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An efficient annulation involving pyrone addition to a quinone and Dieckmann condensation was developed for rapid assembly of a γ-naphthopyrone monomeric precursor to the bis-naphthoquinone natural product aurofusarin. Dimerization was achieved through Pd II -catalyzed dehydrogenative coupling. Further studies employing asymmetric nucleophilic epoxidation indicate that the atropisomers of aurofusarin and derivatives are not configurationally stable at ambient temperature., (© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The 1,4-naphthoquinone derivatives bearing 5,7-dimethoxyl moiety were designed, synthesized, and tested as the antitumor agents against five human cancer cell lines (A549, Hela, HepG2, NCI-H460 and HL-60). All the compounds are described herein for the first time. The structure-activity relationships indicated that the presence of chlorine atom at the 2-position was crucial for the antiproliferative activity. Further, the electrochemical properties of the representative compounds (7e, 8e and 9e) were evaluated and a definite correlation between the redox potential and the antiproliferative activity. The most potent compound 9e displayed significant anti-leukemic activity with IC 50 value of 3.8 μM in HL-60 cells and weak cytotoxicity with IC 50 of 40.7 μM in normal cells WI-38. In mechanistic study for 9e, the increased numbers of apoptotic cells and increased cell population at G2/M phase correlated with ROS generation. Together, our results suggested that the derivatives of 2-chlorine-1,4-naphthoquinone might be the promising candidates for the treatment of promyelocytic leukemia., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

The limited efficacy of benznidazole (Bz) indicated by failures of current Phase II clinical trials emphasizes the urgent need to identify new drugs with improved safety and efficacy for treatment of Chagas disease (CD). Herein, we analyzed the efficacy of a series of 2-hydroxy-3-phenylsulfanylmethyl-[1,4]-naphthoquinones against different Trypanosoma cruzi discrete type units (DTUs) of relevant clinical forms of CD. Cytotoxic and trypanocidal effect of naphthoquinone derivatives were assessed in mammalian cells, trypomastigotes and intracellular amastigotes using, luminescent assays (CellTiter-Glo and T. cruzi Dm28c-luciferase) and/or counting with a light microscope. Reactive oxygen species (ROS) production and intracellular targets of promising compounds were assessed with 2',7'-dichlorodihydrofluorescein diacetate (H 2 DCFDA) probe and ultrastructural analysis, respectively. ADMET properties were analyzed by in silico modeling. Most of the compounds showed low cytotoxic effect. Only two compounds (Compounds 2 and 11) had IC 50 values lower than Bz, showing higher susceptibility of bloodstream trypomastigotes. Compound 2 exhibited greater efficacy against trypomastigotes from different T. cruzi DTUs, even better than Bz against Brazil and CL strains. Ultrastructural analysis revealed changes in intracellular compartments, suggesting autophagy as one possible mechanism of action. Oxidative stress, induced by Compound 2, resulted in elevated level of ROS, leading to parasite death. Compound 2 was also effective against intracellular amastigotes, showing high selectivity index. ADMET analysis predicted good oral bioavailability, reduced drug metabolism and no carcinogenic potential for Compound 2. The data highlight Compound 2 as a hit compound and stimulate further structural and pharmacological optimization to potentiate its trypanocidal activity and selectivity., (Copyright © 2017. Published by Elsevier Masson SAS.)

Colorectal cancer (CRC) is a disease with high incidence and mortality, constituting the fourth most common cause of death from cancer worldwide. Naphthoquinones are attractive compounds due to their biological and structural properties. In this work, 36 naphthoquinone derivatives were synthesized and their activity evaluated against HT-29 cells. Overall, high to moderate anti-proliferative activity was observed in most members of the series, with 15 compounds classified as active (1.73 < IC 50 < 18.11 μM). The naphtho[2,3- b ]thiophene-4,9-dione analogs showed potent cytotoxicity, 8-hydroxy-2-(thiophen-2-ylcarbonyl)naphtho[2,3- b ]thiophene-4,9-dione being the compound with the highest potency and selectivity. Our results suggest that the toxicity is improved in molecules with tricyclic naphtho[2,3- b ]furan-4,9-dione and naphtho[2,3- b ]thiophene-4,9-dione systems 2-substituted with an electron-withdrawing group. A 3D-QSAR study of comparative molecular field analysis (CoMFA) was carried out, resulting in the generation of a reliable model (r² = 0.99 and q² = 0.625). This model allowed proposing five new compounds with two-fold higher theoretical anti-proliferative activity, which would be worthwhile to synthesize and evaluate. Further investigations will be needed to determine the mechanism involved in the effect of most active compounds which are potential candidates for new anticancer agents., Competing Interests: The authors declare no conflict of interest.

Background: Recognition of a new therapeutic agent may activate an alternative programmed cell death for the treatment of breast cancer., Objective: Here, it has been tried to evaluate the effects of Shikonin, a naphthoquinone derivative of Lithospermum erythrorhizon, on the induction of necroptosis and apoptosis mediated by RIPK1-RIPK3 in the ER+ breast cancer cell line, MCF-7., Methods: In the current study, cell death modalities, cell cycle patterns, RIPK1 and RIPK3 expressions, caspase-3 and caspase-8 activities, reactive oxygen species and mitochondrial membrane potential have been evaluated in the Shikonin-treated MCF-7 cells., Results: Necroptosis and apoptosis have been occurred by Shikonin, with a significant increase in RIPK1 and RIPK3 expressions, although necroptosis was the major rout in MCF-7 cells. Shikonin significantly increased the percentage of the cells in sub-G1 and also those in the later stages of cell cycle, which represents an increase in necroptosis and apoptosis. Under caspase inhibition by Z-VAD-FMK, Shikonin has stimulated necroptosis, which could be arrested by Nec-1. An increase in ROS levels and a decrease in the mitochondrial membrane potential have also been observed., Conclusion: On the basis of present findings, Shikonin has been suggested as a good candidate for the induction of cell death in ER+ breast cancer, although further investigations, experimental and clinical, are required., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

