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Objectives: Breast cancer is a prevalent disease that has a substantial impact on women's mortality rates. Shikonin, a naphthoquinone derived from Lithospermum erythrorhizon, has demonstrated substantial anticancer effects. This study aims to conduct a comprehensive review of the latest research findings regarding the therapeutic efficacy of shikonin in the context of breast cancer treatment, with a specific emphasis on elucidating the underlying molecular mechanisms., Methods: A comprehensive literature review was conducted on shikonin and breast cancer by searching PubMed, Scopus, Web of Science, and Google Scholar databases., Key Findings: Shikonin significantly reduces tumor cell viability, proliferation, migration, invasion, and metastasis in both in vivo and in vitro across all breast cancer subtypes. Additionally, when combined with other pharmaceutical agents, it exhibits synergistic effects. Shikonin stimulates immunogenic cell death, resulting in apoptosis and necroptosis. The induction of immunogenic cell death by shikonin enhances the immunogenicity of breast cancer cells, leading to its involvement in the development of dendritic cell-based tumor vaccines against breast cancer., Conclusion: Shikonin exhibits potent anti-breast cancer properties and shows significant potential for the advancement of immunotherapeutic approaches against breast cancer, as well as enhancing the efficacy of conventional treatment strategies., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Royal Pharmaceutical Society.)

A talented endophytic Streptomyces sp. PH9030 is derived from the medicinal plant Kadsura coccinea (Lem.) A.C. Smith. The undescribed naphthoquinone naphthgeranine G ( 5 ) and seven previously identified compounds, 6 - 12 , were obtained from Streptomyces sp. PH9030. The structure of 5 was identified by comprehensive examination of its HRESIMS, 1D NMR, 2D NMR and ECD data. The inhibitory activities of all the compounds toward α-glucosidase and their antibacterial properties were investigated. The α-glucosidase inhibitory activities of 5 , 6 , 7 and 9 were reported for the first time, with IC 50 values ranging from 66.4 ± 6.7 to 185.9 ± 0.2 μM, as compared with acarbose (IC 50 = 671.5 ± 0.2 μM). The molecular docking and molecular dynamics analysis of 5 with α-glucosidase further indicated that it may have a good binding ability with α-glucosidase. Both 9 and 12 exhibited moderate antibacterial activity against methicillin-resistant Staphylococcus aureus , with minimum inhibitory concentration (MIC) values of 16 μg/mL. These results indicate that 5 , together with the naphthoquinone scaffold, has the potential to be further developed as a possible inhibitor of α-glucosidase.

Leishmaniasis is a neglected tropical disease (endemic in 99 countries) caused by parasitic protozoa of the genus Leishmania. As treatment options are limited, there is an unmet need for new drugs. The hydroxynaphthoquinone class of compounds demonstrates broad-spectrum activity against protozoan parasites. Buparvaquone (BPQ), a member of this class, is the only drug licensed for the treatment of theileriosis. BPQ has shown promising antileishmanial activity but its mode of action is largely unknown. The aim of this study was to evaluate the ultrastructural and physiological effects of BPQ for elucidating the mechanisms underlying the in vitro antiproliferative activity in Leishmania donovani. Transmission and scanning electron microscopy analyses of BPQ-treated parasites revealed ultrastructural effects characteristic of apoptosis-like cell death, which include alterations in the nucleus, mitochondrion, kinetoplast, flagella, and the flagellar pocket. Using flow cytometry, laser scanning confocal microscopy, and fluorometry, we found that BPQ induced caspase-independent apoptosis-like cell death by losing plasma membrane phospholipid asymmetry and cell cycle arrest at sub-G0/G1 phase. Depolarization of the mitochondrial membrane leads to the generation of oxidative stress and impaired ATP synthesis followed by disruption of intracellular calcium homeostasis. Collectively, these findings provide valuable mechanistic insights and demonstrate BPQ's potential for development as an antileishmanial agent., Competing Interests: Conflict of Interest The authors declare that they have no competing interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Microscopy Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Chronic Inflammation is associated with various types of diseases that involves pro-inflammatory cytokines like IL-6 and TNF-α. High costs and serious side effects of available anti-inflammatory/immunomodulatory drugs led us to design new compounds with promising anti-inflammatory activities. Many drugs and biologically important compounds involve naphthoquinone and thiazole moieties in their core structures. Thereby, here we report the synthesis, characterization and anti-inflammatory activities of new naphthoquinone thiazole hybrids by reaction of naphthoquinone acyl thioureas with various α-bromoketone derivatives. The position of NO 2 group in one of the phenyl rings of naphthoquinone thiazole hybrids was changed while different substituents were introduced at the para position of the second phenyl ring. All compounds were tested for potential immunomodulatory effect. No inflammatory cytokines were observed in the absence of LPS stimulant. On the other hand, they had promising anti-inflammatory immunomodulatory activities by being able to decrease the production of the pro-inflammatory cytokines (TNF-α and IL-6) in the LPS-stimulated cells. In an effort to find the possible mechanism of action, several enzymes involved in signalling pathways that play critical roles in inflammatory responses were screened in silico. Subsequent to inverse molecular docking approach, PI3K was predicted be the potential target. The docked complexes of the most potent compounds 5g and 5i were subjected to molecular dynamics simulation to assess the binding stability of the igands with the putative target. Acid dissociation constants (pK a ) of the products were also determined potentiometrically., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Time-resolved step-scan FTIR difference spectroscopy at 77 K has been used to study photosystem I (PSI) from Synechocystis sp. PCC 6803 with four high-potential, 1,4-naphthoquinones (NQs) incorporated into the A 1 binding site. The incorporated quinones are 2-chloro-NQ (2ClNQ), 2-bromo-NQ (2BrNQ), 2,3-dichloro-NQ (Cl 2 NQ), and 2,3-dibromo-NQ (Br 2 NQ). For completeness 2-methyl-NQ (2MNQ) was also incorporated and studied. Previously, PSI with the same quinones incorporated were studied in the, so-called, anion spectral region between 1550 and 1400 cm -1 (Agarwala et al. in Biochim Biophys Acta 1864(1):148918, 2023). Here we focus on spectra in the previously unexplored 1400-1200 cm -1 spectral region. In this region several bands are identified and assigned to the neutral state of the incorporated quinones. This is important as identification of neutral state quinone bands in the regular 1700-1600 cm -1 region has proven difficult in the past. For neutral PhQ in PSI a broad, intense band appears at ~ 1300 cm -1 . For the symmetric di-substituted NQs (Cl 2 NQ/Br 2 NQ) a single intense neutral state band is found at ~ 1280/1269 cm -1 , respectively. For both mono-substituted NQs, 2ClNQ and 2BrNQ, however, two neutral state bands are observed at ~ 1280 and ~ 1250 cm -1 , respectively. These observations from time-resolved spectra agree well with conclusions drawn from absorption spectra of the NQs in THF, which are also presented here. Density functional theory based vibrational frequency calculations were undertaken allowing an identification of the normal modes associated with the neutral state quinone bands., (© 2023. The Author(s), under exclusive licence to Springer Nature B.V.)

Based on previous studies, we synthesized a novel class of ortho- and para-naphthoquinones derivatives bearing a phenolic hydroxy or sulfonamide moiety and evaluated their in vitro antiproliferative and signal transducer and activator of transcription-3 (STAT3) phosphorylation inhibitory activities. The biological evaluations of these naphthoquinones revealed that ortho-naphthoquinones containing a phenolic hydroxyl group exhibited greater antiproliferative activity compared to compounds without a phenolic hydroxyl group. Among the synthesized para-naphthoquinones, 21, which has a condensed sulfonamide structure, showed substantially higher antiproliferative activity than that of the parent compound, and was also found to inhibit the phosphorylation of STAT3(Y705) in a dose-dependent manner. A docking simulation using AutoDock Vina suggested that 21 could directly bind to the hinge region of STAT3., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Naphthoquinones are natural plants products or synthesized compounds. They have α, β-cyclic aromatic dienones structure with a naphthalene skeleton. Little is known about naphthoquinone and nothing about naphtho [2,3-b] thiophen-4,9-quinone effects on bladder cancer. In this study, a naphthoquinone containing a hetero sulfur atom was synthesized using classical synthetic method. The molecular structure was elucidated by NMR techniques and the antitumor effects were evaluated on bladder tumor cell lines with different TP53 status using tripan blue and MTT cytotoxic method, quantification of reactive oxygen species (ROS), wound healing, cell morphology and cell cycle progression assays. The results showed selective cytotoxicity, colonies reduction, morphological change, inhibition of the cell migration process, induction of ROS production and cell cycle arrest. Naphtho [2,3- b ] thiophen-4,9-quinone presents antiproliferative activity regardless TP53 status and may be a promising agent in the treatment of bladder cancer, as they have an oxidizing effect and interfere with cell cycle.

