane potential in KBvin cells. In addition, 43 also inhibited P-gp function by interfering with ATPase activity. Meanwhile, cotreatment with compound 43 and paclitaxel significantly suppressed tumor growth (TGI = 55.5%) at a dose of 200 mg/kg (PO) in a xenograft model and showed no obvious liver or kidney toxicity by H&E staining. Overall, compound 43 may serve as a safe and effective oral resistance reversal chemotherapeutic agent.

Design and synthesis of pyrazole derivatives against neutrophilic inflammation.

Neutrophils are the most abundant immune cells. However, neutrophil dysregulation leads to acute and chronic inflammation and is involved in various diseases. The aim of this study was to develop anti-inflammatory agents in human neutrophils. A drug screening was conducted on in-house compounds with the potential to inhibit the respiratory burst, which involves the generation of superoxide anions in human neutrophils. Bioisosteric replacement was then applied to design more active derivatives. The most potent inhibitors of superoxide anion generation activity were compounds 58 and 59, which had IC50 values of 13.30 and 9.06 nM, respectively. The inhibitory effects of 58 and 59 were reversed by H89, a PKA inhibitor. PDE selective screening indicated that the best inhibitory effects were PDE4B1 and PDE4D2, and the inhibitory activities were 83% and 85%, respectively, at a 10 µM concentration of 59. The final molecular simulation experiment highlighted the slightly different binding poses of 58 and 59 in the PDE4 active site. An in vivo pharmacokinetic study revealed that the half-life of 59 was approximately 79 min when using intravenous bolus administration. This work introduced a new class structure of PDE4 inhibitors resulting in potent neutrophil inactivation activity, with the aim of contributing to new anti-inflammatory drug discovery.

Novel (-)-arctigenin derivatives inhibit signal transducer and activator of transcription 3 phosphorylation and P-glycoprotein function resensitizing multidrug resistant cancer cells in vitro and in vivo.

Multidrug resistance (MDR) is considered one of the significant chemotherapy failures of cancer patients and resulting in tumor recurrence and refractory cancer. The collateral sensitivity phenomenon is suggested as a potential alternative therapy for coring multidrug resistance in cancer. To achieve better effects and reduce toxicity, a polypharmacology strategy was applied. Arctigenin has been reported as a signal transducer and activator of transcription 3 (STAT3) inhibitor as an anticancer drug with low toxicity. However, the effective dosage of arctigenin was too high for re-sensitization in MDR cell lines. Therefore, we have designed and synthesized arctigenin derivatives and have evaluated their chemoreversal effects in KBvin and KB cells. The results conveyed that compounds 9, 10, and 12 displayed significant collateral sensitivity effects on MDR cancer cells, and the corresponding calculated RF values were 32, 174, and 133, respectively. In addition, compounds 9, 10, and 12 were identified to influence the activation of STAT3 and the function of P-glycoprotein in KBvin cells. Combining the active compounds (9, 10, and 12) with paclitaxel significantly inhibits MDR tumor growth in a zebrafish xenograft tumor model without toxicity. Thus, this study provided novel effective arctigenin derivatives and is considered a potential co-treatment with paclitaxel for treating MDR tumors.

In vitro and in silico cholinesterase inhibitory potential of metabolites from Laurencia snackeyi (Weber-van Bosse) M. Masuda.

