Novel 2-amino-1,4-naphthoquinone hybrids: Design, synthesis, cytotoxicity evaluation and in silico studies.

In the present work, a novel series of 2-amino-1,4-naphthoquinones bearing oxyphenyl moiety (5a-5m) were designed and synthesized via a two-step route and evaluated for their in vitro cytotoxic activity against three different cancer cell lines (MCF-7, HL-60 and U937) and normal human cell line (HEK-293) by MTT assay. Compounds 5b (4-nitro-benzyl-) and 5k (4-bromo-benzyl-) were identified to possess the highest cytotoxic activity against MCF-7 cancerous cells (IC50 values of 27.76 and 27.86 µM, respectively). At the same time, none of the compounds exert significant toxicity against HEK-293 normal human kidney cells. Cell cycle analysis showed that the selected derivatives increased the population of MCF-7 cells in the S phase at 25 and 50 µM concentrations. Annexin V-FITC/PI staining assay also confirmed that compounds 5b and 5k induced apoptosis in the cell death pathway. Molecular docking and molecular dynamics studies were also performed to evaluate the probable interactions between the hybrids and human ATP binding domain of topo IIα protein. Our findings may provide new insight for further development of novel naphthoquinone-containing compounds.

Justicidin B: A Promising Bioactive Lignan.

Adverse effects and drug resistance to the current onchopharmacologicals have increased the demand for alternative novel therapeutics. We herein introduce justicidin B, an arylnaphthalen lignan isolated from different plant origins, especially Justicia, Phyllanthus, Haplophyllum and Linum species. This cyclolignan exhibits a wide array of biological properties ranges from piscicidal to antifungal, antiviral and antibacterial activities. Activity against Trypanosoma brucei makes justicidin B a potential antiprotozoal agent for the treatment of neglected tropical diseases. Pharmacological properties like antiplatelet, anti-inflammatory and bone resorption inhibition have been also attributed to justicidin B. This compound is a potent cytotoxic substance on several cell lines, especially chronic myeloid and chronic lymphoid leukemia. Pharmacological values, natural variation, as well as biotechnological production of justicidin B by plant cell, tissue and organ culture are also described in this review. Chemical characteristics and chromatographic methods to identify justicidin B and its biosynthetic pathway have been discussed. Different approaches to the total synthesis of justicidin B are compared. This review would shed light on the role of justicidin B as an intriguing natural compound and provides a chance to optimize conditions for industrial applications.

Amitriptyline, clomipramine, and doxepin adsorption onto sodium polystyrene sulfonate.

PURPOSE OF THE STUDY: Comparative in vitro studies were carried out to determine the adsorption characteristics of 3 drugs on activated charcoal (AC) and sodium polystyrene sulfonate (SPS). Activated charcoal (AC) has been long used as gastric decontamination agent for tricyclic antidepressants (TCA). METHODS: Solutions containing drugs (amitriptyline, clomipramine, or doxepin) and variable amount of AC or SPS were incubated for 30 minutes. RESULTS: At pH 1.2 the adsorbent: drug mass ratio varied from 2 : 1 to 40 : 1 for AC, and from 0.4 : 1 to 8 : 1 for SPS. UV-VIS spectrophotometer was used for the determination of free drug concentrations. The qmax of amitriptyline was 0.055 mg/mg AC and 0.574 mg/mg SPS, qmax of clomipramine was 0.053 mg/mg AC and 0.572 mg/mg SPS, and qmax of doxepin was 0.045 mg/mg AC and 0.556 mg/mg SPS. The results of adsorption experiments with SPS revealed higher values for the qmax parameters in comparison with AC. CONCLUSION: In vitro gastric decontamination experiments for antidepressant amitriptyline, clomipramine, and doxepin showed that SPS has higher qmax values than the corresponding experiments with AC. Therefore, we suggest SPS is a better gastric decontaminating agent for the management of acute TCA intoxication.

Armenian bole: a historical medicinal clay.