A series of novel noncovalent glycine/β-alanine anilide derivatives possessing 2-chloronaphthoquinone structure as a pharmacophoric unit were designed, synthesized, and evaluated for their antiproliferative and antiproteasomal activities against MCF-7 cell line, in vitro. According to biological activity results, all the target compounds showed antiproliferative activity in the range of IC 50  = 7.10 ± 0.10-41.08 ± 0.14 μM and most of them exhibited inhibitory efficacy with varying ratios against the three catalytic subunits (β1, β2, and β5) presenting caspase-like (C-L), trypsin-like (T-L) and chymotrypsin-like (ChT-L) activities of proteasome. The antiproteasomal activity evaluations revealed that compounds preferentially inhibited the β5 subunit compared with β1 and β2 subunits of the proteasome. Among the compounds, compounds 7 and 9 showed the highest antiproliferative activity with an IC 50 value of 7.10 ± 0.10 and 7.43 ± 0.25 μM, respectively. Additionally, compound 7 displayed comparable potency to PI-083 lead compound in terms of β5 antiproteasomal activity with an inhibition percentage of 34.67 at 10 μM. This compound showed an IC 50 value of 32.30 ± 0.45 μM against β5 subunit. Furthermore, molecular modeling studies of the most active compound 7 revealed key interactions with β5 subunit. The results suggest that this class of compounds may be beneficial for the development of new potent proteasome inhibitors., (© 2023 John Wiley & Sons Ltd.)

The subclass naphthoquinone represents a substance group containing several compounds with important activities against various pathogenic microorganisms. Accordingly, we evaluated O-allyl-lawsone (OAL) antiparasitic and antifungal activity free and encapsulated in 2-hydroxypropyl-β-cyclodextrin (OAL MKN) against Trypanosoma cruzi and Sporothrix spp. OAL and OAL MKN were synthesized and characterized by physicochemical methods. The IC 50 values of OAL against T. cruzi were 2.4 µM and 96.8 µM, considering epimastigotes and trypomastigotes, respectively. At the same time, OAL MKN exhibited a lower IC 50 value (0.5 µM) for both trypanosome forms and low toxicity for mammalian cells. Additionally, the encapsulation showed a selectivity index approximately 240 times higher than that of benznidazole. Regarding antifungal activity, OAL and OAL MKN inhibited Sporothrix brasiliensis growth at 16 µM, while Sporothrix schenckii was inhibited at 32 µM. OAL MKN also exhibited higher selectivity toward fungus than mammalian cells. In conclusion, we described the encapsulation of O-allyl-lawsone in 2-hydroxypropyl-β-cyclodextrin, increasing the antiparasitic activity compared with the free form and reducing the cytotoxicity and increasing the selectivity towardSporothrix yeasts and the T. cruzi trypomastigote form. This study highlights the potential development of this inclusion complex as an antiparasitic and antifungal agent to treat neglected diseases., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purinergic receptors are transmembrane proteins responsive to extracellular nucleotides and are expressed by several cell types throughout the human body. Among all identified subtypes, the P2×7 receptor has emerged as a relevant target for the treatment of inflammatory disease. Several clinical trials have been conducted to evaluate the effectiveness of P2×7R antagonists. However, to date, no selective antagonist has reached clinical use. In this work, we report the pharmacological evaluation of eleven N, S-acetal juglone derivatives as P2×7R inhibitors. Using in vitro assays and in vivo experimental models, we identified one derivative with promising inhibitory activity and low toxicity. Our in silico studies indicate that the 1,4-naphthoquinone moiety might be a valuable molecular scaffold for the development of novel P2×7R antagonists, as suggested by our previous studies., Competing Interests: Conflict of interest statement The authors declare that they have no conflict of interest., (Copyright © 2023. Published by Elsevier Masson SAS.)

Eumycetoma, the fungal form of the neglected tropical disease mycetoma, is a crippling infectious disease with low response rates to currently available antifungal drugs. In this study, a series of natural naphthoquinones and anthraquinones was evaluated for their activity against Madurella mycetomatis, which is the most common causative agent of eumycetoma. The metabolic activity of Madurella mycetomatis as well as the viability of Galleria mellonella larvae upon treatment with quinones was investigated. Several hydroxy-substituted naphthoquinones exhibited activity against Madurella mycetomatis. In particular, naphthazarin (5,8-dihydroxy-1,4-naphthoquinone) was identified as a considerably active antifungal compound against Madurella mycetomatis (IC 50 =1.4 μM), while it showed reduced toxicity to Galleria mellonella larvae, which is a well-established in vivo invertebrate model for mycetoma drug studies., (© 2023 The Authors. Chemistry & Biodiversity published by Wiley-VHCA AG, Zurich, Switzerland.)

Shikonin is a red naphthoquinone natural product from plants with high economical and medical values. The para-hydroxybenzoic acid geranyltransferase (PGT) catalyzes the key regulatory step of shikonin biosynthesis. PGTs from Lithospermum erythrorhizon have been well-characterized and used in industrial shikonin production. However, its perennial medicinal plant Arnebia euchroma accumulates much more pigment and the underlying mechanism remains obscure. Here, we discovered and characterized the different isoforms of AePGTs. Phylogenetic study and structure modeling suggested that the N-terminal of AePGT6 contributed to its highest activity among 7 AePGTs. Indeed, AePGT2 and AePGT3 fused with 60 amino acids from the N-terminal of AePGT6 showed even higher activity than AePGT6, while native AePGT2 and AePGT3 don't have catalytic activity. Our result not only provided a mechanistic explanation of high shikonin contents in Arnebia euchroma but also engineered a best-performing PGT to achieve the highest-to-date production of 3-geranyl-4-hydroxybenzoate acid, an intermedium of shikonin., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Natural products and their derivatives have been sources of search and research for new drugs for the treatment of neglected diseases. Naphthoquinones, a special group of quinones, are products of natural metabolites with a wide spectrum of biological activities and represent a group of interesting molecules for new therapeutic propositions. Among these compounds, lapachol stands out as a molecule from the heartwood of Tabebuia sp. whose structural changes resulted in compounds considered promising, such as epoxy-α-lapachone (ELAP). The biological activity of ELAP has been demonstrated, so far, for parasitic protozoa such as Leishmania spp., Trypanosoma cruzi and Plasmodium spp., species causing diseases needing new drug development and adequate health policy. This work gathers in vitro and in vivo studies on these parasites, as well as the toxicity profile, and the probable mechanisms of action elucidated until then. The potential of ELAP-based technology alternatives for a further drug is discussed here., Competing Interests: Conflicts of interest The authors declare no conflicts of interest., (Copyright © 2023 Sociedade Brasileira de Infectologia. Published by Elsevier España, S.L.U. All rights reserved.)

In this study, eight naphthoquinone derivatives were synthesized in yields ranging from 52 to 96% using easy, fast, and low-cost methodologies. All naphthoquinone derivatives were screened for their in vitro anti-proliferative activities against OVCA A2780 cancer cell lines. Amongst all analysed compounds, derivatives 3-5 presented the most prominent cytotoxic potential. Naphthoquinones 3 and 4, bearing sulfur-containing groups, were identified as having high potential for ROS production, in particular the superoxide anion. Furthermore, 3 and 4 compounds caused a decrease in the cell population in G0/G1 and induced more than 90% of the cell population to apoptosis. Compound 5 did not act in any of these processes. Finally, compounds 3-5 were tested for their inhibitory ability against PI3K and MAPK. Compounds 3 and 4 do not inhibit the PI3K enzyme. On the other hand, the naphthoquinone-polyphenol 5 was only able to inhibit the percentage of cells expressing pERK., (© 2022 Wiley-VHCA AG, Zurich, Switzerland.)