Alzheimer's disease (AD) is a neurodegenerative disease that causes deterioration in intelligence and psychological activities. Yet, till today, no cure is available for AD. The marine environment is an important sink of bioactive compounds with neuroprotective potential with reduced adverse effects. Recently, we collected the red algae Laurencia snackeyi from Terumbu Island, Malaysia which is known to be rich in halogenated metabolites making it the most sought-after red algae for pharmaceutical studies. The red alga was identified based on basic morphological characteristics, microscopic observation and chemical data from literature. The purplish-brown algae was confirmed a new record. In Malaysia, this species is poorly documented in Peninsular Malaysia as compared to its eastern continent Borneo. Thus, this study intended to investigate the diversity of secondary metabolites present in the alga and its cholinesterase inhibiting potential for AD. The extract inhibited both acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) with IC50 values of  14.45 ± 0.34 µg mL-1 and 39.59 ± 0.24 µg mL-1, respectively. Subsequently, we isolated the synderanes, palisadin A (1), aplysistatin (2) and 5-acetoxypalisadin B (3) that was not exhibit potential. Mass spectrometry analysis detected at total of 33 additional metabolites. The computational aided molecular docking using the AChE and BChE receptors on all metabolites shortlisted 5,8,11,14-eicosatetraynoic acid (31) and 15-hydroxy-1-[2-(hydroxymethyl)-1-piperidinyl]prost-13-ene-1,9-dione (42) with best inhibitory properties, respectively with the lowest optimal combination of S-score and RMSD values. This study shows the unexplored potential of marine natural resources, however, obtaining sufficient biomass for detailed investigation is an uphill task. Regardless, there is a lot of potential for future prospects with a wide range of marine natural resources to study and the incorporation of synthetic chemistry, in vivo studies in experimental design. Supplementary Information: The online version contains supplementary material available at 10.1007/s13205-023-03725-6.

A Modified 1H-NMR Quantification Method of Ephedrine Alkaloids in Ephedrae Herba Samples.

A previous 1H-NMR method allowed the quantification of ephedrine alkaloids; however, there were some disadvantages. The cyclized derivatives resulted from the impurities of diethyl ether were identified and benzene was selected as the better extraction solvent. The locations of ephedrine alkaloids were confirmed with 2D NMR. Therefore, a specific 1H-NMR method has been modified for the quantification of ephedrine alkaloids. Accordingly, twenty Ephedrae Herba samples could be classified into three classes: (I) E. sinica-like species; (II) E. intermedia-like species; (III) others (lower alkaloid contents). The results indicated that ephedrine and pseudoephedrine are the major alkaloids in Ephedra plants, but the concentrations vary greatly determined by the plant species and the collection locations.

Continuous Positive Airway Pressure Reduces Plasma Neurochemical Levels in Patients with OSA: A Pilot Study.

Obstructive sleep apnea (OSA) is a risk factor for neurodegenerative diseases. This study determined whether continuous positive airway pressure (CPAP), which can alleviate OSA symptoms, can reduce neurochemical biomarker levels. Thirty patients with OSA and normal cognitive function were recruited and divided into the control (n = 10) and CPAP (n = 20) groups. Next, we examined their in-lab sleep data (polysomnography and CPAP titration), sleep-related questionnaire outcomes, and neurochemical biomarker levels at baseline and the 3-month follow-up. The paired t-test and Wilcoxon signed-rank test were used to examine changes. Analysis of covariance (ANCOVA) was performed to increase the robustness of outcomes. The Epworth Sleepiness Scale and Pittsburgh Sleep Quality Index scores were significantly decreased in the CPAP group. The mean levels of total tau (T-Tau), amyloid-beta-42 (Aß42), and the product of the two (Aß42 × T-Tau) increased considerably in the control group (ΔT-Tau: 2.31 pg/mL; ΔAß42: 0.58 pg/mL; ΔAß42 × T-Tau: 48.73 pg2/mL2), whereas the mean levels of T-Tau and the product of T-Tau and Aß42 decreased considerably in the CPAP group (ΔT-Tau: -2.22 pg/mL; ΔAß42 × T-Tau: -44.35 pg2/mL2). The results of ANCOVA with adjustment for age, sex, body mass index, baseline measurements, and apnea-hypopnea index demonstrated significant differences in neurochemical biomarker levels between the CPAP and control groups. The findings indicate that CPAP may reduce neurochemical biomarker levels by alleviating OSA symptoms.

Age-related differences in ERP correlates of value-based decision making.