The medical use of earths and minerals is probably as old as the history of mankind. Particular types of clays and earths are still being used worldwide as therapeutic agents in the folk medicine of different countries. From the 19th century, the medicaments included in countries' pharmacopeias whose exact pharmacological activity or the chemistry of their active components was not known gradually decreased in number, despite their popularity among patients. With today's analytical armamentarium it may be time to reconsider returning some of those compounds to pharmacopeias. By using modern techniques in the past two decades, researchers have studied the active components of healing clays and their pharmacological properties. Many of them possess valuable therapeutic properties which could be used in modern medicine in pharmaceutical dosage forms. Our knowledge about the medical substances that our ancestors used through centuries could be used today as an evidence base for further clinical and pharmacological research. One of these substances is Armenian bole. In this work we studied the historical perspective of its therapeutic use in different countries. Also a sample sold in the market in Iran was purchased and X-ray diffraction analysis was performed on it to find out its chemical composition.

Immunomodulatory Peptides as Vaccine Adjuvants and Antimicrobial Agents.

The underdevelopment of adjuvant discovery and diversity, compared to core vaccine technology, is evident. On the other hand, antibiotic resistance is on the list of the top ten threats to global health. Immunomodulatory peptides that target a pathogen and modulate the immune system simultaneously are promising for the development of preventive and therapeutic molecules. Since investigating innate immunity in insects has led to prominent achievements in human immunology, such as toll-like receptor (TLR) discovery, we used the capacity of the immunomodulatory peptides of arthropods with concomitant antimicrobial or antitumor activity. An SVM-based machine learning classifier identified short immunomodulatory sequences encrypted in 643 antimicrobial peptides from 55 foe-to-friend arthropods. The critical features involved in efficacy and safety were calculated. Finally, 76 safe immunomodulators were identified. Then, molecular docking and simulation studies defined the target of the most optimal peptide ligands among all human cell-surface TLRs. SPalf2-453 from a crab is a cell-penetrating immunoadjuvant with antiviral properties. The peptide interacts with the TLR1/2 heterodimer. SBsib-711 from a blackfly is a TLR4/MD2 ligand used as a cancer vaccine immunoadjuvant. In addition, SBsib-711 binds CD47 and PD-L1 on tumor cells, which is applicable in cancer immunotherapy as a checkpoint inhibitor. MRh4-679 from a shrimp is a broad-spectrum or universal immunoadjuvant with a putative Th1/Th2-balanced response. We also implemented a pathway enrichment analysis to define fingerprints or immunological signatures for further in vitro and in vivo immunogenicity and reactogenicity measurements. Conclusively, combinatorial machine learning, molecular docking, and simulation studies, as well as systems biology, open a new opportunity for the discovery and development of multifunctional prophylactic and therapeutic lead peptides.

Structure-Selectivity Relationship Prediction of Tau Imaging Tracers Using Machine Learning-Assisted QSAR Models and Interaction Fingerprint Map.

Protein aggregates composed of tau fibrils are major pathologic findings in different tauopathies. An ideal agent for imaging tau fibrils must be highly selective. The molecular basis for the binding of current available compounds to tau aggregates is not well understood. Herein, we provide insights into previously studied positron emission tomography tracers using various computational methods, including machine learning-based quantitative structure-activity relationship (QSAR) classification, docking, and molecular dynamics (MD) simulations to investigate the structural basis of selective tau aggregate binding for potential compounds. The QSAR classification model based on the Random Forest algorithm with an accuracy of 96.6% for the selective and 97.6% for the nonselective class of compounds revealed essential selective moieties. The combination of molecular docking, MD simulations, and molecular mechanics Poisson-Boltzmann surface area (MM/PBSA) binding free-energy calculation showed superior binding energy of ligand 63 toward tau and PHF6, a key hexapeptide in tau aggregation, as the most selective compound in the data set. Dissecting the binding properties of ligand 63 and ligand 8 (the least selective compound) within tau and Aß structures confirmed that these two compounds favor different binding sites of tau; however, the preferential binding site in Aß was similar for both with lower binding energies calculated for ligand 8. Results revealed that the number of N-heterocycles, the position of nitrogen atoms, and the presence of tertiary amine are important components of selective binding moieties, and they should be maintained in molecules for selective binding to tau aggregates. The predicted structure-selectivity relationship will facilitate the rational design and further development of selective tau imaging agents.

Microtubule Disruption Without Learning Impairment in the Unicellular Organism, Paramecium: Implications for Information Processing in Microtubules.