Time-resolved step-scan Fourier transform infrared difference spectroscopy has been used to study cyanobacterial photosystem I photosynthetic reaction centers from Synechocystis sp. PCC 6803 (S6803) with four high-potential, 1,4-naphthoquinones incorporated into the A 1 binding site. The high-potential naphthoquinones are 2-chloro-, 2-bromo-, 2,3-dichloro- and 2,3-dibromo-1,4-naphthoquinone. "Foreign minus native" double difference spectra (DDS) were constructed by subtracting difference spectra for native photosystem I (with phylloquinone in the A 1 binding site) from corresponding spectra obtained using photosystem I with the different quinones incorporated. To help assess and assign bands in the difference and double difference spectra, density functional theory based vibrational frequency calculations for the different quinones in solvent, or in the presence of a single asymmetric H- bond to either a water molecule or a peptide backbone NH group, were undertaken. Calculated and experimental spectra agree best for the peptide backbone asymmetrically H- bonded system. By comparing multiple sets of double difference spectra, several new bands for the native quinone (phylloquinone) are identified. By comparing calculated and experimental spectra we conclude that the mono-substituted halogenated NQs can occupy the binding site in either of two different orientations, with the chlorine or bromine atom being either ortho or meta to the H- bonded CO group., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Gary Hastings reports financial support was provided by US Department of Energy Basic Energy Sciences., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: Snails of the genus Biomphalaria are intermediate hosts of Schistosoma mansoni, the main etiological agent of schistosomiasis mansoni, which affects about 236.6 million people in tropical and subtropical regions of the world. The World Health Organization recommends the population control of vector snails as one of the strategies to reduce the prevalence and incidence of schistosomiasis. In this study, molluscicidal and antiparasitic activities of plumbagin, a naturally sourced naphthoquinone with a range of biological effects, were evaluated against B. glabrata and cercariae of S. mansoni., Results: After 24 h of exposure, plumbagin demonstrated molluscicidal activity at low concentrations against embryos (LC 50 of 0.56, 0.93, 0.68, 0.51 and 0.74 μg mL -1 for the blastula, gastrula, trochophore, veliger and hippo stage, respectively) and adult snails (LC 50 of 3.56 μg mL -1 ). There were no changes in exposed snails' fecundity or fertility; however, plumbagin was able to increase the frequency of DNA damage and the number of hemocytes, with apoptosis and binucleation being the main hemocyte alterations. In addition, plumbagin showed death of S. mansoni cercariae in the concentration of 1.5 μg mL -1 in 60 min, while showing moderate toxicity to Artemia salina., Conclusion: Plumbagin proved to be a promising substance for the control of B. glabrata population, intermediate host of S. mansoni, as well as the cercariae, infective stage for humans (definitive host), while being moderately toxic to A. salina, a crustacean widely used in ecotoxicity tests. © 2022 Society of Chemical Industry., (© 2022 Society of Chemical Industry.)

A new pentacyclic triterpenoid, 2-hydroxy-1-ene-hydroxyhopanone (19), and a new benzoxepin-5-one, 3-(4-methyl-3-penten-1-yl)-6-hydroxy-9-methoxy-2H-1-benzoxepin-5-one (25), along with 26 known compounds (1-18, 20-24, 26-28), were isolated from the roots of Arnebia euchroma (Royle) Johnst. The structures of the new compounds were elucidated by extensive spectroscopic analyses. The absolute configurations of shikonofurans 9-13 were determined by quantum chemical ECD calculations and CD spectra comparison for the first time. Pharmacological study revealed that naphthoquinones 1-5, 7, and 8 had obvious cytotoxicity toward human lung adenocarcinoma A549 cell line. Meanwhile, the hypoglycemic and lipid-lowering effects of isolated compounds were assessed by checking their inhibitory effects on key enzymes regulating glucose and lipid metabolism. Results showed that compounds 1, 3, 5, 6, 8, 18, and 19 could inhibit the activity of ATP-citrate lyase (ACL); compound 7 could inhibit the activity of acetyl-CoA carboxylase (ACC1); while compounds 8 and 19 showed inhibitory effects on protein tyrosine phosphatase 1B (PTP1B). Among them, the naphthoquinone 6, steroid 18, and triterpenoid 19 showed moderate inhibitory effects on ACL and PTP1B, but didn't exhibit obvious cytotoxicity. This study demonstrated that compounds 6, 18, and 19 show great promising for the development of new agents for the treatment of metabolic diseases., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2022 Elsevier B.V. All rights reserved.)

A series of naphthoquinones, namely, 1,4-naphthoquinone, menadione, plumbagin, juglone, naphthazarin, and lawsone, were reacted with N -acetyl- L -cysteine, and except for lawsone, which did not react, the related adducts were obtained. After the tuning of the solvent and reaction conditions, the reaction products were isolated as almost pure from the complex reaction mixture via simple filtration and were fully characterized. Therefore, the aim of this work was to evaluate whether the antitumor activity of new compounds of 1,4-naphthoquinone derivatives leads to an increase in ROS in tumor cell lines of cervical carcinoma (HeLa), neuroblastoma (SH-SY5Y), and osteosarcoma (SaOS2, U2OS) and in normal dermal fibroblast (HDFa). The MTT assay was used to assay cell viability, the DCF-DA fluorescent probe to evaluate ROS induction, and cell-cycle analysis to measure the antiproliferative effect. Compounds 8 , 9 , and 12 showed a certain degree of cytotoxicity towards all the malignant cell lines tested, while compound 11 showed biological activity at higher IC 50 values. Compounds 8 and 11 induced increases in ROS generation after 1 h of exposure, while after 48 h of treatment, only 8 induced an increase in ROS formation in HeLa cells. Cell-cycle analysis showed that compound 8 caused an increase in the number of G0/G1-phase cells in the HeLa experiment, while for the U2OS and SH-SY5Y cell lines, it led to an accumulation of S-phase cells. Therefore, these novel 1,4-naphthoquinone derivatives may be useful as antitumoral agents in the treatment of different cancers.

Structure-guided isolation of a CH 2 Cl 2 -soluble fraction of the heartwood of Catalpa bungei "Jinsi" provided two new naphthoquinones, 9-hydroxy-4-oxo-α-lapachone (1) and 6-hydroxy-4-oxo-α-lapachone (2), together with three undescribed ones (3-5) and six known ones (6-11). The structures were elucidated on the basis of spectroscopic methods including electronic circular dichroism calculation. The antiproliferative effects of these isolates were evaluated in human breast adenocarcinoma cells MCF7. (4R)-4,9-dihydroxy-α-lapachone (5) and (4S)-4,9-dihydroxy-α-lapachone (6) exhibited the significant activities with IC 50 values of 2.19 and 2.41 μM, respectively. The structure-activity relationship of 1-11 in the antiproliferative assay was then discussed. The most potent 5 and 6 were found to induce cell arrest in G1 phage through DNA damage. The findings provided some valuable insights for the discovery and structural modification of α-lapachone as antiproliferative lead compounds against human breast adenocarcinoma cells., (Copyright © 2022. Published by Elsevier B.V.)

The Wnt/β-catenin signaling pathway plays extensive roles in cancer initiation, proliferation, and development, and has been implicated in the regulation of stem cells in the intestinal crypt, widely accepted as responsible for colorectal cancer (CRC) origination. This pathway has been a target of interest for many years for chemotherapeutic development of CRC due to its implication in most cases. Previously, a series of naphthoquinone analogs have been identified to inhibit the Wnt/β-catenin. It was postulated that these compounds exhibit their inhibitory activity via binding to β-catenin at the β-catenin/TCF4 interaction interface. In this study, we aimed to further define the critical pharmacophore for these compounds and verify their mechanisms of action for their abilities to inhibit the Wnt/β-catenin signaling pathway. Interestingly, our data suggested two of the compounds, compounds 3 and 6, may potently inhibit the Wnt/β-catenin signaling pathway via inhibition of the TCF4/DNA interaction, a novel finding compared to previous studies on these compounds. Our computational studies suggested that the compounds bound within the DNA binding HMG-box domain of TCF4 to elicit their inhibitory action. These compounds inhibited Wnt signaling in a dose dependent manner, suppressed Wnt direct target genes and demonstrated unforeseen degradation of the TCF4 protein. Thus, this study revealed a potentially novel mechanism of action of the chloro-naphthoquinone as possibly a multi-targeting scaffold, which warrants further investigation in future drug discovery on the 'undruggable" TCF proteins and an aberrantly activated Wnt/β-catenin signaling pathway., (Copyright © 2022 Elsevier Inc. All rights reserved.)

