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A series of new fluorinated dihydrofurano-napthoquinone compounds were sucessfully synthesized in good yields using microwave-assisted multi-component reactions of 2-hydroxy-1,4-naphthoquinone, fluorinated aromatic aldehydes, and pyridinium bromide. The products were fully characterized using spectroscopic techniques and evaluated for their anti-inflammatory activity using lipopolysaccharide (LPS)-stimulated RAW264.7 macrophage cells. Among 12 new compounds, compounds 8b, 8d, and 8e showed high potent NO inhibitory activity in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophage cells with IC 50 values ranging from 1.54 to 3.92 µM. The levels of pro-inflammatory cytokines IL-1β and IL-6 in LPS-stimulated RAW264.7 macrophages were remarkably decreased after the application of 8b, 8d, 8e and 8k. Molecular docking simulations revealed structure-activity relationships of 8b, 8d, and 8e toward NO synthase, cyclooxygenase (COX-2 over COX-1), and prostaglandin E synthase-1 (mPGES-1). Further physicochemical and pharmacokinetic computations also demonstrated the drug-like characteristics of synthesized compounds. These findings demonstrated the importance of fluorinated dihydrofurano-napthoquinone moieties in the development of potential anti-inflammatory agents., 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 © 2024 Elsevier Ltd. All rights reserved.)

In this study, a series of novel shikonin N-benzyl matrinic acid ester derivatives (PMMB-299-PMMB-310) were synthesized and tested for their ability to inhibit the proliferation of cancer cells. Compared with shikonin and matrine, some of the ester derivatives were found to exhibit better anti-proliferative activity against seven different cancer cell lines, with less cytotoxicity toward non-cancerous cells. The strongest anti-proliferative activity was exhibited by PMMB-302, which had an IC 50 value of 2.71 μM against A549 cells. The compound caused cell cycle arrest in the G2/M phase and induced apoptosis. Effects on the expression of apoptosis-related molecules such as Bcl2, Bcl-XL, caspase-3, caspase-9 and FADD suggested that PMMB-302 has tumor suppressive roles in lung cancer cells. In addition, PMMB-302 inhibited expression of telomerase core proteins, dyskerin and NHP2, and telomerase reverse transcriptase RNA. Moreover, molecular docking of PMMB-302 was subsequently conducted to determine the probable binding mode with telomerase. Taken together, the results indicate that PMMB-302 acts as a tumor suppressor in lung cancer cells by negatively regulating telomerase expression., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

We synthesized ten enamine naphthoquinones with yields ranging from 43 to 76%. These compounds were screened for their in vitro antiproliferative activities by MTT assay against four types of human cancer cell lines: HCT116, PC3, HL60 and SNB19. The naphthoquinones bearing the picolylamine (7) and quinoline (12) moieties were the most actives (IC 50  < 24 μM for all the cell lines), which were comparable or better to the values obtained for the control drugs. In silico evaluations allowed us to develop a qualitative Structure-Activity Relationship which suggest that electrostatic features, particularly the C 2 -C 3 internuclear repulsion and the molecular dipole moment, relate to the biological response. Furthermore, Molecular Docking simulations indicate that the synthetic compounds have the potential to act as anticancer molecules by inhibiting topoisomerase-II and thymidylate synthase., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Two series of (hetero)arylamino-naphthoquinones and benzo-fused carbazolequinones were considered for study with the rationale that related structural motifs are present in numerous drugs, clinical trial agents, natural products and hTopoIIα inhibitors. Total 42 compounds were synthesized by reactions including dehydrogenative CN and Pd-catalyzed CC bond forming transformations. These compounds were screened against numerous cancer cells including highly metastatic one (MCF-7, MDA-MB-231, H-357 and HEK293T), and normal cells (MCF 10A). Some of the active compounds were evaluated for clonogenic cell survival and apoptotic effects in cancer cells (DAPI nuclear staining, Comet assay, Annexin-V-FITC/PI dual staining, flow cytometry, and western blot analysis with relevant proteins). All compounds were tested for hTopoIIα inhibitory activity. The investigated series compounds showed important properties like significant apoptotic antiproliferation in cancer cells with cell cycle arrest at S-phase and downregulation of NF- κβ signaling cascade, relatively less cytotoxicity to normal cells, and hTopoIIα inhibition with more efficiency compared to an anticancer drug etoposide., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