As a continuation of our research on developing potent and potentially safe antineoplastic agents, a set of forty five sulfur-containing shikonin oxime derivatives were synthesized and evaluated for their in vitro cytotoxic activity against human colon cancer (HCT-15), gastric carcinoma (MGC-803), liver (Bel7402), breast (MCF-7) cancer cells and human skin fibroblast (HSF) cells. All the synthesized compounds exhibited potent cytotoxic activity selectively towards HCT-15 cells and did not display apparent toxicity to the normal HSF cells, some of which were more or comparatively effective to the parent compound against HCT-15, MGC-803 and Bel7402 cells. The most active agent 9m displayed high potency against human cancer cells with IC 50 ranging from 0.27 ± 0.02 to 9.23 ± 0.12 μM. The structure-activity relationships (SARs) studies suggested that the nature of substituent group in the side chain is important for antitumor potency in vitro. Additionally, nitric oxide release studies revealed that the amount of nitric oxide generated from these oxime derivatives was relatively low. Furthermore, cellular mechanism investigations indicated that compound 9m could arrest cell cycle at G1 phase and induce a strong apoptotic response in HCT-15 cells. Moreover, western blot studies revealed that compound 9m induced apoptosis through the down-regulation of Bcl-2 and up-regulation of Bax, caspase 3 and 9. For all these reasons, compound 9m hold promising potential as antineoplastic agent., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

In current study, a series of shikonin derivatives were synthesized and its anticancer activity was evaluated. As a result, PMMB232 showed the best antiproliferation activity with an IC 50 value of 3.25±0.35μM. Further, treatment of HeLa cells with a variety of concentrations of target drug resulted in dose-dependent event marked by apoptosis. What's more, the mitochondrial potential (Δym) analysis was consistent with the apoptosis result. In addition, PARP was involved in the progress of apoptosis revealed by western blotting. To identify the detailed role and mechanism of PMMB232 in the progression of human cervical cancer, we detected the expression of HIF-1α and E-cadherin in HeLa cells. Results showed that expression of HIF-1α was downregulated, while E-cadherin protein was upregulated. Meanwhile, glycolysis related protein PDK1 was decreased in HeLa cells. Conversely, the expression of PDH-E1α was upregulated. Docking simulation results further indicate that PMMB232 could be well bound to HIF-1α. Taken together, our data indicate that compound PMMB232 could be developed as a potential anticancer agent., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

Background: Cancer is a leading cause of mortality in the world and metastasis is to blame. A number of naphthoquinones (NQs) have shown ability to reduce cancer stemness and metastatic potential. Furano-naphthoquinones (FNQs), which is a class of NQ characterized by the incorporation of an additional furan ring, have demonstrated improved anti-cancer potency as compared to the other classes of NQs., Objective: In this study, the natural origins, synthetic routes and derivatives of migrastatic NQs were reviewed. The anti-invasive and anti-metastatic mechanisms of NQs and the more powerful FNQs in targeting cancer were also discussed., Methods: The articles related to the anti-invasive mechanisms of NQs were comprehensively reviewed. The plant origins, synthetic routes and antitumor effects of more than 360 FNQs were also covered and presented according to their chemical structures., Results: Anti-cancer NQs inhibit cancer invasion by acting on epithelial-mesenchymal transition (EMT), cancer stem cells (CSCs) and signal transducer and activator of transcription 3 (STAT3) signaling. BBI608, a natural FNQ, has entered phases I and II clinical trials. It has been regarded as a potential candidate for new-generation lead compound acting directly on CSCs to overcome the problem of chemotherapy resistance. Apart from the plant-derived FNQs, there are a number of synthetic FNQs that were found to intervene in cancer invasion and metastasis., Conclusion: The anti-invasive mechanisms of NQs have been thoroughly studied. FNQs generally show higher anti-cancer activity than that of NQs. The mechanisms of action of FNQs are worth further investigation., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

In an effort to develop potent and selective antitumor agents, a series of 1,4-naphthoquinone oxime derivatives were designed and synthesized. The cytotoxicity of these compounds were evaluated against five human cancer cell lines (colorectal cancer cell: HCT-15, breast cancer cell: MDA-MB-231, liver cancer cell: BEL-7402, colorectal cancer cell: HCT-116 and ovarian cancer cell: A2780) in vitro. Among them, compound 14 was found to be the most potent cytotoxic compound against three cell lines (MDA-MB-231, BEL-7402 and A2780) with IC 50 values of 0.66±0.05, 5.11±0.12 and 8.26±0.22 µM, respectively. Additionally, the length of the side chains and the position of the substituent may also affect the cytotoxic activity of the naphthoquinone oxime derivatives. In general, compound 14 effectively inhibited breast cancer cell proliferation and may become a promising anticancer agent.