In filamentous fungi, the secondary metabolism is environmentally sensitive. Most of the biosynthetic gene clusters of secondary metabolites are silent under laboratory conditions. In this study, a highly conserved naphthopyrone PKS ATEG_06206 was identified in the genome sequence of A. terreus MEFC01. This gene is silent under laboratory conditions. To study the function of this PKS, we activated the silent biosynthetic pathway by replacing the promoter of cluster-specific transcriptional factor ATEG_06205 in A. terreus MEFC01. With this strategy, we confirmed that the products of this cryptic PKS are naphthoquinones. These naphthoquinones are soluble pigments, which could be secreted into the agar medium and culture broth. For this reason, the colour of mycelium and conidia of the activated mutant was significantly darker than that of the parental strain. The gene cluster and biosynthetic pathway were further elucidated through the reverse genetics approach and enzymatic assay in vitro., (Copyright © 2022 Elsevier Inc. All rights reserved.)

In recent years there has been interest in incorporating substituted 1,4-naphthoquinones (NQs) into the A 1 binding site in photosystem I (PSI) photosynthetic protein complexes. This interest in part stems from the considerably altered bioenergetics of electron transfer that occur in PSI with such substitutions. Time resolved FTIR studies of PSI complexes with disubstituted NQs incorporated have and currently are being undertaken, and with this in mind it is worth considering FTIR absorption spectra of these disubstituted NQs in solution. Here we present FTIR absorbance spectra for 2-bromo-3-methyl-1,4-naphthoquinone (BrMeNQ), 2-chloromethyl-3-methyl-1,4-naphthoquinone (CMMeNQ) and 2-ethylthio-3-methyl-1,4-naphthoquinone (ETMeNQ) in tetrahydrofuran (THF). The FTIR spectra of these di-substituted naphthoquinones (NQs) were compared to FTIR spectra of 2-methyl-3-phytyl-1,4-naphthoquinone [phylloquinone (PhQ)], 2,3-dimethyl-1,4-naphthoquinone (DMNQ), and 2-methyl-1,4-naphthoquinone (2MNQ). To aid in the assignment of bands in the experimental spectra, density functional theory (DFT) based vibrational frequency calculations for all the substituted NQs in solution were undertaken. The calculated and experimental spectra agree well. By calculating normal mode potential energy distributions, unambiguous quantitative band assignments were made. The calculated and experimental spectra together make predictions about what may be observable in time resolved FTIR difference spectra obtained using PSI with the different NQs incorporated. Time resolved FTIR difference spectra are presented that support these predictions., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Thioredoxin reductase 1 (TrxR1 or TXNRD1) is a major enzyme in cellular redox regulation and is considered as a drug target for cancer therapy. Previous studies have reported that plumbagin caused reactive oxygen species (ROS)-dependent apoptosis via inhibiting TrxR1 activity or being reduced by TrxR1, leading to selectively cancer cell death. However, the mechanism of TrxR1-mediated redox cycling of plumbagin is obscure and the evidence for plumbagin targeting TrxR1 is still lacking. Herein, we demonstrated that TrxR1 catalyzed plumbagin reduction in both selenocysteine (Sec)-dependent and independent manners, and its activity relied on the intact N-terminal motif of TrxR1, but a high-efficiency reduction was supported by the C-terminal thiols. During the redox cycling of plumbagin, excessive ROS production was observed coupled with oxygen. Using LC-MS and TrxR1 mutants, we found that the Sec residue of TrxR1 was modified by plumbagin, which converted the enzyme from antioxidant to pro-oxidant. Furthermore, we evaluated the therapeutic potential of plumbagin in non-small cell lung cancer (NSCLC), and found that Kelch-like ECH-associated protein 1 (KEAP1)-mutant NSCLC cells, which possess constitutive nuclear factor erythroid 2-related factor 2 (NRF2) activity, were insensitive to plumbagin; however, inhibition of glucose transporter 1 (GLUT1) by small-molecule BAY-876 or inhibiting glucose-6-phosphate dehydrogenase (G6PD) by 6-aminonicotinamide (6-AN) overcame the plumbagin-resistance of KEAP1-mutant NSCLC cells. Taken together, this study elucidated the pharmacological mechanism of plumbagin by targeting TrxR1 and revealed the synergy effect of plumbagin and BAY-876, which may be helpful for applying naphthoquinone compounds to chemotherapy, particularly for treating KEAP1-mutant NSCLC cells., (Copyright © 2021 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Background: The synthesis and biological evaluation of 1,4-naphthoquinone derivatives are of great interest since these compounds exhibit strong antibacterial, antifungal, antimalarial, and anticancer activities. The electronic properties of naphthoquinones are usually modulated by attaching functional groups containing nitrogen, oxygen, and sulfur atoms, which tune their biological potency and selectivity., Methods: A series of 13 amino acid 1,4-naphthoquinone derivatives was synthesized under assisted microwave and ultrasound conditions. The antibacterial activity of compounds was tested against American Type Culture Collection (ATCC): Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, and Enterococcus faecalis, as well as 2 multidrug resistant pathogens: E. coli and S. aureus from clinical isolated. Minimal inhibitory concentration (MIC) was determined using the broth microdilution method., Results: MIC of derivatives 4-11, 14, and 16 showed antimicrobial activity against Gram-positive and Gram-negative bacteria. Antimicrobial activities of the compounds 4-8 and 14 were ≤MIC 24.7 μg mL-1 against all the reference strains; even more, compound 6 showed the most potent activity with an MIC of 3.9 μg mL-1 on S. aureus. On the clinical isolated, the compounds 7, 8, and 14 showed an MIC of 49.7 and 24.7 μg mL-1 against S. aureus and E. coli, respectively. About ADME properties and Osiris analysis, the compounds 4-16 presented high gastrointestinal absorption and good characteristics for oral bioavailability, and compound 14 was the less toxic., Conclusion: Amino acid 1,4-naphthoquinone derivatives showed good in vitro antibacterial activity against clinical strains, and modifications on C-3 with a chloride atom enhanced the efficiency against the same pathogens., (© 2021 S. Karger AG, Basel.)

Naphthoquinone is a heterocyclic moiety whose natural derivatives are present as bioactive compounds in many plants and have stimulated a resurgence of interest in the past decades due to their wide range of pharmacological activities. Naphthoquinone agents have dynamic pharmacophores and privileged sub-structures in the chemistry of medicine. They have received much interest in drug discovery as trypanocidal because naphthoquinone and their derivatives revealed massive significance potential against the trypanosomes. Among natural naphthoquinones, lapachol, β-lapachone and its α-isomer exhibited useful trypanocidal activities. Some naphthoquinones have already been used commercially as an antiparasitic agent. Several naphthoquinones with diverse structural motifs have been synthesized and evaluated mainly against Trypanosoma cruzi and some studies have also been reported against Trypanosoma brucei and Trypanosoma evansi. This review summarized various mechanisms of action of naphthoquinone like reductive activation of quinone by the production of the semiquinone, generation of reactive oxygen species and free radicals such as superoxide anion radical and H2O2, and oxidative stress in the parasite. The information assembled in this review will help to understand the mechanism behind the activity and may also be useful to find the bio-efficacy of naphthoquinone compounds upon substitution against trypanosomatids., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Recently, natural products have been became the center of attraction for the scientific society and exploration of their biologically abilities is proceeding continuously. In search for novel antiparasitic agents with an objective of protecting humans from parasitic infections, the present work was focused on naphthoquinones possessing antiparasitic activity. Among naphthoquinones, plumbagin is one of the secondary metabolites exhibiting diverse biological properties such as antibacterial, antimalarial, antiinflammatory, insecticidal and antiparasitic. Plumbagin is reported to have antischistosomiasis, anti-haemonchosis, anti-fascioliasis, antiotoacariasis, anti-leishmaniasis, antimalaria, antiallergic and anthelmintic activities. Besides, various methods of extraction of plumbagin from different methods, their effectiveness against different parasites, and the structure-activity relationship reported by different researchers. This work highlight on recent advancements in the phytochemistry of plumbagin, studies associated with various biological activities. The structure-activity relationship studies have also been summarized. To conclude, present review could be beneficial for the scientific community to get better insight into medicinal research of plumbagin and may provide a new horizon for the rational design of plumbagin based compounds., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: The clinical outcomes of patients with Acute Myeloid Leukemia (AML) remain unsatisfactory. Therefore the development of more efficacious and better-tolerated therapy for AML is critical. We have previously reported anti-leukemic activity of synthetic halohydroxyl dimeric naphthoquinones (BiQ) and aziridinyl BiQ., Objective: This study aimed to improve the potency and bioavailability of BiQ compounds and investigate antileukemic activity of the lead compound in vitro and a human AML xenograft mouse model., Methods: We designed, synthesized, and performed structure-activity relationships of several rationally designed BiQ analogues with amino alcohol functional groups on the naphthoquinone core rings. The compounds were screened for anti-leukemic activity and the mechanism as well as in vivo tolerability and efficacy of our lead compound was investigated., Results: We report that a dimeric naphthoquinone (designated BaltBiQ) demonstrated potent nanomolar anti-leukemic activity in AML cell lines. BaltBiQ treatment resulted in the generation of reactive oxygen species, induction of DNA damage, and inhibition of indoleamine dioxygenase 1. Although BaltBiQ was tolerated well in vivo, it did not significantly improve survival as a single agent, but in combination with the specific Bcl-2 inhibitor, Venetoclax, tumor growth was significantly inhibited compared to untreated mice., Conclusion: We synthesized a novel amino alcohol dimeric naphthoquinone, investigated its main mechanisms of action, reported its in vitro anti-AML cytotoxic activity, and showed its in vivo promising activity combined with a clinically available Bcl-2 inhibitor in a patient-derived xenograft model of AML., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