A series of 1,4-naphthoquinone derivatives of lawsone (1), 6-hydroxy-1,4-naphthoquinone (2), and juglone (3) were synthesized by alkylation, acylation, and sulfonylation reactions. The yields of lawsone derivatives 1a-1k (type A), 6-hydroxy-1,4-naphthoquinone derivatives 2a-2j (type B), and juglone derivatives 3a-3h (type C) were 52-99%, 53-96%, and 28-95%, respectively. All compounds were tested in vitro for the cytotoxicity against human oral epidermoid carcinoma (KB) and cervix epithelioid carcinoma (HeLa) cells and their structure-activity relationship was studied. Compound 3c was found to be most potent in KB cell line (IC 50  = 1.39 µM). Some compounds were evaluated for DNA topoisomerase I inhibition. Compounds 2c, 3, 3a, and 3d showed topoisomerase inhibition activity with IC 50 values of 8.3-91 µM. Standard redox potentials (E°) of all naphthoquinones in phosphate buffer at pH 7.2 were examined by means of cyclic voltammetry. A definite correlation has been found between the redox potentials and inhibitory effects of type A compounds., (Copyright © 2021 Elsevier Ltd. 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.)

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.)

In continuation with the previous work, a series of 5-hydroxy-2-amidomethoxy-1,4-naphthoquinones were prepared to establish the structure-activity relationship studies toward anticancer activity (IC 50 in µM) against three cell lines; colo205 (colon adenocarcinoma), T47D (breast ductal carcinoma) and K562 (chronic myelogenous leukemia). Among the synthesized compounds, naphthoquinone amines, 5 (0.8; 0.6; 0.8), 14 (0.8; 0.6; 0.5) and the amine precursor, 4 (1.3; 0.3; 1.0) displayed potent anticancer activities. A tumor targeting drug delivery system was achieved by synthesizing the conjugate 6 (1.4; 0.5; 1.1) of naphthoquinone-amine 5 and Biotin which also proved its potency. Finally, to introduce polyamine conjugate, spermidine was attached with 2-amidomethoxy-1,4-naphthoquinone. The naphthoquinone-spermidine conjugate 27 (1.2; 1.7; 1.7) also retained the activity. Thus, potent naphthoquinone amines were explored and Biotin/polyamine conjugate was developed as tumor targeting drug delivery system., (Copyright © 2020. Published by Elsevier Ltd.)

Breast cancer is the most incident and mortal cancer type in women, with an estimated 2 million new cases expected by 2020 worldwide, with 600,000 deaths. As not all breast cancer types respond to the anti-hormonal therapy, the development of new antineoplastic drugs is necessary. Lawsone (2-hydroxy-1,4-naphtoquinone) is a natural bioactive naphtoquinone displaying a range of activities, with dozens of derivatives described in the literature, including some glycosides possessing antitumor activity. Here, a series of glycosides of lawsone are reported for the first time and all compounds displayed good activity against the SKBR-3 cell line, with IC 50 below 10 µM. The most promising derivative was the glycosyl triazole derived from peracetylated d-glucose (11), which showed better cytotoxicity against SKBR-3 (IC 50  = 0.78 µM), being the most selective toward this tumoral cell (SI > 20). All compounds described in this work were more active than lawsone, indicating the importance of the carbohydrate and glycosyl triazole moiety for activity., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

A series of novel, substituted 2-chloro-3-[(thiazol-2-yl)amino]-1,4-naphthoquinones have been prepared and shown to exhibit promising concentration-dependent activity against human SH-SY5Y cells, Plasmodium falciparum, Mycobacterium tuberculosis and P. aeruginosa. Substituent effects on observed bioactivity have been explored; the para-fluorophenyl derivative 3d exhibited activity across the range of the bioassays employed, indicating the potential of the 2-chloro-3-[(4-arylthiazol-2-yl)amino]-1,4-naphthoquinone scaffold in the development of novel, broad spectrum therapeutics., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

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 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.)