Background: 2-Methoxystypandrone (2-MS), isolated from the roots of Polygonum cuspidatum, is a potent dual inhibitor of the STAT3 and NF-κB pathways., Objective: To investigate the molecular targets and mechanisms of 2-MS., Method: A biotin-conjugated 2-MS analog, named 2-MS-Biotin, was designed and synthesized. The effects of 2-MS-Biotin on the STAT3 and NF-κB pathways were examined by Western blotting. The cytotoxicity of 2- MS-Biotin was evaluated using real-time cell analysis system. Proteins directly bound to 2-MS-Biotin were pulled down through streptavidin agarose beads and were detected using Western blotting., Results: 2-MS-Biotin retained the inhibition activities of the parent compound 2-MS on the STAT3 and NF-κB pathways as well as on cancer cell growth. Also, JAK2 and IKK proteins can be effectively pulled down by 2- MS-Biotin., Conclusion: Using 2-MS-Biotin as a tool, both JAK2 and IKK were identified as the targets of 2-MS., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Background: Recent years have brought the dynamic development in studies of naphthoquinones obtained from plants, in vitro cultures and semi- or total synthesis. This review presents the hairy root cultures approach for producing naphthoquinones and summarizes their most recent anti-cancer investigations., Objective: This review aimed to define biotechnological strategies impacted on naphthoquinones production in hairy root cultures. Up to now the major source of shikonin/alkannin derivatives, rhinacanthins and ramentaceone is isolation from plant material, also derived via biotechnological methods. Moreover, the most recent anti-cancer activity studies on naphthoquinones which could be produced in hairy root cultures were outlined., Methods: For databases survey two selection criteria were used: (i) naphthoquinone could be produced in hairy roots, and (ii) it exhibits anti-cancer properties., Results: Ninety two papers were included in the review, thirty described biotechnological approaches enhancing naphthoquinones production, among them twenty seven were dedicated to hairy root cultures. Forty papers outlined the anti-cancer activity of targeted naphthoquinones including the type of cancer and bioassays description. The synergistic effect of natural naphthoquinones and other anti-cancer therapies was reviewed and toxicity of natural naphthoquinones and plant extracts was discussed. The review highlights tendencies in hairy root investigations and indicates the possible future research directions for improving biotechnological production efficacy., Conclusion: This review demonstrates a great potential of hairy root cultures for naphthoquinones production, which could be furtherly developed for future medical purposes, especially as anti-cancer agents. This area of plant biotechnology will be surely still developed with traditional and new strategies., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

We have discovered a transition-metal-free approach to the synthesis of 2,2'-bis(naphthoquinones) using a Diels-Alder reaction of conjugated ketene silyl acetals with benzoquinone. Its monomer analogue can also be synthesized by simply increasing the equivalents of benzoquinone.

The signal transducer and activator of transcription 3 is a constitutively activated oncogenic protein in various human tumors and represents a valid target for anticancer drug design. In this study, we have achieved a new type of STAT3 inhibitors based on structural modifications on shikonin scaffold, guided by computational modelling. By tests, PMMB-187 exhibited a more outstanding profile than shikonin on a small panel of human breast cancer cells, especially for the MDA-MB-231 cells. For the cellular mechanisms research, PMMB-187 was found to induce cell apoptosis in MDA-MB-231 cells, associated with the reduction of mitochondrial membrane potential, production of ROS and alteration of the levels of apoptosis-related proteins. Furthermore, PMMB-187 inhibited constitutive/inducible STAT3 activation, transcriptional activity, nuclear translocation and downstream target genes expression in STAT3-dependent breast cancer cells MDA-MB-231. Besides, no obvious inhibitory effect on activation of STAT1 and STAT5 was observed with PMMB-187 treatment. Most notably, the in vivo studies further revealed that PMMB-187 could dramatically suppress the MDA-MB-231 cells xenografted tumor growth. The in vitro and in vivo results collectively suggest that PMMB-187 may serve as a promising lead compound for the further development of potential therapeutic anti-neoplastic agents., (Copyright © 2017 Elsevier Inc. All rights reserved.)

The ubiquitin-proteasome system has been largely investigated for its key role in protein degradation mechanisms that regulate both apoptosis and cell division. Because of their antitumour activity, different classes of proteasome inhibitors have been identified to date. Some of these compounds are currently employed in the clinical treatment of several types of cancer among which multiple myeloma. Here, we describe the design, chemistry, biological activity and modelling studies of a large series of amino acid derivatives linked to a naphthoquinone pharmacophoric group through variable spacers. Some analogues showed interesting inhibitory potency for the β1 and β5 subunits of the proteasome with IC 50 values in the sub-µm range.

A series of 1,4-naphthoquinones (10a-10q) were synthesized and evaluated for anticancer activity. Compound 10e was identified as an inhibitor of Itch, a HECT domain-E3 ligase. In an evaluation of in vivo efficacy, 10e exhibited remarkable anticancer activity with TGI values of 98.3% and 100% at 25 mg/kg and 50 mg/kg orally daily, respectively, against human RPMI-8226 multiple myeloma xenograft. Treatment with 10e also showed a decrease of Itch level in human RPMI-8226 multiple myeloma cells. Thus 10e is a lead compound for further development of inhibitors targeting E3 ligase for treatment of multiple myeloma., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

Mammalian thioredoxin reductase (TrxR) enzymes play a crucial role in regulating multiple redox-based signaling pathways and have attracted increasing attention as promising anticancer drug targets. We report here the synthesis of a panel of naphthazarin derivatives and discovery of 2-methyl-5,8-dihydroxy-1,4-naphthoquinone (3, 2-methylnaphthazarin) as a potent cytotoxic agent with a submicromolar half maximal inhibitory concentration to the human promyelocytic leukemia HL-60 cells. Mechanism studies reveal that the compound selectively inhibits TrxR to induce oxidative stress-mediated apoptosis of HL-60 cells. Knockdown of TrxR sensitizes the cells to 3 insults, while overexpression of the functional enzyme confers resistance to the compound treatment, underpinning the physiological significance of targeting TrxR by 3. Clarification of the interaction of compound 3 with TrxR unveils a mechanism underlying the cellular action of the compound, and sheds light in considering development of the compound as a potential cancer chemotherapeutic agent., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

Pyruvate kinase M2 (PKM2) is a rate-limiting enzyme of the glycolytic pathway which is highly expressed in cancer cells. Cancer cells rely heavily on PKM2 for anabolic and energy requirements, and specific targeting of PKM2 therefore has potential as strategy for cancer therapy. Here, we report the synthesis and biologic evaluation of novel naphthoquinone derivatives as selective small molecule inhibitors of PKM2. Some target compounds, such as compound 3k, displayed more potent PKM2 inhibitory activity than the reported optimal PKM2 inhibitor shikonin. The well performing compound 3k also showed nanomolar antiproliferative activity toward a series of cancer cell lines with high expression of PKM2 including HCT116, Hela and H1299 with IC 50 values ranging from 0.18 to 1.56 μM. Moreover, compound 3k exhibited more cytotoxicity on cancer cells than normal cells. The identification of novel potent small molecule inhibitors of PKM2 not only offers candidate compounds for cancer therapy, but also provides a tool with which to evaluate the function of PKM2 in depth., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