A new (naphthalenyl)methyl acetate, (1,4,5-trimethoxynaphthalen-2-yl)methyl acetate ( 1 ) and ( ± )-4,5-dihydroxy-2-methyltetralone ( 2 ) were isolated together with five lupane triterpenes ( 3-7 ), naphthoquinone derivatives ( 8 - 13 ), coumarins ( 14 and 15 ) and a vanillic acid ( 16 ) from the stems of Diospyros ehretioides. Their structures were established through spectroscopic analysis, IR, 1D and 2D NMR. Both 1 and 2 displayed significant cytotoxicity against three cancer cell lines including HeLa, HCT116 and MCF-7, with IC 50 values in the range of 5.05-15.90 µg/mL, while 16 exhibited moderate cytotoxicity against HeLa and HCT116 cell lines and was not toxic to Vero cells.

The most abundant active compound in Droseraceae is plumbagin, a naphthoquinone widely used for medical purposes due to its antimicrobial, antitussive, antimalarial and anticancer properties. In this work, we created a light-emitting diode (LED) based culture illumination setup as an alternative to fluorescent lamps traditionally used as a light source in plant in vitro cultures. The plants of Drosera binata and Drosera peltata cultured under LED illumination grew equally well and produced similar amounts of biologically active compounds as plants grown under fluorescent lamps. The plants were cultured on two media differing in mineral composition, sucrose content and pH. Secondary metabolites were extracted with ethanol from the plants after harvesting. The extracts were subjected to HPLC and microbiological analyses. We observed differences in morphology and secondary metabolism between plants of the same species grown on different media. However, we did not note significant changes in secondary metabolite yield under assessed lighting conditions. We propose LEDs as a more efficient, eco-friendly and economically reasonable source of light for big scale in vitro production of plumbagin in Drosera species than fluorescent lamps., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Cysticercosis is a disease caused by the metacestode of the parasite Taenia solium (T. solium). In humans, the most severe complication of the disease is neurocysticercosis. The drug of choice to treat this disease is albendazole; however, the bioavailability and efficacy of the drug are variable. Therefore, new molecules with therapeutic effects against this and other parasitic infections caused by helminths must be developed. Naphthoquinones are naphthalene-derived compounds that possess antibacterial, antifungal, antitumoral, and antiparasitic properties. The aim of this work was to evaluate the in vitro anti-helminthic effect of 2-[(3-chlorophenylamino)phenylmethyl]-3-hydroxy-1,4-naphthoquinone, isolated from a natural source and then synthesized (naphthoquinone 4a), using an experimental model of murine cysticercosis caused by Taenia crassiceps (T. crassiceps). This compound causes paralysis in the cysticerci membrane from day 3 of the in vitro treatment. Additionally, it induces changes in the shape, size, and appearance of the cysticerci and a decrease in the reproduction rate. In conclusion, naphthoquinone 4a has in vitro cysticidal activity on T. crassiceps cysticerci depending on the duration of the treatment and the concentration of the compound. Therefore, it is a promising drug candidate to be used in T. crassiceps and possibly T. solium infections., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

We investigated the antiophidic properties of isohemigossypolone (ISO), a naphthoquinone isolated from the outer bark of the Pachira aquatic Aubl. The inhibition of phospholipase A 2 , coagulant, fibrinogenolytic, hemorrhagic and myotoxic activities induced by Bothrops pauloensis venom (Pb) was investigated. For this, we use samples resulting from the incubation of Pb with ISO in different concentrations (1:1, 1:5 and 1:10 w/w), we also evaluated the condition of treatment using ISO after 15 min of venom inoculation. The activities of phospholipase A 2 , coagulant, fibrinogenolytic, hemorrhagic and myotoxic induced by the B. pauloensis venom were significantly inhibited when the ISO was pre-incubated with the crude venom. For in vivo neutralization tests, the results were observed even when the ISO was applied after 15 min of inoculation of the venom or metalloprotease (BthMP). Also, to identify the inhibition mechanism, we performed in silico assays, across simulations of molecular coupling and molecular dynamics, it was possible to identify the modes of interaction between ISO and bothropic toxins BmooMPα-I, Jararacussin-I and BNSP-7. The present study shows that naphthoquinone isohemigossypolone isolated from the P. aquatica plant inhibited part of the local and systemic damage caused by venom proteins, demonstrating the pharmacological potential of this compound in neutralizing the harmful effects caused by snakebites., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Quinones are plant-derived secondary metabolites that present diverse pharmacological properties, including antibacterial, antifungal, antiviral, anti-inflammatory, antipyretic and anticancer activities. In the present study, we evaluated the cytotoxic effect of a new naphthoquinone 6b,7-dihydro-5H-cyclopenta [b]naphtho [2,1-d]furan-5,6 (9aH)-dione) (CNFD) in different tumor cell lines. CNFD displayed cytotoxic activity against different tumor cell lines, especially in MCF-7 human breast adenocarcinoma cells, which showed IC 50 values of 3.06 and 0.98 μM for 24 and 48 h incubation, respectively. In wound-healing migration assays, CNFD promoted inhibition of cell migration. We have found typical hallmarks of apoptosis, such as cell shrinkage, chromatin condensation, phosphatidylserine exposure, increase of caspases-9 and-3 activation, increase of internucleosomal DNA fragmentation without affecting the cell membrane permeabilization, increase of ROS production, and loss of mitochondrial membrane potential induced by CNFD. Moreover, gene expression experiments indicated that CNFD increased the expression of the genes CDKN1A, FOS, MAX, and RAC1 and decreased the levels of mRNA transcripts of several genes, including CCND1, CDK2, SOS1, RHOA, GRB2, EGFR and KRAS. The CNFD treatment of MCF-7 cells induced the phosphorylation of c-jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinases (MAPKs) and inactivation of extracellular signal-regulated protein kinase 1/2 (ERK1/2). In a study using melanoma cells in a murine model in vivo, CNFD induced a potent anti-tumor activity. Herein, we describe, for the first time, the cytotoxicity and anti-tumor activity of CNFD and sequential mechanisms of apoptosis in MCF-7 cells. CNFD seems to be a promising candidate for anti-tumor therapy., (Copyright © 2021 Elsevier B.V. All rights reserved.)