Introduction: Information processing in microtubules is an open question that has not been adequately addressed. It was suggested that microtubules could store and process information in the nervous system or even support consciousness. The unicellular organism, Paramecium caudatum, has a microtubular structure but lacks a neuron or neural network. However, it shows intelligent behaviors such as associative learning. This property may suggest that the microtubules are involved in intelligent behavior, information storage, or information processing in this organism. Methods: To test this hypothesis and study the role of microtubules in P. caudatum learning, we utilized a learning task in which the organism associates brightness in its swimming medium with attractive cathodal shocks. To see if microtubules are an integral part of information storage and processing in P. caudatum, we disrupted the microtubular dynamics in the organism using an antimicrotubular agent (parbendazole). Results: We observed that while a partial allosteric modulator of GABA (midazolam) could disrupt the learning process in P. caudatum, the antimicrotubular agent could not interfere with the learning. Conclusion: Microtubules are probably not vital for the learning behavior in P. caudatum. Consequently, our results call for further investigation of the microtubular information processing hypothesis. Highlights: Importance of Information processing in microtubules;Microtubules could store and process information in the nervous system;Unicellular organism, Paramecium caudatum, has a microtubular structure but lacks a neuron or neural network. Plain Language Summary: Information processing in microtubules is an open question that has not been adequately addressed. It was suggested that microtubules could store and process information in the nervous system or even support consciousness. The unicellular organism, Paramecium caudatum, has a microtubular structure but lacks a neuron or neural network. However, it shows intelligent behaviors such as associative learning. This property may suggest that the microtubules are involved in intelligent behavior, information storage, or information processing in this organism. To test this hypothesis and study the role of microtubules in P. caudatum learning, we utilized a learning task in which the organism associates brightness in its swimming medium with attractive cathodal shocks. To see if microtubules are an integral part of information storage and processing in P. caudatum, we disrupted the microtubular dynamics in the organism using an antimicrotubular agent (parbendazole). We observed that while a partial allosteric modulator of GABA (midazolam) could disrupt the learning process in P. caudatum, the antimicrotubular agent could not interfere with the learning. Microtubules are probably not vital for the learning behavior in P. caudatum. Consequently, our results call for further investigation of the microtubular information processing hypothesis.

Two new cytotoxic ursane triterpenoids from the aerial parts of Salvia urmiensis Bunge.

Bioassay-guided fractionation of a dichloromethane extract of the aerial parts of Salvia urmiensis, an endemic plant species of Iran, led to the isolation of two new cytotoxic ursane triterpenoids, Salvurmin A and Salvurmin B. Their structures were elucidated by a combination of 1D and 2D NMR, HR-ESI-MS, IR and UV analysis. Cytotoxicity of the above-mentioned compounds were evaluated against two human cancerous cell lines (SW1116, MCF-7). IC50 values for Salvurmin A and Salvurmin B on colon cancer cell line (SW1116) were 41.6 ± 2.6 and 23.2 ± 0.4 µM respectively, in comparison to cisplatin as control positive. In addition, these two compounds exhibited cytotoxic activity on breast cancer cell line (MCF-7) with an IC50 of 54.2 ± 5.3 and 40.2 ± 3.1 µM for Salvurmin A and Salvurmin B, respectively. The cytotoxic activities of these two compounds present a promising potential for the future investigation on this endemic species of Salvia.

Viral 3CLpro as a Target for Antiviral Intervention Using Milk-Derived Bioactive Peptides.

Viruses of the picornavirus-like supercluster mainly achieve cleavage of polyproteins into mature proteins through viral 3-chymotrypsin proteases (3Cpro) or 3-chymotrypsin-like proteases (3CLpro). Due to the essential role in processing viral polyproteins, 3Cpro/3CLpro is a drug target for treating viral infections. The 3CLpro is considered the main protease (Mpro) of coronaviruses. In the current study, the SARS-CoV-2 Mpro inhibitory activity of di- and tri-peptides (DTPs) resulted from the proteolysis of bovine milk proteins was evaluated. A set of 326 DTPs were obtained from virtual digestion of bovine milk major proteins. The resulted DTPs were screened using molecular docking. Twenty peptides (P1-P20) showed the best binding energies (ΔG b < - 7.0 kcal/mol). Among these 20 peptides, the top five ligands, namely P1 (RVY), P3 (QSW), P17 (DAY), P18 (QSA), and P20 (RNA), based on the highest binding affinity and the highest number of interactions with residues in the active site of Mpro were selected for further characterization by ADME/Tox analyses. For further validation of our results, molecular dynamics simulation was carried out for P3 as one of the most favorable candidates for up to 100 ns. In comparison to N3, a peptidomimetic control inhibitor, high stability was observed as supported by the calculated binding energy of the Mpro-P3 complex (- 59.48 ± 4.87 kcal/mol). Strong interactions between P3 and the Mpro active site, including four major hydrogen bonds to HIS41, ASN142, GLU166, GLN189 residues, and many hydrophobic interactions from which the interaction with CYS145 as a catalytic residue is worth mentioning. Conclusively, milk-derived bioactive peptides, especially the top five selected peptides P1, P3, P17, P18, and P20, show promise as an antiviral lead compound. Supplementary Information: The online version contains supplementary material available at 10.1007/s10989-021-10284-y.