Aim: Naphthoquine (NQ) was discovered by our institute as an antimalarial candidate in 1980s, and currently employed as an artemisinin-based combination therapy partner drug. Resistance to NQ was found in mouse model in laboratory, and might emerge in future as widely used., Methodology: We herein report the design and synthesis of NQ derivatives by replacing t-butyl moiety with linear/cyclic structured pendants. All the target compounds 6a-l and intermediates 5a-h were tested for their in vivo antimalarial activity against Plasmodium berghei K173 strain in mice., Results: Compounds 6a and 6j were found to have a comparable or slightly more potent activity (the 50% effective dose [ED 50 ], which is required to decrease parasitemia by 50%: 0.38-0.43 mg/kg) than NQ (ED 50 : 0.48 mg/kg)., Conclusion: The newly designed compounds 6a and 6j might be promising antimalarial candidates for further research.

Signal transducer and activator of transcription 3 (STAT3) is hyper-activated in diversiform human tumors and has been validated as an attractive therapeutic target. Current research showed that a natural product, shikonin, along with its synthetic analogues, is able to inhibit the activity of STAT3 potently. The potential space of shikonin in developing novel anti-cancer agents encouraged us to carry out the investigation of the probable binding mode with STAT3. From this foundation, we have designed new types of STAT3 SH2 inhibitors. Combined simulations were performed to filter for the lead compound, which was then substituted, synthesized and evaluated by a variety of bioassays. Among the entities, PMM-172 exhibited the best anti-proliferative activity against MDA-MB-231 cells with IC 50 value 1.98 ± 0.49 μM. Besides, it was identified to decrease luciferase activity, induce cell apoptosis and reduce mitochondrial transmembrane potential in MDA-MB-231 cells. Also, PMM-172 inhibited constitutive/inducible STAT3 activation without affecting STAT1 and STAT5 in MDA-MB-231 cells, and had no effect in non-tumorigenic MCF-10A cells. Moreover, PMM-172 suppressed STAT3 nuclear localization and STAT3 downstream target genes expression. Overall, these results indicate that the antitumor activity of PMM-172 is at least partially due to inhibition of STAT3 in breast cancer cells.

Aim: Due to the complex nature of Alzheimer's disease, there is a renewed search for multitarget directed drugs., Results: This paper describes the synthesis and in vitro biological evaluation of six racemic 13-aryl-2,3,4,13-tetrahydro-1H,12H-benzo[6,7]chromeno[2,3-d]pyrido[1,2-a]pyrimidine-7,12,14-triones (1a-6a), and six racemic 15-aryl-8,9,10,11,12,15-hexahydro-14H-benzo[6',7']chromeno[2',3:4,5] pyr-imido [1,2-a]azepine-5,14,16-triones (1b-6b), showing antioxidant and cholinesterase inhibitory capacity. Among these compounds, 13-phenyl-2,3,4,13-tetrahydro-1H,12H-benzo[6,7]chromeno[2,3-d]pyrido[1,2-a]pyrimidine-7,12,14-trione (1a) is a nonhepatotoxic at 300 μmol/l dose concentration, and a selective EeAChE inhibitor showing good antioxidant power., Conclusion: A new family of racemic benzochromenopyrimidinetriones has been investigated for their potential use in the treatment of Alzheimer's disease.

A series of 50 derivatives of 1,4-naphthoquinone tested against human HL-60 leukaemic cells showed activity at a wide range of concentrations. A multivariate quantitative structure-activity relationship (QSAR) study of 45 compounds was performed through principal component analysis (PCA) and partial least squares (PLS) regression. A good PLS regression model was obtained with two factors describing 60.1% of the total variance, and the selected descriptors were partial atomic charge at carbons 1 and 10 (C1 and C10) and total dipole moment (DIP). The calibration model exhibited the determination coefficient r 2 = 0.78 and the standard error of calibration = 0.29. For external validation, r 2 and the standard error of prediction were 0.74 and 0.32, respectively. DIP and C1 were the main descriptors for PCA, as well as for PLS, such that the pIC 50 value increases when C1 increases and DIP diminishes. The selected descriptors are in accordance with the literature, once C10 and C1 are bound or close to the quinone oxygens involved in the production of radical anions (O 2 -∙). From the QSAR analysis, the structures of two new naphthoquinones were proposed and their estimated IC 50 values were 1.42 and 1.13 μmol L -1 .

The biological importance of microtubules in mitosis makes them an interesting target for the development of anticancer agents. In this study, a series of novel chalcone-containing shikonin derivatives was designed, synthesized, and evaluated for biological activities. Among them, derivative PMMB-259 [(R)-1-(5,8-dihydroxy-1,4-dioxo-1,4-dihydronaphthalen-2-yl)-4-methylpent-3-en-1-yl (E)-2-(4-(3-oxo-3-(3-(trifluoromethoxy)phenyl)prop-1-en-1-yl)phenoxy)acetate] was identified as a potent inhibitor of tubulin polymerization. Further investigation confirmed that PMMB-259 can induce MCF-7 cell apoptosis, reduce the mitochondrial transmembrane potential, and arrest the cell cycle at the G 2 /M phase. Moreover, the morphological variation of treated cells was visualized by confocal microscopy. The results, along with docking simulations, further indicated that PMMB-259 can bind well to tubulin at the colchicine site. Overall, these studies may provide a new molecular scaffold for the further development of antitumor agents that target tubulin., (© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Naphthoquinones are naturally occurring biologically active entities. Practical de novo syntheses of three naphthoquinones i.e. lawsone (1), lapachol (2), and β-lapachone (3b) have been achieved from commercially available starting materials. The conversion of lapachol (2) to β-lapachone (3b) was achieved through p-TSA/Iodine/BF 3 -etherate mediated regioselective cyclisation. Further, 2-alkyl and 2-benzyllawsone derivatives have been prepared as possible anticancer agents. Four derivatives exhibited significant anticancer activity and the best analogue i.e. compound 21a exhibited potential anticancer activity (IC 50 =5.2μM) against FaDu cell line. Compound 21a induced apoptosis through activation of caspase pathway and exerted cell cycle arrest at S phase in FaDU cells. It also exhibited significant topoisomerase-II inhibition activity. Compound 21a was found to be safe in Swiss albino mice up to 1000mg/kg oral dose., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Covering: 2008 to 2015. A review on the isolation, biological activity and synthesis of pyranonaphthoquinone natural products from 2008-2015 is providedThis review discusses the isolation, biological activity and synthesis of pyranonaphthoquinone natural products, covering the years 2008-2015. The pyranonaphthoquinones are a group of metabolites sharing a common naphtho[2,3-c]pyran-5,10-dione ring system that have been isolated from a wide range of microorganisms, plants and insects. In addition to their synthetically challenging molecular structures, pyranonaphthoquinones exhibit a wide array of biological activity, including anti-bacterial, anti-fungal and anti-cancer properties. The therapeutic potential of these compounds has led to a dynamic interplay between total synthesis and biological evaluation.