In order to expand structural diversity and improve antitumor efficiency, forty new naphthoquinone phenacylimidazolium derivatives were designed, synthesized and evaluated. Good synthetic yields were obtained under mild conditions using easily available starting materials. Cytotoxicity of these compounds was evaluated in vitro against a panel of human tumor cell lines: human breast carcinoma cell lines (MCF-7), human cervical carcinoma cell lines (HeLa), and human lung carcinoma cell lines (A549). Among them, the optimal compound 7m showed splendid antiproliferative activity with low to 50 nM IC 50 values against MCF-7 and excellent selectivity of 256-fold compared with the normal cell lines L929. Compound 7m induced apoptosis in a dose-dependent manner. Further mechanism experiments showed that compound 7m dramatically inhibited the expression of survivin and activated the pro-apoptotic protein caspase-3. Our results indicated that the structural modification on the 1,3-substituents of naphthoquinone imidazoliums without 2-substituent is also promising to obtain new antitumor compounds., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Two new naphthoquinone derivatives, 6-hydroxy-astropaquinone B ( 1 ) and astropaquinone D ( 2 ) as well as the known compound 3- O -methyl-9- O -methylfusarubin ( 3 ) were isolated from Fusarium napiforme , an endophytic fungus isolated from the mangrove plant, Rhizophora mucronata . The structures of 1 and 2 were determined by 1D and 2D NMR spectroscopic analyses. Compounds 1 , 2 and 3 exhibited moderate antibacterial activity against Staphylococcus aureus and Pseudomonas aeruginosa . Furthermore, 1 , 2 and 3 were phytotoxic action in lettuce seeding at a concentration of 30 μg · mL -1 .

A series of novel podophyllotoxin-naphthoquinone compounds 5a-p were synthesized in good yields using microwave-assisted four-component reactions of 2-hydroxy-1,4-naphthoquinone, aromatic benzaldehydes, tetronic acid and ammonium acetate. All the synthesized compounds were fully characterized by spectral data and evaluated for their cytotoxicity activities against KB, HepG2, Lu1, MCF7, and non-cancerous Hek-293 cell lines. Among 16 new compounds screened, compounds 5a, 5d, 5h, and 5k displayed high potent inhibitory activities with IC 50  < 40 nM against HepG2 and SK-Lu-1 cell lines, and showed lower toxicity for non-cancerous Hek-293 cell line, demonstrating the potential importance of these compounds in the development of potential anticancer agents., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Alzheimer's disease is a progressive brain disorder with characteristic symptoms and several pathological hallmarks. The concept of "one drug, one target" has not generated any new drugs since 2004. The new era of drug development in the field of AD builds upon rationally designed multi-target directed ligands that can better address the complexity of AD. Herewith, we designed ten novel derivatives of 2-propargylamino-naphthoquinone. The biological evaluation of these compounds includes inhibition of monoamine oxidase A/B, inhibition of amyloid-beta aggregation, radical-scavenging, and metal-chelating properties. Some of the compounds possess low cytotoxicity profile with an anti-inflammatory ability in the lipopolysaccharide-stimulated cellular model. All these features warrant their further testing in the field of AD., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

A series of novel 4-aminobenzensulfonamide/carboxamide derivatives bearing naphthoquinone pharmacophore were designed, sythesized and evaluated for their proteasome inhibitory and antiproliferative activities against human breast cancer cell line (MCF-7). The structures of the synthesized compounds were confirmed by spectral and elemental analyses. The proteasome inhibitory activity studies were carried out using cell-based assay. The antiproteasomal activity results revealed that most of the compounds exhibited inhibitory activity with different percentages against the caspase-like (C-L, β1 subunit), trypsin-like (T-L, β2 subunit) and chymotrypsin-like (ChT-L, β5 subunit) activities of proteasome. Among the tested compounds, compound 14 bearing 5-chloro-2-pyridyl ring on the nitrogen atom of sulfonamide group is the most active compound in the series and displayed higher inhibition with IC 50 values of 9.90 ± 0.61, 44.83 ± 4.23 and 22.27 ± 0.15 μM against ChT-L, C-L and T-L activities of proteasome compared to the lead compound PI-083 (IC 50  = 12.47 ± 0.21, 53.12 ± 2.56 and 26.37 ± 0.5 μM), respectively. The antiproliferative activity was also determined by MTT (3-(4,5-Dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide) assay in vitro. According to the antiproliferative activity results, all of the compounds exhibited cell growth inhibitory activity in a range of IC 50  = 1.72 ± 0.14-20.8 ± 0.5 μM and compounds 13 and 28 were found to be the most active compounds with IC 50 values of 1.79 ± 0.21 and 1.72 ± 0.14 μM, respectively. Furthermore, molecular modeling studies were carried out for the compounds 13, 14 and 28 to investigate the ligand-enzyme binding interactions., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

In this study, based on our previous study, derivatives of naphtho[2,3-b]furan-4,9-diones were synthesized and their antimicrobial activities were evaluated. The screening of these naphthoquinones revealed that the fluorine-containing NQ008 compound exhibited potent and broad antimicrobial activities against Gram-positive bacteria including methicillin-resistant Staphylococcus aureus (MRSA), Gram-negative bacteria, and fungi. The results of the ratio of the minimum bactericidal concentration (MBC) to the minimum inhibitory concentrations (MICs) and time-kill assays suggest that the mode of action of NQ008 is bactericidal. Additionally, the results of a drug resistance study revealed that NQ008 exhibited potent antibacterial activity and may delay the development of bacteria resistance. Furthermore, NQ008 exhibited preliminary antiviral activity against the swine influenza virus and Feline calicivirus.

&lt;b&gt;Background and Objective:&lt;/b&gt; The medicinal herb &lt;i&gt;Plumbago indica&lt;/i&gt; (PI) and its major constituent plumbagin have reported pharmacological properties but there is a lack of information about their herb-drug interactions. The effects of methanolic (PI-MeOH) and ethanolic (PI-EtOH) crude extracts of PI and plumbagin on the expression of cytochrome P450s (&lt;i&gt;CYP1A2&lt;/i&gt;, &lt;i&gt;CYP2E1&lt;/i&gt; and &lt;i&gt;CYP3A4&lt;/i&gt;) and transporters (&lt;i&gt;ABCC1&lt;/i&gt;, &lt;i&gt;ABCG2&lt;/i&gt; and &lt;i&gt;SLC22A11&lt;/i&gt;) were investigated in BeWo and HepG2 cells. &lt;b&gt;Materials and Methods:&lt;/b&gt; BeWo or HepG2 cells were treated with 0.5-5 μM plumbagin or 25-500 μg mL&lt;sup&gt;1&lt;/sup&gt; of PI-MeOH or PI-EtOH for 24 hrs. Total RNA was extracted and mRNA expression of CYPs and transporters were determined using RT-qPCR. &lt;b&gt;Results:&lt;/b&gt; PI and plumbagin affected mRNA expression differently in the two tested cell types. In BeWo cells, all concentrations of PI-MeOH induced &lt;i&gt;CYP2E1&lt;/i&gt;, 100 and 500 μg Ml&lt;sup&gt;1&lt;/sup&gt; PI-MeOH and PI-EtOH up-regulated &lt;i&gt;CYP1A2&lt;/i&gt;, &lt;i&gt;CYP3A4 &lt;/i&gt;and &lt;i&gt;ABCG2 &lt;/i&gt;and 500 μg mL&lt;sup&gt;1&lt;/sup&gt; PI-EtOH induced &lt;i&gt;ABCG2&lt;/i&gt; expression. Plumbagin suppressed &lt;i&gt;CYP1A2&lt;/i&gt; and induced &lt;i&gt;SLC22A11 &lt;/i&gt;expression at the highest concentration, 5 μM. In HepG2 cells, 5 μM plumbagin and 500 μg Ml&lt;sup&gt;1&lt;/sup&gt; PI-EtOH suppressed &lt;i&gt;CYP3A4 &lt;/i&gt;expression and 500 μg mL&lt;sup&gt;1&lt;/sup&gt; PI-MeOH and PI-EtOH up-regulated &lt;i&gt;CYP1A2&lt;/i&gt; and &lt;i&gt;CYP2E1 &lt;/i&gt;expression. &lt;i&gt;ABCC1&lt;/i&gt; expression was induced by all treatments while &lt;i&gt;ABCG2&lt;/i&gt; and &lt;i&gt;SLC22A11 &lt;/i&gt;were induced only by 500 μg mL&lt;sup&gt;1&lt;/sup&gt; PI-MeOH and PI-EtOH. &lt;b&gt;Conclusion:&lt;/b&gt; The use of PI or plumbagin supplements in large quantities or for long periods should be carefully considered due to the risk of herbal drug interactions via modulated expression of CYPs and transporters.