Synthesis, metabolism and in vitro cytotoxicity studies on novel lavendamycin antitumor agents.

A series of lavendamycin analogues with two, three or four substituents at the C-6, C-7 N, C-2', C-3' and C-11' positions were synthesized via short and efficient methods and evaluated as potential NAD(P)H:quinone oxidoreductase (NQO1)-directed antitumor agents. The compounds were prepared through Pictet-Spengler condensation of the desired 2-formylquinoline-5,8-diones with the required tryptophans followed by further needed transformations. Metabolism and toxicity studies demonstrated that the best substrates for NQO1 were also the most selectively toxic to NQO1-rich tumor cells compared to NQO1-deficient tumor cells.

Identification and functional prediction of stress responsive AP2/ERF transcription factors in Brassica napus by genome-wide analysis.

Using homology and domain authentication, 321 putative AP2/ERF transcription factors were identified in Brassica napus, called BnAP2/ERF TFs. BnAP2/ERF TFs were classified into five major subfamilies, including DREB, ERF, AP2, RAV, and BnSoloist. This classification is based on phylogenetic analysis, motif identification, gene structure analysis, and physiochemical characterization. These TFs were annotated based on phylogenetic relationship with Brassica rapa. BnAP2/ERF TFs were located on 19 chromosomes of B. napus. Orthologs and paralogs were identified using synteny-based methods Ks calculation within B. napus genome and between B. napus with other species such as B. rapa, Brassica oleracea, and Arabidopsis thaliana indicated that BnAP2/ERF TFs were formed through duplication events occurred before B. napus formation. Kn/Ks values were between 0 and 1, suggesting the purifying selection among BnAP2/ERF TFs. Gene ontology annotation, cis-regulatory elements and functional interaction networks suggested that BnAP2/ERF TFs participate in response to stressors, including drought, high salinity, heat and cold as well as developmental processes particularly organ specification and embryogenesis. The identified cis-regulatory elements in the upstream of BnAP2/ERF TFs were responsive to abscisic acid. Analysis of the expression data derived from Illumina Hiseq 2000 RNA sequencing revealed that BnAP2/ERF genes were highly expressed in the roots comparing to flower buds, leaves, and stems. Also, the ERF subfamily was over-expressed under salt and fungal treatments. BnERF039 and BnERF245 are candidates for salt-tolerant B. napus. BnERF253-256 and BnERF260-277 are potential cytokinin response factors. BnERF227, BnERF228, BnERF234, BnERF134, BnERF132, BnERF176, and BnERF235 were suggested for resistance against Leptosphaeria maculan and Leptosphaeria biglobosa.

Novel lavendamycin analogues as antitumor agents: synthesis, in vitro cytotoxicity, structure-metabolism, and computational molecular modeling studies with NAD(P)H:quinone oxidoreductase 1.

Novel lavendamycin analogues with various substituents were synthesized and evaluated as potential NAD(P)H:quinone oxidoreductase (NQO1)-directed antitumor agents. Pictet-Spengler condensation of quinoline- or quninoline-5,8-dione aldehydes with tryptamine or tryptophans yielded the lavendamycins. Metabolism studies with recombinant human NQO1 revealed that addition of NH2 and CH2OH groups at the quinolinedione-7-position and indolopyridine-2'-position had the greatest positive impact on substrate specificity. The best and poorest substrates were 37 (2'-CH2OH-7-NH2 derivative) and 31 (2'-CONH2-7-NHCOC3H7-n derivative) with reduction rates of 263 +/- 30 and 0.1 +/- 0.1 micromol/min/mg NQO1, respectively. Cytotoxicity toward human colon adenocarcinoma cells was determined for the lavendamycins. The best substrates for NQO1 were also the most selectively toxic to the NQO1-rich BE-NQ cells compared to NQO1-deficient BE-WT cells with 37 as the most selective. Molecular docking supported a model in which the best substrates were capable of efficient hydrogen-bonding interactions with key residues of the active site along with hydride ion reception.