DNA topoisomerase I inhibitors, both synthetic and of natural origin, are receiving increasing consideration primarily as drugs against refractory tumors. Alkannin and shikonin, two enantiomeric dyes from Alkanna tinctoria and Lithospermum erythrorhizon, have been known over many centuries as dyestuff, wound healing, anti-inflammatory, antibacterial and antitumor substances. Although multiple mechanisms appear to be implicated, their potency is associated with the inhibition of topoisomerase I and with the redox properties of the naphthazarin scaffold. Here, the synthesis of new naphthalene and naphthoquinone derivatives inspired by alkannin and shikonin is described and their structural and biological properties were examined. Different oxidation states of the naphthalene nucleus were examined to observe the effect of this parameter on cytotoxicity. Antiproliferative activities against a panel of human cancer cell lines were evaluated and the implication of topoisomerase I was assessed., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The synthesis, characterization and antileukemic activity of rationally designed amino dimeric naphthoquinone (BiQ) possessing aziridine as alkylating moiety is described. Bis-aziridinyl BiQ decreased proliferation of acute myeloid leukemia (AML) cell lines and primary cells from patients, and exhibited potent (nanomolar) inhibition of colony formation and overall cell survival in AML cells. Effective production of reactive oxygen species (ROS) and double stranded DNA breaks (DSB) induced by bis-aziridinyl BiQ is reported. Bis-dimethylamine BiQ, as the isostere of bis-aziridinyl BiQ but without the alkylating moiety did not show as potent anti-AML activity. Systemic administration of bis-aziridinyl BiQ was well tolerated in NSG mice., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

The weakly coordinating ketone group directed C-H functionalizations of chromones, 1,4-naphthoquinones, and xanthones with various maleimides under rhodium(III) catalysis are described. These protocols efficiently provide a range of succinimide-containing chromones, naphthoquinones, and xanthones with excellent site selectivity and functional group compatibility. All synthetic compounds were screened for in vitro anticancer activity against human breast adenocarcinoma cell lines (MCF-7). In particular, compounds 7aa and 7ca with a naphthoquinone scaffold were found to be highly cytotoxic, with an activity competitive with anticancer agent doxorubicin.

An efficient and regioselective synthetic route to naphthoquinone/naphthoquinol-carbohydrate hybrids has been developed. It is based upon anionic annulation of 3-nucleofugalphthalides with an acrylate appended sugar moiety. In each of the annulations studied, the arene-carbohydrate hybrids were obtained in good to excellent yields. The in vitro cytotoxic activity of the synthetic naphthoquinone/naphthonol-carbohydrate hybrids were evaluated against the human cervical cancer cell line (HeLa), and a few of them were found to exhibit potent anticancer activity against the cell line.

A series of novel lapachol derivatives possessing indole scaffolds was designed and synthesized. The in vitro anti-proliferative activity of these novel compounds was evaluated in Eca109 and Hela cell lines. Almost all the tested compounds showed manifested potent inhibitory activity against the two tested cancer cell lines. Topo I-mediated DNA relaxation activity indicated that these novel compounds have potent Topoisomerase I inhibition activity. The most potent compounds 4n and 4k demonstrated more cytotoxicity than camptothecin and was comparable to camptothecin in inhibitory activities on Topoisomerase I in our biological assay. In addition, the Hoechst 33342 staining method also showed that the complex can induce Hela cell apoptosis., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Microbial water quality monitoring for the presence of faecal indicator bacteria (FIB) is a mandatory activity in many countries and is key in public health protection. Despite technological advances and a need for methodological improvements, chromogenic and fluorogenic enzymatic techniques remain the mainstays of water quality monitoring for both public health agencies and regulated utilities. We demonstrated that bioelectroanalytical approaches to FIB enumeration are possible and can be achieved using commercially available enzyme-specific resorufin glycosides, although these are expensive, not widely available or designed for purpose. Following this, we designed two naphthoquinone glycosides which performed better, achieving Escherichia coli detection in the range 5.0 × 10 2 to 5.0 × 10 5 CFU ml -1 22-54% quicker than commercially available resorufin glycosides. The molecular design of the naphthoquinone glycosides requires fewer synthetic steps allowing them to be produced for as little as US$50 per kg. Tests with environmental samples demonstrated the low tendency for abiotic interference and that, despite specificity being maintained between β-glucuronidase and β-galactosidase, accurate enumeration of E. coli in environmental samples necessitates development of a selective medium. In comparison to a commercially available detection method, which has U.S. Environmental Protection Agency (EPA) approval, our approach performed better at high organism concentrations, detecting 500 organisms in 9 h compared with 13.5 h for the commercial method. Bioelectroanalytical detection is comparable to current approved methods and with further development could result in improved detection times. A recent trend for low-cost open-source hardware means that automated, potentiostatically controlled E. coli detection systems could be constructed for less than US$100 per channel., (© 2016 The Authors. Microbial Biotechnology published by Society for Applied Microbiology and John Wiley & Sons Ltd.)