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.)

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.)

A series of naphthoimidazoles derivatives (3a-3f) were tested for potential anti-inflammatory activity on lipopolysaccharide (LPS)-treated macrophages. Naphthoimidazole 3e exhibited significant inhibitory effects on nitric oxide (NO) production (IC50 <10μM) and decreased the expression of nitric oxide synthase-2 (NOS-2) and cycloxygenase-2 (COX-2) enzymes. It also inhibited the activation of transcription factor NF-κB. Naphthoimidazole 3e might represent a starting point for the synthesis of new anti-inflammatory naphthoimidazoles derivatives., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

1,4-Dihydroxy-2-naphthoic acid was used as a substrate for a straightforward five-step synthesis of 3-substituted 1H-benzo[g]isochromene-5,10-diones, with a Michael addition of N-acylmethylpyridinium ylides across 2-hydroxymethyl-1,4-naphthoquinone and a subsequent acid-mediated dehydratation of intermediate hemiacetals as the key steps. The obtained benzo[g]isochromene-5,10-diones were subsequently deployed for further synthetic elaboration to produce new 3,4-dihydrobenzo[g]isochromene-5,10-diones and (3,4-dihydro-)4a,10a-epoxybenzo[g]isochromene-5,10-diones. All compounds were screened for their cytotoxic and antimicrobial effects, revealing an interesting cytotoxic activity of 1H-benzo[g]isochromene-5,10-diones against different cancer cell lines., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Natural product (±)-dunnione (2) and its ortho-quinone analogues (3-8) were synthesized and found to be substrates for NQO1. The structure-activity relationship study revealed that the biological activity was favored by the presence of methyl group at the C ring and methoxy group at the A ring. The docking studies supported the rationalization of the metabolic studies. Deeper location in the active site of NQO1, interactions with hydrophobic pocket and C-H…π interactions with the adjacent Phe178 residue contributed to the better catalytic efficiency and specificity to NQO1. Cytotoxicity studies and determination of superoxide (O2(-)) production in the presence and absence of the NOQ1 inhibitor dicoumarol confirmed that the ortho-quinones exerted their antitumor activity through NQO1-mediated ROS production by redox cycling., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

A set of forty alkannin and shikonin oxime derivatives were firstly designed and synthesized. Their cytotoxicities against three kinds of tumor cells and a normal cell line were tested and compared with alkannin and shikonin. The cell-based investigation demonstrated that some oxime derivatives were more or comparatively effective to the lead compounds, especially their selective and excellent antitumor activities towards K562 cells with no toxicity in normal cells. We may conclude that oximate modification to the mother nucleus of alkannin and shikonin is an available approach to acquire potent antitumor agents., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

We have synthesized, structurally characterized and examined cytotoxicity of novel plumbagin hydrazones against estrogen and progesterone receptor positive (ER+/PR+) MCF-7 and triple negative MDA-MB-231 breast cancer cell lines in order to evaluate the potential of these novel phytochemical analogs. Compounds were docked into the protein cavity of p50-subunit of NF-κB protein revealing better fit and better binding energies than the parent plumbagin compound. This was also reflected in their superior cytotoxicities which were found to be mediated by inhibition of NF-κB expression. These compounds can provide a starting point for the development of novel drug molecules against triple negative breast cancers., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

The pyranonaphthoquinone (PNQ) lactone natural products, including 7-deoxykalafungin, have been reported to be potent and selective covalent inhibitors of AKT kinase. In this work we seek to identify structural features of the natural product scaffold that are essential for potency and selectivity. Using a deconstruction approach, we designed and prepared simplified analogues of 7-deoxykalafungin. Testing of the compounds for their ability to inhibit AKT and the closely related kinase PKA revealed that the 3,6-dihydro-2H-pyran ring of the PNQ lactones is required for potent and selective inhibition of AKT. We have also unexpectedly identified a new submicromolar inhibitor of PKA., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Concise syntheses of two Leucetta-derived naphthimidazole alkaloids, kealiiquinone and 2-deoxy-2-aminokealiiquinone, are described based on a biosynthetic-guided hypothesis. Advanced intermediates containing the full naphthimidazole framework are constructed through Friedel-Crafts chemistry followed by oxidation of the electron rich C-ring with hydrogen peroxide. The cytotoxicity of these alkaloids in a breast cancer cell line along with several closely related marine-derived natural products kealiinines A-C and analogs are reported., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