Chemical modification of the thiol group on protein tyrosine phosphatase (PTP) 1B triggers an activation of epidermal growth factor receptor (EGFR) signaling that is mimicked by environmental electrophiles through S-modification of PTP1B. While activation of PTP1B/EGFR by a single exposure to an electrophile has been established, the effects of combined exposure to electrophiles are unknown. Here, we examined the activation of EGFR signaling by combined exposure to ambient electrophiles in human epithelial carcinoma A431 cells. Simultaneous exposure to 1,2- and 1,4-naphthoquinone (NQ) augmented the S-modification of endogenous and recombinant human PTP1B (hPTP1B). Combined exposure of hPTP1B or A431 cells to 1,2- and 1,4-NQ escalated the inactivation of PTP compared with individual exposure. Phosphorylation of EGFR and its downstream kinase extracellular signal-regulated kinase (ERK) 1/2 by 1,2-NQ exposure was facilitated by simultaneous exposure to 1,2-NQ with 10 µM 1,4-NQ. An EGFR inhibitor diminished the phosphorylation of ERK1/2, indicating that ERK was phosphorylated following EGFR activation by the NQ cocktail. The combined exposure to NQs also accelerated cell death in A431 cells compared with each NQ alone. While no EGFR/ERK activation was seen following 1,4-benzoquinone (BQ) treatment, exposure to 1,4-NQ in the presence of 1,4-BQ increased 1,4-NQ-mediated activation of EGFR. This suggests that the enhancement of 1,4-NQ-dependent EGFR activation by 1,4-BQ is caused by a different mechanism than 1,2-NQ with 1,4-NQ. These results suggest that combined exposure to ambient electrophiles, even at low concentrations, can induce stronger activation of redox signaling than individual exposure. Our findings indicate that combining different electrophiles may produce unexpected effects.

A series of novel 1,4-naphthoquinone-triazole hybrids, N-(3-amino-1,4-dioxo-1,4-dihydronaphthalen-2-yl)-2-(4-R-1H-1,2,3-triazol-1-yl)acetamide, was synthesized by click chemistry in the presence of sodium ascorbate and copper(II) sulfate pentahydrate in 81-94% yield. Various biological properties of the synthesized compounds including DNA binding/cleavage, antioxidant, antibacterial and antifungal properties were evaluated. The DNA binding study was performed using dsDNA and G-quadruplex DNA. All of the compounds showed fluorescence increase in the presence of DNA, regardless of the structure. Up to 2.9 and 2.5 times fluorescence increase upon incubation with double stranded or G-quadruplex DNA was detected for 5f and 5g, respectively. The docking studies performed on dsDNA and G-quadruplex structures suggested compounds' mode of interactions were populated around the grooves. All of the compounds showed excellent DNA cleavage activity and 5e was almost degraded the plasmid DNA. The highest radical scavenging activity was obtained as 89.9% at 200 mg/L with 5d. However, the highest ferrous chelating activity was obtained as 68.1% at 200 mg/L with 5g. The compounds exhibited antimicrobial activity against Bacillus cereus, Legionella pneumophila subsp. pneumophila, Staphylococcus aureus, Pseudomonas aeruginosa, Escherichia coli and Enterococcus hirae as bacteria strains and Candida albicans and Candida tropicalis as microfungus strains. The compounds exhibited antibacterial and antifungal activity in the range of 4-128 μg/mL and 16-128 μg/mL, respectively. The best antimicrobial activity was obtained with 5d and 5e with a MIC value of 4 μg/mL against Enterococcus hirae. The acid dissociation constants (pK a ) were determined potentiometrically in 20% (v/v) dimethyl sulfoxide-water hydro-organic solvent at an ionic background of 0.1 mol/L of NaCl, at 25 ± 0.1 °C. Five pK a values were obtained for each ligand., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Naphthoquinone-based meroterpenoids are hybrid polyketide-terpenoid natural products with chemical diversity and a broad range of biological activities. Here, we report the isolation of a group of naphthoquinone-containing compounds from Streptomyces sp. B9173, and their structures were elucidated by using a combination of spectroscopic techniques, including 1D, 2D NMR, and high-resolution mass (HRMS) analysis. Seven flaviogeranin congeners or intermediates, three of which were new, have been derived from common naphthoquinone backbone and subsequent oxidation, methylation, prenylation, and amino group incorporation. Both flaviogeranin B1 ( 1 ) and B ( 2 ) contain an amino group which was incorporated into the C8 of 1,3,6,8-terhydroxynaphthalene (THN). Flaviogeranin D ( 3 ) contains an intact C -geranylgeranyl residue attached to the C2 of THN, while the O -geranylgeranyl group of 2 links with the hydroxyl on the C2 site of THN. Four compounds were selected and tested for antibacterial activity and cytotoxicity, with 3 and flaviogeranin C2 ( 5 ) displaying potent activity against selected bacteria and cancer cell lines. In light of the structure features of isolated compounds and the biosynthetic genes, a biosynthetic pathway of naphthoquinone-based flaviogeranins has been proposed. These isolated compounds not only extend the structural diversity but also represent new insights into the biosynthesis of naphthoquinone-based meroterpenoids.

We previously showed that microwave assisted synthesis is the best method for the synthesis of naphthoquinone amino acid and chloride-naphthoquinone amino acid derivatives by a complete evaluation of reaction conditions such as stoichiometry, bases, and pH influence. Following the same strategy, we synthesized chloride and non-chloride tyrosine, valine, and tryptophan-naphthoquinones achieving 85-95%, 80-92%, and 91-95% yields, respectively. The cyclic voltammetry profiles showed that both series of naphthoquinone amino acid derivatives mainly display one redox reaction process. Overall, chloride naphthoquinone amino acid derivatives exhibited redox potential values (E 1/2 ) more positive than non-chloride compounds. The six newly synthesized compounds were tested in HPV positive and negative as well as in immortal and tumorigenic cell lines to observe the effects in different cellular context simulating precancerous and cancerous status. A dose-response was achieved to determine the IC50 of six newly synthesized compounds in SiHa (Tumorigenic and HPV16 positive), CaLo (Tumorigenic and HPV18 positive), C33-A (Tumorigenic and HPV negative) and HaCaT (Keratinocytes immortal HPV negative) cell lines. Non-chloride tryptophan-naphthoquinone (3c) and chloride tyrosine-naphthoquine (4a) effects were more potent in tumorigenic SiHa, CaLo, and C33-A cells with respect to non-tumorigenic HaCaT cells. Interestingly, there seems to be a differential effect in non-chloride and chloride naphthoquinone amino acid derivatives in tumorigenic versus non tumorigenic cells. Considering all naphthoquinone amino acid derivatives that our group synthesized, it seems that hydrophobic and aromatic amino acids have the greatest effect on cell proliferation inhibition. These results show promising compounds for cervical cancer treatment.