Quambalarine B (QB) is a secondary metabolite produced by the basidiomycete Quambalaria cyanescens with potential anticancer activity. Here we report that QB at low micromolar concentration inhibits proliferation of several model leukemic cell lines (Jurkat, NALM6, and REH), whereas higher concentrations induce cell death. By contrast, the effect of QB on primary leukocytes (peripheral blood mononuclear cells) is significantly milder with lower toxicity and cytostatic activity. Moreover, QB inhibited expression of the C-MYC oncoprotein and mRNA expression of its target genes, LDHA, PKM2, and GLS. Finally, QB blocked the phosphorylation of P70S6K, a downstream effector kinase in mTOR signaling that regulates translation of C-MYC. This observation could explain the molecular mechanism behind the antiproliferative and cytotoxic effects of QB on leukemic cells. Altogether, our results establish QB as a promising molecule in anticancer treatment.

Pluripotent stem cells are uniquely positioned for regenerative medicine, but their clinical potential can only be realized if their tumorigenic tendencies are decoupled from their pluripotent properties. Deploying small molecules to remove remnant undifferentiated pluripotent cells, which would otherwise transform into teratomas and teratomacarcinomas, offers several advantages over non-pharmacological methods. Dioxonapthoimidazolium YM155, a survivin suppressant, induced selective and potent cell death of undifferentiated stem cells. Herein, the structural requirements for stemotoxicity were investigated and found to be closely aligned with those essential for cytotoxicity in malignant cells. There was a critical reliance on the quinone and imidazolium moieties but a lesser dependence on ring substituents, which served mainly to fine-tune activity. Several potent analogues were identified which, like YM155, suppressed survivin and decreased SOX2 in stem cells. The decrease in SOX2 would cause an imbalance in pluripotent factors that could potentially prompt cells to differentiate and hence decrease the risk of aberrant teratoma formation. As phosphorylation of the NF-κB p50 subunit was also suppressed, the crosstalk between phospho-p50, SOX2, and survivin could implicate a causal role for NF-κB signaling in mediating the stem cell clearing properties of dioxonaphthoimidazoliums., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Annulin B, isolated from the marine hydroid isolated from Garveia annulata, is a potent inhibitor of the tryptophan catabolizing enzyme indoleamine-2,3-dioxygenase (IDO). A synthesis of the reported pyranonaphthoquinone structure is described, in which the key step is a regioselective Diels-Alder reaction between a pyranobenzoquinone dienophile and a silyl ketene acetal diene.

A simple and effective synthesis of spinochrome D (1) (2,3,5,6,8-pentahydroxy-1,4-naphthoquinone), a pigment of different sea urchin species, has been developed starting from 2,3-dichloro-5,8-dihydroxy-1,4-naphthoquinone (13), easily available by cycloacylation of 1,4-dimethoxybenzene (11) with dichloromaleic anhydride (12). Bromination of 13 with either bromine or dioxane dibromide to 6-bromo-2,3-dichloro-5,8-dihydroxy-1,4-naphthoquinone (21), followed by nucleophilic substitution of the halogen atoms by methoxy groups in 21 and hydrolysis of trimethyl ether 10 produce the target compound in overall yield from 62 to 65%.

Previously, we presented the chemical design of a promising series of antimalarial agents, 3-[substituted-benzyl]-menadiones, with potent in vitro and in vivo activities. Ongoing studies on the mode of action of antimalarial 3-[substituted-benzyl]-menadiones revealed that these agents disturb the redox balance of the parasitized erythrocyte by acting as redox cyclers-a strategy that is broadly recognized for the development of new antimalarial agents. Here we report a detailed parasitological characterization of the in vitro activity profile of the lead compound 3-[4-(trifluoromethyl)benzyl]-menadione 1c (henceforth called plasmodione) against intraerythrocytic stages of the human malaria parasite Plasmodium falciparum We show that plasmodione acts rapidly against asexual blood stages, thereby disrupting the clinically relevant intraerythrocytic life cycle of the parasite, and furthermore has potent activity against early gametocytes. The lead's antiplasmodial activity was unaffected by the most common mechanisms of resistance to clinically used antimalarials. Moreover, plasmodione has a low potential to induce drug resistance and a high killing speed, as observed by culturing parasites under continuous drug pressure. Drug interactions with licensed antimalarial drugs were also established using the fixed-ratio isobologram method. Initial toxicological profiling suggests that plasmodione is a safe agent for possible human use. Our studies identify plasmodione as a promising antimalarial lead compound and strongly support the future development of redox-active benzylmenadiones as antimalarial agents., (Copyright © 2016, American Society for Microbiology. All Rights Reserved.)

The first total synthesis of hamigerans D, G, L, and N-Q has been accomplished. A convergent approach was used to build the basic tricarbocyclic ring system bearing a 5-6-6 structure. A sequence of oxidative cleavage, homologation, and ring regeneration provided access to the 5-7-6 skeleton of hamigeran G. Based on the biogenetic hypothesis, elegant and highly efficient biomimetic transformations of hamigeran G into hamigerans D, N-Q, and L were achieved., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Herein we describe the structure-activity relationship of a large library of Mannich bases (MBs) synthesized from 2-hydroxy-1,4-naphthoquinone. In general, the compounds have shown high to moderate activity against the HL-60 (promyelocytic leukaemia) cell line with IC50=1.1-19.2μM. Our results suggest that the nature of the aryl moiety introduced in the structure of MBs by the aldehyde component is crucial to the cytotoxicity, and although the group originated from the primary amine has a lesser influence, aromatic ones were found to suppress the activity. Thus, MBs derived from salicylaldehydes or 2-pyridinecarboxaldehyde and aliphatic amines are the most active compounds. A satisfactory correlation of the EpIIc versus IC50 (μM) in dimethylsulfoxide was observed. The most cytotoxic MBs (Series a-c, derived from salicylaldehydes) showed the least negative EpIIc values. Noteworthy, however, Series d (derived from 2-pyridinecarboxaldehyde) did not follow this correlation. They exhibited both the lowest IC50 and the most negative EpIIc values, thus suggesting that other factors also influence the cytotoxicity of the MBs, such as lipophilicity, electronic distribution and hydrogen bonding., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