This study evaluates age-related differences in the temporal dynamics underlying neural processing of value for decision-making in younger and older adults. We applied a lottery-choice task with event-related potentials to determine how and when brain activity during choice and outcome processing diverge between younger and older adults. Behaviorally, older adults accepted more losing stakes than younger adults. During choice, younger adults evinced higher P2 ERP-response positivity with a later P3 positivity that monotonically increased with low to middle to high win probability. Older adults evinced lower P2 responses and P3 amplitudes with more positivity for high and low relative to middle win probability. Both age groups showed similar feedback-related negativity and late parietal positivity, indicating intact reward prediction error representations and salience integration. Feedback-P3 showed more complex sensitivity to expectancy violations in older than younger adults, suggesting subjective uncertainty about reward expectations. Reduced early general neural processing of objective stimulus value with greater contribution of downstream subjective processes might underlie older adult risk-taking behaviors.

Exploration and biological evaluation of 7-methoxy-3-methyl-1H-chromeno[4,3-c]pyrazol-4-one as an activating transcription factor 3 inducer for managing metabolic syndrome.

The induction of activating transcription factor 3 (ATF3) was identified as a promising therapeutic mechanism to overcome metabolic syndrome. Hence, a structure-activity relationship campaign on the chiral lead (1b) was conducted with a scaffold-hopping approach, whereby achiral 7-methoxy-3-methyl-1H-chromeno[4,3-c]pyrazol-4-one (16c) was recognized as a potential ATF3 inducer with a lipid-lowering feature in a pre-differentiated 3T3-L1 cell model. Also, in a high-fat diet scenario, mice subjected to 16c demonstrated robust weight loss with shrinkage of the white adipose mass and fewer hypertrophic adipocytes, accompanied by a preferable glycemic profile compared to 1b. Additionally, the biochemical analysis revealed that 16c further ameliorated the liver function and improved the plasma triglyceride profile that were absent from mice treated with 1b. Taken together, 16c shows promise as an ATF3 stimulant for further development to alleviate metabolic syndrome.

Discovery of 5,7-Dimethoxy-2-(3,4,5-trimethoxyphenoxy)-chromen-4-one with Lipid Lowering Effects in Hepatocytes.

The population with nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) is increasing. However, no medicine is indicated for treating these diseases clinically nowadays. Therefore, there is an urgent need to develop a new drug to overcome NAFLD and NASH. Capillarisin, a 2-phenoxychromone originating from Artemisia capillaris Thunb., is well-known for its liver-protective effects. As a result, a series of 2-phenoxychromones was prepared and evaluated for its protective activity against lipid droplet formation in oleic acid (OA)-treated Huh7 cells by means of high-content screening. In the light of the results, the compounds with trimethoxy groups on the phenyl ring possessed better inhibitory properties against lipid accumulation in Huh7 cells, compared to other functional groups on the same ring. Nonetheless, the compounds with a hydroxy group at the C-5 position of the chromone exhibited apparent cytotoxicity. Finally, the active compound, 5,7-dimethoxy-2-(3,4,5-trimethoxyphenoxy)-chromen-4-one (7e), with an IC50 value of 32.2 ± 2.1 µM against lipid accumulation and no significant cytotoxicity, reduced the accumulation of lipid droplets by up-regulating peroxisome proliferator-activated receptor gamma coactivator 1α (PGC1α) to facilitate the catabolism of fat, which shows promise for further optimization to manage NAFLD and NASH.

Recent advances in natural anti-obesity compounds and derivatives based on in vivo evidence: A mini-review.