A Randomized Double Blind Clinical Trial on a Sabgh Formulation for Patients With Vitiligo.

BACKGROUND: The cosmetic problem that vitiligo produces affects patients psychologically. Many patients with vitiligo are suggested to cover their white skin patches with cosmetic products. There are formulations in traditional Iranian pharmacy to color these white skin patches. In this study, one of these formulations was compared with a cosmetic formulation. METHODS: Two groups of patients were selected. One group used a marketed formulation and other group used a traditional Iranian Pharmacy formulation. The quality of life of the patients was compared based on the Dermatology Life Quality Index Questionnaire. RESULTS: Both interventions were associated with statistically improved Dermatology Life Quality Index scores over the 8-week intervention (P < .05), although the difference between the 2 was not statistically significant (P = .436). CONCLUSION: Traditional Iranian Pharmacy formulation is effective in increasing the quality of life in vitiligo patients.

Synthesis of the bryostatin 1 northern hemisphere (C1-C16) via desymmetrization by ketalization/ring-closing metathesis.

[reaction: see text] Synthesis of the northern hemisphere (C1-C16) of bryostatin 1, a potent anticancer agent, has been accomplished in 14 steps and 11% overall yield via desymmetrization by ketalization/ring-closing metathesis. A 2,9-dioxabicyclo[3.3.1]nonane template facilitated stereoselective A-ring functionalization, while an efficient hetero-Diels-Alder reaction was used to elaborate the B-ring.

Total synthesis of novel 6-substituted lavendamycin antitumor agents.

[structure: see text] Novel 6-substituted lavendamycins have been synthesized for the first time. The key step in these syntheses is a Pictet-Spengler condensation (Scheme 1). Efficient methods for the synthesis of each compound, including a novel reaction for the facile introduction of alkylamino groups at the C-6 position of the lavendamycin system, are discussed. Possible mechanisms for these reactions are also presented.

Randomized and double-blinded clinical trial of the safety and calcium kidney stone dissolving efficacy of Lapis judaicus.

ETHNOPHARMACOLOGICAL RELEVANCE: Kidney stones are one of the most common disorders of the urinary tract and cause a great deal of morbidity and economic loss. Because of the side effects and costs of current interventional procedures, researchers are interested in finding medicinal therapies. In this regard, some reports have focused on traditional medicines as a drug discovery resource. Iranian scholars in the medieval era recommended Lapis judaicus for the prevention and treatment of kidney stones. The present study assessed the efficacy and safety of Lapis judaicus on the size of calcium kidney stones and some related biochemical factors in blood and urine. MATERIALS AND METHODS: Sixty patients with kidney stone disease were included in this double-blind randomized clinical study. Thirty patients received 2g of Lapis judaicus powder in hard capsules per day for 10 weeks, and another 30 patients received a placebo for the same period. Ultrasonography was performed on patients, and blood and urine samples were collected before and after the study to evaluate the efficacy and safety of Lapis judaicus in calcium kidney stone patients. RESULTS: The size of the kidney stones was reduced significantly (p<0.001) in the drug group. In 9 patients from the drug group, the stone was completely dissolved. Moreover, urine calcium concentration and specific gravity were reduced and urine magnesium was increased (p<0.05). Lapis judaicus did not affect BUN, creatinine, ALT, or AST. CONCLUSION: Contrary to the placebo group, the size of kidney stones was reduced significantly in the treatment group after oral administration of Lapis judaicus. This preliminary study confirms traditional knowledge of the efficacy and safety of Lapis judaicus in kidney stone diseases and suggests a new method to treat calcium kidney stones. Further detailed in vitro and in vivo studies aimed at discovering the mechanism of action of Lapis judaicus and clinical studies involving a larger population of patients will be necessary to fully explain and confirm the results obtained in the present study.