DMAKO-05((S)-1-((5E,8E)-5,8-bis(hydroxyimino)-1,4-dimethoxy-5,8-dihydronaphthalen-2-yl)-4-methylpent-3-enyl 3-methylbutanoate) is a novel oxime derivative of shikonin, the major component extracted from Chinese herb Lithospermun erythrorhizon. Here, we report that DMAKO-05 had an antitumor activity against mouse melanoma cell line B16F0. Our studies indicated that DMAKO-05 not only inhibited B16F0 proliferation and migration but also led to cell cycle arrest at G1 phase and cell apoptosis, in which DMAKO-05 triggered mitochondrial-mediated apoptosis signal including caspase-9/3 and PARP. In response to DMAKO-05 treatment, the Akt-mediated survival signals were remarkably attenuated in B16F0 cells. Collectively, DMAKO-05 has a strong cytotoxicity in B16F0 cells via inhibiting Akt activation, inducing G1 arrest, and promoting B16F0 cell apoptosis. DMAKO-05 might serve as a potential candidate lead compound for melanoma., (© 2016 John Wiley & Sons A/S.)

The mechanisms of disorders in cell functions induced by 1,4-naphthoquinone amide derivatives are not clarified yet. The article is dedicated to the study of features of these substances influence on loach Misgurnus fossilis L. embryos pro/antioxidant homeostasis during early embryogenesis. The aim of this work was to study the effect of 2-chloro-3-hydroxy-1,4-naphthoquinone, 2-chloro-3-(3-oxo-3-(piperidine-1-yl)propylamine)-1,4-naphthoquinone (FO-1), 2-chloro-3-(3-(morpholine-4-yl)-3-oxopropylamine)-1,4-naphthoquinone (FO-2 at concentrations of 10-3, 10-5, 10-7 M on the content of TBA-reactive substances (a byproduct of lipid peroxidation) and the activities of superoxide dismutase and catalase in loach embryos. It was established that 1,4-naphthoquinone amide derivatives and 2-chloro-3-hydroxy-1,4-naphthoquinone decreased the content of lipid peroxidation products in embryo cells in a dose-dependent manner. The investigated compounds cause an increase in superoxide dismutase and catalase activities compared with the control value. The results of the two-factor ANOVA test indicate that 2-chloro-3-hydroxy-1,4-naphthoquinone and 1,4-naphthoquinone amide derivatives (FO-1, FO-2) have predominant influence on the TBA-reactive substances content and superoxide dismutase activity. However, the time of loach embryos development has a more pronounced effect on catalase activity than the studied 1,4-naphthoquinone derivatives.

A mild, catalytic method for the synthesis of 3,4-dihydro-2H-pyrans is described. The FeCl3-catalyzed transformation of aryl- and alkyl β-diketones enables synthetic access to functionalized pyran core structures incorporated in many natural products and biologically active target structures. The method represents a mild alternative to currently available reaction protocols relying on stoichiometric reagents and harsh reaction conditions. This FeCl3-catalyzed transformation has enabled the selective synthesis of α-lapachone in two synthetic transformations and subsequently β-lapachone in three synthetic transformations, which is currently undergoing clinical trials as a potent anticancer agent.

A new strategy featuring an iridium-catalyzed asymmetric hydrogenation of a racemic ketone via dynamic kinetic resolution to generate a cyclopentanol with three contiguous stereocenters and a SmI2-promoted pinacol coupling to install the six-membered ring with correct stereochemistry has been described for the enantioselective total synthesis of (-)-hamigeran B (19 steps, 10.6% overall yield) and (-)-4-bromohamigeran B (19 steps, 12.3% overall yield).

2-Methyl-3-[1-(N,N-dimethylamino)diazen-1-ium-1,2-diol-2-ato-methyl]-naphthalene-1,4-dione 1 (HyPR-1), a small molecule containing a superoxide generator strategically linked to a diazeniumdiolate-based nitric oxide donor, is reported. Evidence for HyPR-1's ability to generate peroxynitrite in the presence of an enzyme as well as enhance peroxynitrite within cells is provided. The utility of this tool in generating peroxynitrite for cellular studies is demonstrated.

We report a Rh-catalyzed enantioselective cycloisomerization of α,ω-heptadienes to afford cyclohexenes bearing quaternary carbon centers. Rhodium(I) and a new SDP ligand promote chemoselective formation of a cyclohex-3-enecarbaldehyde motif that is inaccessible by the Diels-Alder cycloaddition. Various α,α-bisallylaldehydes rearrange to generate six-membered rings by a mechanism triggered by aldehyde C-H bond activation. Mechanistic studies suggest a pathway involving regioselective carbometalation and endocyclic β-hydride elimination.