Obesity is not only viewed as a chronic aggressive disorder but is also associated with an increased risk for various diseases. Nonetheless, new anti-obesity drugs are an urgent need since few pharmacological choices are available on the market. Natural compounds have served as templates for drug discovery, whereas modified molecules from the leads identified based on in vitro models often reveal noncorresponding bioactivity between in vitro and in vivo studies. Therefore, to provide inspiration for the exploration of innovative anti-obesity agents, recent discoveries of natural anti-obesity compounds with in vivo evidence have been summarized according to their chemical structures, and the comparable efficacy of these compounds is categorized using animal models. In addition, several synthetic derivatives optimized from the phytochemicals are also provided to discuss medicinal chemistry achievements guided by natural sources.

Chemical Constituents of Hedyotis diffusa and Their Anti-Inflammatory Bioactivities.

Seven new anthraquinones with rare 2-isopropyldihydrofuran (1-3) and 2,2-dimethylpyrano (4-7) moieties together with thirty-four known compounds were isolated from the extracts of whole Hedyotis diffusa plants. Their structures were elucidated and established by various spectroscopic and spectrometric analytical methods. Among these isolates, selected compounds were examined for their anti-inflammatory activity. The results showed that rare substituted anthraquinones displayed potent inhibitory activity with IC50 values ranging from 0.15 ± 0.01 to 5.52 ± 1.59 µM on the N-formyl-methionyl-leucyl-phenylalanine/cytochalasin B (fMLP/CB)-induced superoxide anion generation and elastase release cellular models. Meanwhile, the proposed drug target of the active anthraquinone was studied by computer modeling. The binding affinity between the anti-inflammatory anthraquinone and elastase was evaluated by molecular docking. These results provided the scientific insight into the medicinal values of Hedyotis diffusa and vision of development as lead compounds.

Betulinic acid-nucleoside hybrid prevents acute alcohol -induced liver damage by promoting anti-oxidative stress and autophagy.

Alcoholic abuse is one of the most serious causes of liver diseases worldwide. Although detailed molecular pathogenesis of alcohol-induced liver damages remains elusive with intensive debates, it has been widely recognized that hepatic damage caused by free radicals generated from alcohol metabolism is one of the most critical factors for alcohol-induced liver diseases. Betulinic acid is a potent antioxidant with additional known pharmacological safety characteristics and minimal toxicity. However, poor solubility limited its usage. In this study, we assessed the efficacy of BAN, a betulinic acid and nucleoside hybrid with good water solubility, in reversing acute liver damages using an established alcohol overdose animal model. The results indicated that BAN is an extremely promising therapeutic agent against acute alcohol-induced liver damage. BAN effectively protects liver from alcohol damage by reducing serum ALT level by up to 47%, as well as liver oxidative stress indicated by significantly increased SOD, CAT, and GSH-Px levels. Moreover, hepatic FXR activation and a corresponding downstream anti-oxidative stress transcriptional cascade including Nrf2, HO-1, and NOQ1 induce the protective role of BAN. On the other hand, BAN administration also leads to increase cellular autophagy response, as indicated by the key ATG protein activation. We concluded that BAN, comparing with Betulinic acid, prevents acute alcohol-induced liver damages more effectively, with the dual mechanisms of neutralizing oxidative stress and promoting autophagy.

Morphological variations in a widely distributed Eastern Asian passerine cannot be consistently explained by ecogeographic rules.

Ecogeographic rules that describe quantitative relationships between morphologies and climate might help us predict how morphometrics of animals was shaped by local temperature or humidity. Although the ecogeographic rules had been widely tested in animals of Europe and North America, they had not been fully validated for species in regions that are less studied. Here, we investigate the morphometric variation of a widely distributed East Asian passerine, the vinous-throated parrotbill (Sinosuthora webbiana), to test whether its morphological variation conforms to the prediction of Bergmann's rule, Allen's rules, and Gloger's rule. We at first described the climatic niche of S. webbiana from occurrence records (n = 7838) and specimen records (n = 290). The results of analysis of covariance (ANCOVA) suggested that the plumage coloration of these parrotbills was darker in wetter/warmer environments following Gloger's rule. However, their appendage size (culmen length, beak volume, tarsi length) was larger in colder environments, the opposite of the predictions of Allen's rule. Similarly, their body size (wing length) was larger in warmer environments, the opposite of the predictions of Bergmann's rule. Such disconformity to both Bergmann's rule and Allen's rule suggests that the evolution of morphological variations is likely governed by multiple selection forces rather than dominated by thermoregulation. Our results suggest that these ecogeographic rules should be validated prior to forecasting biological responses to climate change especially for species in less-studied regions.