A novel synthetic approach was developed for the synthesis of 3-hydrazinotriazolothiadiazines in just one step from Purpald and phenacyl bromides. They were then selectively tethered to naphthoquinone fragments through hydrazine moiety generating novel Naphthoquinone-hydrazinotriazolothiadiazine analogues. In vitro cytotoxicity for the synthesized chemical entities was validated against HepG2 and MCF-7 cell lines and recorded IC 50 inhibitory profile range of 0.07-19.68 µM and 1.19-67.32 µM respectively. Among the synthesized series, compound 4c had maximal cytotoxicity against HepG2 and was therefore selected for further downstream biological investigations. Caspase 3 apoptotic marker was significantly upregulated in cells treated with compound 4c with induction of apoptosis at Pre-G1 phase and cell death at G2/M phase. Compounds 4a, 4c and 4d exhibited the most powerful inhibitory range (0.55-0.64 µM) against Topo IIB. Molecular docking study revealed potential interactions of those compounds within the ATP catalytic binding domain of Topo-IIB with high scores. In conclusion, the novel Naphthoquinone-hydrazinotriazolothiadiazine analogues could serve as promising anticancer agents through inhibition of Topoisomerase-IIB., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Despite the important biological activities of natural product naphthoquinones, the biosynthetic pathways of and resistance mechanisms against such compounds remain poorly understood in fungi. Here, we report that the genes responsible for the biosynthesis of Monascus naphthoquinones (monasones) reside within the gene cluster for Monascus azaphilone pigments (MonAzPs). We elucidate the biosynthetic pathway of monasones by a combination of comparative genome analysis, gene knockouts, heterologous coexpression, and in vivo and in vitro enzymatic reactions to show that this pathway branches from the first polyketide intermediate of MonAzPs. Furthermore, we propose that the monasone subset of biosynthetic genes also encodes a two-tiered resistance strategy in which an inducible monasone-specific exporter expels monasones from the mycelia, while residual intracellular monasones may be rendered nontoxic through a multistep reduction cascade. IMPORTANCE The genes for Monascus naphthoquinone (monasone) biosynthesis are embedded in and form a composite supercluster with the Monascus azaphilone pigment biosynthetic gene cluster. Early biosynthetic intermediates are shared by the two pathways. Some enzymes encoded by the supercluster play double duty in contributing to both pathways, while others are specific for one or the other pathway. The monasone subcluster is independently regulated and inducible by elicitation with competing microorganisms. This study illustrates genomic and biosynthetic parsimony in fungi and proposes a potential path for the evolution of the mosaic-like azaphilone-naphthoquinone supercluster. The monasone subcluster also encodes a two-tiered self-resistance mechanism that models resistance determinants that may transfer to target microorganisms or emerge in cancer cells in case of naphthoquinone-type cytotoxic agents., (Copyright © 2020 Li et al.)

Naturally occurring naphthoquinones (NQs) comprising highly reactive small molecules are the subject of increasing attention due to their promising biological activities such as antioxidant, antimicrobial, apoptosis-inducing activities, and especially anticancer activity. Lapachol, lapachone, and napabucasin belong to the NQs and are in phase II clinical trials for the treatment of many cancers. This review aims to provide a comprehensive and updated overview on the biological activities of several new NQs isolated from different species of plants reported from January 2013 to January 2020, their potential therapeutic applications and their clinical significance., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

T cell metabolic activation plays a crucial role in inflammation of atherosclerosis. Shikonin (SKN), a natural naphthoquinone with anti-inflammatory activity, has shown to exert cardioprotective effects, but the effect of SKN on atherosclerosis is unclear. In addition, SKN was found to inhibit glycolysis via targeting pyruvate kinase muscle isozyme 2 (PKM2). In the present study, we investigated the effects of SKN on hyperhomocysteinemia (HHcy)-accelerated atherosclerosis and T cell inflammatory activation in ApoE -/- mice and the metabolic mechanisms in this process. Drinking water supplemented with Hcy (1.8 g/L) was administered to ApoE -/- mice for 2 weeks and the mice were injected with SKN (1.2 mg/kg, i.p.) or vehicle every 3 days. We showed that SKN treatment markedly attenuated HHcy-accelerated atherosclerosis in ApoE -/- mice and significantly decreased inflammatory activated CD4 + T cells and proinflammatory macrophages in plaques. In splenic CD4 + T cells isolated from HHcy-ApoE -/- mice, SKN treatment significantly inhibited HHcy-stimulated PKM2 activity, interferon-γ secretion and the capacity of these T cells to promote macrophage proinflammatory polarization. SKN treatment significantly inhibited HHcy-stimulated CD4 + T cell glycolysis and oxidative phosphorylation. Metabolic profiling analysis of CD4 + T cells revealed that Hcy administration significantly increased various glucose metabolites as well as lipids and acetyl-CoA carboxylase 1, which were reversed by SKN treatment. In conclusion, our results suggest that SKN is effective to ameliorate atherosclerosis in HHcy-ApoE -/- mice and this is at least partly associated with the inhibition of SKN on CD4 + T cell inflammatory activation via PKM2-dependent metabolic suppression.

Evolution fine-tunes biological pathways to achieve a robust cellular physiology. Two and a half billion years ago, rapidly rising levels of oxygen as a byproduct of blooming cyanobacterial photosynthesis resulted in a redox upshift in microbial energetics. The appearance of higher-redox-potential respiratory quinone, ubiquinone (UQ), is believed to be an adaptive response to this environmental transition. However, the majority of bacterial species are still dependent on the ancient respiratory quinone, naphthoquinone (NQ). Gammaproteobacteria can biosynthesize both of these respiratory quinones, where UQ has been associated with aerobic lifestyle and NQ with anaerobic lifestyle. We engineered an obligate NQ-dependent γ-proteobacterium, Escherichia coli Δ ubiC , and performed adaptive laboratory evolution to understand the selection against the use of NQ in an oxic environment and also the adaptation required to support the NQ-driven aerobic electron transport chain. A comparative systems-level analysis of pre- and postevolved NQ-dependent strains revealed a clear shift from fermentative to oxidative metabolism enabled by higher periplasmic superoxide defense. This metabolic shift was driven by the concerted activity of 3 transcriptional regulators (PdhR, RpoS, and Fur). Analysis of these findings using a genome-scale model suggested that resource allocation to reactive oxygen species (ROS) mitigation results in lower growth rates. These results provide a direct elucidation of a resource allocation tradeoff between growth rate and ROS mitigation costs associated with NQ usage under oxygen-replete condition., Competing Interests: The authors declare no competing interest., (Copyright © 2019 the Author(s). Published by PNAS.)

Cell division cycle 25 (Cdc25) and mitogen-activated protein kinase kinase 7 (MKK7) are enzymes involved in intracellular signaling but can also contribute to tumorigenesis. We synthesized and characterized the biological activity of 1,4-naphthoquinones structurally similar to reported Cdc25 and(or) MKK7 inhibitors with anticancer activity. Compound 7 (3-[(1,4-dioxonaphthalen-2-yl)sulfanyl]propanoic acid) exhibited high binding affinity for MKK7 (K d  = 230 nM), which was greater than the affinity of NSC 95397 (K d  = 1.1 μM). Although plumbagin had a lower binding affinity for MKK7, this compound and sulfur-containing derivatives 4 and 6-8 were potent inhibitors of Cdc25A and Cdc25B. Derivative 22e containing a phenylamino side chain was selective for MKK7 versus MKK4 and Cdc25 A/B, and its isomer 22f was a selective inhibitor of Cdc25 A/B. Docking studies performed on several naphthoquinones highlighted interesting aspects concerning the molecule orientation and hydrogen bonding interactions, which could help to explain the activity of the compounds toward MKK7 and Cdc25B. The most potent naphthoquinone-based inhibitors of MKK7 and/or Cdc25 A/B were also screened for their cytotoxicity against nine cancer cell lines and primary human mononuclear cells, and a correlation was found between Cdc25 A/B inhibitory activity and cytotoxicity of the compounds. Quantum chemical calculations using BP86 and ωB97X-D3 functionals were performed on 20 naphthoquinone derivatives to obtain a set of molecular electronic properties and to correlate these properties with cytotoxic activities. Systematic theoretical DFT calculations with subsequent correlation analysis indicated that energy of the lowest unoccupied molecular orbital E(LUMO), vertical electron affinity (VEA), and reactivity index ω of these molecules were important characteristics related to their cytotoxicity. The reactivity index ω was also a key characteristic related to Cdc25 A/B phosphatase inhibitory activity. Thus, 1,4-naphthoquinones displaying sulfur-containing and phenylamino side chains with additional polar groups could be successfully utilized for further development of efficacious Cdc25 A/B and MKK7 inhibitors with anticancer activity., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

We aimed to synthesize novel liver X receptor (LXR) agonists with potent agonist activity and subtype selectivity. Our synthetic scheme started with naphthoquinone derivatives, such as menadione and 2,3-dichloro-1,4-naphthoquinone. We introduced different substituents into the naphthoquinone structures, including aniline, piperidine, pyrrolidine, and morpholine, in one or two steps, and thus, we produced 14 target compounds. All 14 synthetic ligands were tested to determine whether they mediated LXR-mediated transcriptional activity. We investigated the transcriptional activity of each compound with two types of receptors, LXRα and LXRβ. Among all 14 compounds, two showed weak LXRβ-agonist activity, and two others exhibited potent LXRα-agonist activity. We also performed docking studies to obtain a better understanding of the modes of compound binding to LXR at the atomic level. In conclusion, we successfully synthesized naphthoquinone derivatives that act as LXRα/β agonists and selective LXRα agonists.