A new series of ortho-naphthoquinone analogs of β-lapachone were designed, synthesized and evaluated. The biological results indicated that most of our compounds were efficient substrates for NQO1. The new scaffold with water-soluble side chain resulted in greater solubility under acidic condition compared to β-lapachone. Thus avoiding the use of hydroxylpropyl β-cyclodextrin which would finally cause the rapid drug clearance from the blood and dose-limiting toxicity in the form of hemolytic anemia. The most soluble and promising compound in this series was 2-((4-benzylpiperazin-1-yl)methyl)naphtho[2,1-d]oxazole-4,5-dione (3k), which inhibited cancer cell (NQO1-rich A549 cell line) growth at IC50 values of 4.6±1.0μmol·L(-1). Furthermore, compound 3k had in vivo antitumor activity in an A549 tumor xenografts mouse model comparable to the activity obtained with β-lapachone. The results indicated that these ortho-naphthoquinones could serve as promising leads for further optimization as novel substrates for NQO1., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Excellent stereoselective (up to ≤96 : 4 Z/E ratio) construction of pharmaceutically interesting functionalized pyrano[3,2-c]chromenes, pyranonaphthoquinones and related pyrano-fused heterocycles has been achieved in good to high yields (72-89%) through a domino Michael/hydroalkoxylation reaction involving several enolizable cyclic β-keto esters/1,3-dicarbonyls and α-arylacetylenyl-β-nitrostyrenes as binucleophiles in EtOH at room temperature using DABCO as an organocatalyst. Moreover, syn-2-benzyl-4-aryl-3,4-dihydropyrano[3,2-c]chromenes were obtained in high yields (81-86%) via a stereoselective denitrohydrogenation of the corresponding 2-benzylidene-3,4-dihydropyrano[3,2-c]chromenes using a catalytic amount of 10% Pd/C.

Biflorin 1 is a biologically active quinone, isolated from Capraria biflora. Five new biflorin-based nitrogen derivatives were synthesized, of which two were mixtures of (E)- and (Z)- isomers: (Z)-2a, (Z)-2b, (Z)-3a, (Z)- and (E)-3b, (Z)- and (E)-3c. The antibacterial activity was investigated using the microdilution method for determining the minimum inhibitory concentration (MIC) against six bacterial strains. Tests have shown that these derivatives have potential against all bacterial strains. The cytotoxic activity was also evaluated against three strains of cancer cells, but none of the derivatives showed activity., (Copyright © 2015. Published by Elsevier Ltd.)

Naphtho[1',2':4,5]imidazo[1,2-a]pyridine-5,6-diones (NPDOs), a new type of N-heterocycle-fused o-quinones, have been synthesized. They have been found to be efficient electron-accepting substrates of NADPH-dependent single-electron-transferring P-450R and two-electron transferring NQO1, generating reactive oxygen species (ROS) with a concomitant decrease in NADPH, which is consistent with redox-cycling. The reactivity of NPDOs toward P-450R (in terms of kcat/Km) varied in the range of 10(6)-10(7)M(-1)s(-1), while their reduction by NQO1 proceeded much faster, approaching the diffusion control limit (kcat/Km∼10(8)-10(9)M(-1)s(-1)). NPDOs exhibited relatively high cytotoxic activity against human lung carcinoma (A-549) and breast tumor (MCF-7) cell lines (LC50=0.1-8.3μM), while promyelocytic leukemia cells (HL-60) were less sensitive to NPDOs (LC50⩾10μM). 3-Nitro-substituted NPDO (11) revealed the highest potency against both A-549 and MCF-7 cell lines, with LC50 of 0.12±0.03μM and 0.28±0.08μM, respectively. Dicoumarol partly suppressed the activity of the compounds against A-594 and MCF-7 cell lines, suggesting that their cytotoxic action might be partially influenced by NQO1-mediated bioreductive activation., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Juglone 1 an plumbagin 2 are plant secondary metabolites nowadays well known for their anticancer properties. In this study we synthesized analogues of 1 and 2 deriving from the functionalization of the OH group in position 5 with different side chains in form of esters and ethers. Therefore the growth inhibitory activities of these adducts were evaluated in vitro on six cancer cell lines using the MTT colorimetric assays along with the two natural parent compounds. The data revealed that these latter displayed the strongest growth inhibitory activities in vitro. Quantitative videomicroscopy analyses were then carried out on human U373 glioblastoma cells, which are characterized by various level of resistance to pro-apoptotic stimuli. We compared the naturally occurring reference compounds 1 and 2 with the derivatives exerting the best activities in terms of IC50 growth inhibitory values. These analyses showed that both juglone and plumbagin had a cytostatic effect on U373 cells and were able to overcome the intrinsic resistance of U373 cancer cells to pro-apoptotic stimuli., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

The ubiquitin proteasome pathway is crucial in regulating many processes in the cell. Modulation of proteasome activities has emerged as a powerful strategy for potential therapies against much important pathologies. In particular, specific inhibitors may represent a useful tool for the treatment of tumors. Here, we report studies of a new series of peptide-based analogues bearing a naphthoquinone pharmacophoric unit at the C-terminal position. Some derivatives showed inhibition in the µM range of the post-acidic-like and chymotrypsin-like active sites of the proteasome.

Even though β-lapachone is a promising compound with antitumor, antiinflammatory, antineoplastic, and wound-healing effects, there are still issues concerning its chemical stability and degradation mechanisms. The objective of this study was to obtain degradation profiles of β-lapachone and evaluate its chemical stability under various stress conditions. Moreover, the correlation between stability and efficacy was evaluated. The degradation study of β-lapachone was performed using heat, acid, base, oxidation, and light conditions. Kinetics and degradation profiles were investigated with HPLC and LC-MS. The stability indicated in the LC method was validated according to the International Conference on Harmonization guidelines. Human dermal fibroblast (HDF) cells were cultured with the standard and its degraded samples in the cellular activity and cytotoxicity test. β-Lapachone was relatively unstable upon exposure to light, and its photodegradation was accelerated with high relative humidity. Three degradants were identified, and their degradation followed zero-order kinetics. It was shown to degrade to phthalic acid under oxidative conditions, and the degradation kinetics were dependent on the concentration of hydrogen peroxide. Two degradation products were identified upon exposure to basic conditions, which followed first-order kinetics. β-Lapachone was relatively stable under acidic and thermal conditions. It increased the synthesis of collagen compared with the control. However, as the contents decreased, the synthesis of collagen also decreased in the photodegraded samples. β-Lapachone did not exert cytotoxic effects at the effective concentration in the cytotoxicity test. Therefore, in order to ensure efficacy and safety, the chemical stability of β-lapachone needs to be controlled carefully while considering instability mechanisms.