Chemoreversal Agents from Taiwanofungus Genus and Their More Potent Methyl Derivatives Targeting Signal Transducer and Activator of Transcription 3 (STAT3) Phosphorylation.

Multidrug resistance (MDR), for which the mechanisms are not yet fully clear, is one of the major obstacles to cancer treatment. In recent years, signal transducer and activator of transcription 3 (STAT3) were found to be one of the important MDR mechanism pathways. Based on the previous research, zhankuic acid A, B, and C were found to have collateral sensitivity effects on MDR cancer cells, and MDR inhibitory activity of zhankuic acid methyl ester was found to be better than that of its acid. Therefore, we executed a systematic examination of the structure-activity relationship of zhankuic acid methyl ester derivatives to collateral sensitivity in MDR cancer cells. The results showed that compound 12 is the best in terms of chemoreversal activity, where the reversal fold was 692, and the IC50 value of paclitaxel combined with 10 µM compound 12 treatment was 1.69 nM in MDR KBvin cells. Among all the derivatives, methyl ester compounds were found to be better than their acids, and a detailed discussion of the structure-activity relationships of all of the derivatives is provided in this work. In addition, compounds 8, 12, and 26 were shown to influence the activation of STAT3 in KBvin cells, accounting for part of their chemoreversal effects. Our results may provide a new combined therapy with paclitaxel to treat multidrug-resistant cancers and provide a new therapy option for patients.

Bioactive naphthoquinones and triterpenoids from the fruiting bodies of Taiwanofungus salmoneus.

Drug resistance of cancer cells stands for the major problem of the treatment failure for chemotherapy or target therapy. Overexpression of efflux pumps leading to multidrug resistance (MDR) is still an important issue needed to be solved. In the present study, Taiwanofungus salmoneus was selected as the topic and eleven undescribed constituents including four naphthoquinones salmonones A-D (1-4) and seven triterpenoids salmoneatins A-G (5-11), along with one chromanone (12) and two benzenoids (13 and 14) reported from the natural sources for the first time, as well as twenty-one known compounds were characterized. The structures of undescribed compounds were established by the spectroscopic and spectrometric analyses. In addition, the plausible biosynthetic mechanism of purified naphthoquinones was proposed and these compounds may be the excellent chemotaxonomic markers. Moreover, the isolates were evaluated for their P-gp inhibitory effects and the results showed that most of the examined compounds were effective. Among the tested compounds, 5, 10, 2,3-dimethoxy-5-(2',5'-dimethoxy-3',4'-methylenedioxyphenyl)-7-methyl-[1,4]naphthoquinone, zhankuic acid A methyl ester, and camphoratin F can reverse the resistance of paclitaxel or vincristine with the reversal folds in the range of 51093.3 and 259.5. These experimental data would initiate the possible development of Taiwanofungus salmoneus for the cancer therapy in the future.

A Rapid and Feasible 1H-NMR Quantification Method of Ephedrine Alkaloids in Ephedra Herbal Preparations.

A highly specific and sensitive proton nuclear magnetic resonance (1H-NMR) method has been developed for the quantification of ephedrine alkaloid derivatives in Ephedra herbal commercial prescriptions. At the region of δ 4.0 to 5.0 ppm in the 1H NMR spectrum, the characteristic signals are separated well from each other, and six analogues in total, methylephedrine (ME), ephedrine (EP), norephedrine (NE), norpseudoephedrine (NP), pseudoephedrine (PE), and methylpseudoephedrine (MP) could be identified. The quantities of these compounds are calculated by the relative ratio of the integral values of the target peak for each compound to the known concentrations of the internal standard anthracene. The present method allows for a rapid and simple quantification of ephedrine alkaloid derivatives in Ephedra-related commercial prescriptions without any preliminary purification steps and standard compounds, and accordingly it can be a powerful tool to verify different Ephedra species. In comparison to conventional chromatographic methods, the advantages of this method include the fact that no standard compounds are required, the quantification can be directly performed on the crude extracts, a better selectivity for various ephedrine alkaloid derivatives, and the fact that a very significant time-gain may be achieved.

The study on structure-activity relationship between chromone derivatives and inhibition of superoxide anion generating from human neutrophils.

Over activation of neutrophils has been linked to many inflammatory diseases; one of critical pathologic mechanisms is that generation and exocellular release of superoxide anion from neutrophils results in peripheral tissues damage. Besides, in this study, 2-(3,5-dimethoxyphenoxy)-5,7-dimethoxy-chromen-4-one (4), a 2-phexnoychromone from our compound bank, was demonstrated to have the moderate inhibitory effect on superoxide anion generating. Therefore, serial chromones substituted with phenols or 3-flourothiophenol were designed, synthesized, and examined for suppression of superoxide anion generation. In accordance with the results, the methoxy group at 7 position (R3) of the chromone, as well as a hydrogen bond donor at a meta site of the phenyl ring greatly impacted on the activity. 2-(3-fluorophenyl)sulfanyl-7-methoxy-chromen-4-one (16), a successful example of bioisosteres from a phenol to a thiophenol, exhibited prominent anti-inflammatory effects with the IC50 value against superoxide anion generation of 5.0 ± 1.4 µM.

Antiinflammatory triterpenoids from the fruiting bodies of Fomitopsis pinicola.

Twelve undescribed lanostane-type triterpenes, and twenty-two known triterpenes were isolated and identified from a medicinal bracket fungus Fomitopsis pinicola (Sw.) P. Karst. The structures of these compounds were determined by spectroscopic and spectrometric analyses. The antiinflammatory potential of thirty-two triterpene compounds was evaluated using neutrophils as an assay model, and pinicolasin J was the most potent inhibitor of superoxide anion generation and elastase release, with IC50 values of 1.81 ± 0.44 and 2.50 ± 0.64 µM, respectively. This study provides scientific insight into the nutritional supplement value and medicinal development of Fomitopsis pinicola.

A new dimeric protoberberine alkaloid and other compounds from the tubers of Tinospora dentata.

A new dimeric quaternary protoberberine alkaloid, bispalmatrubine (1), and thirteen known compounds (2-14) were purified from the tubers of Tinospora dentata. Their structures were determined by spectroscopic and spectrometric analytical methods. Among the isolates, eight compounds were examined for their in vitro anti-inflammatory potential and several tested alkaloids displayed moderate inhibitory effects of N-formyl-methionyl-leucyl-phenylalanine/cytochalasin B (fMLP/CB)-induced superoxide anion generation and elastase release.

Synthetic strategy and structure-activity relationship (SAR) studies of 3-(5'-hydroxymethyl-2'-furyl)-1-benzyl indazole (YC-1, Lificiguat): a review.

Since 1994, YC-1 (Lificiguat, 3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole) has been synthesized, and many targets for special bioactivities have been explored, such as stimulation of platelet-soluble guanylate cyclase, indirect elevation of platelet cGMP levels, and inhibition of hypoxia-inducible factor-1 (HIF-1) and NF-κB. Recently, Riociguat®, the first soluble guanylate cyclase (sGC) stimulator drug used to treat pulmonary hypertension and pulmonary arterial hypertension, was derived from the YC-1 structure. In this review, we aim to highlight the synthesis and structure-activity relationships in the development of YC-1 analogs and their possible indications.