1,4-Naphthoquinone derivatives are known to have relevant activities against several parasites. Among the treatment options for malaria, atovaquone, a 1,4-naphthoquinone derivative, is widely applied in the treatment and prophylaxis of such disease. Based on the structure simplification of atovaquone, we designed and synthesized four novel naphthoquinoidal derivatives. The compounds were obtained by the underexplored epoxide-opening reaction of 1,4-naphthoquinone using aniline derivatives as nucleophiles. The antiplasmodial activity of the synthesized compounds was performed in vivo using Peter's 4days suppression test. Significant parasitemia reduction and increased survival were observed for some of the compounds., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

A series of naphthoquinone derivatives has been synthesized and tested for its biological activity against human African trypanosomiasis. The use of reverse micellar medium not only enhanced the conversion rate, but also showed selectivity towards mono-coupled product in aryl chloride-aniline coupling reactions. Two derivatives of naphthoquinone (9b and 9c) exhibited potent activity against Trypanosoma brucei in vitro with low cytotoxicity., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

4H-Pyrano-[2,3-b]naphthoquinone is a structural motif commonly found in natural products manifesting anticancer activities. As part of a program aimed at structural simplification of bioactive natural products utilizing multicomponent synthetic processes, we developed a compound library based on this heterocyclic scaffold. We found that several library members displayed low micromolar antiproliferative activity and induced apoptosis in human cancer cells. Selected compounds showed promising activity against cancer cell lines resistant to proapoptotic stimuli, demonstrating their potential in treating cancers with dismal prognoses., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Here we report a series of 2-aryl-3-amino-1,4-naphthoquinones that generated reactive oxygen species (ROS) such as superoxide and hydrogen peroxide upon incubation in pH 7.4 under ambient aerobic conditions. ROS generation from these compounds was sensitive to structural modifications at the 3-amino position and a 2-aryl substituent promoted ROS generation. A number of these compounds were found to induce DNA damage in the presence of Cu(II) without any added reducing agent. Our data suggests that 2-aryl-3-amino-1,4-naphthoquinones' propensity to produce ROS correlated well with its DNA damage inducing ability. 2-Phenyl-3-pyrrolid-1-yl-1,4-naphthoquinone (22) was found to damage DNA at 1 μM suggesting that these compounds may have therapeutic relevance in targeting cancers which over-express Cu(II)., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Fourteen naphthoquinone derivatives (1-14) were designed based on a putative proteasome inhibitor PI-083. These compounds were synthesized and evaluated against A549, DU145, KB, and KBvin tumor cell lines. Six compounds (2, 4, 8, 9, 10, and 13) showed antiproliferative activities comparable to that of PI-083. Among them, compound 8 was confirmed as a 20S proteasome inhibitor in both in vitro and cell-based assays. These findings endorse further optimization efforts based on this structural phenotype to develop potential anticancer drug candidates., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

The N-acetyl glucosaminosides of shikonin/alkannin were synthesized by chemical glycosylation, which provided an ideal approach to resolve the mixture of enantiomeric shikonin and alkannin co-existed in the Chinese herbs. The glycosylated shikonin and alkannin exhibited stronger binding activity to human telomeric G-quadruplex DNA than their parent structures. This research indicated that glycosylation of natural product with amino sugars is an effective strategy to improve their DNA-binding affinity., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

A series of azanaphthoquinone pyrrolo-annelated derivatives attached to basic side chains have been synthesized. The antiproliferative activities of all compounds were evaluated on at least four different cell lines. The effects on cell cycle and intercalation were investigated., (2010 Elsevier Ltd. All rights reserved.)

We report here a simple entry into naphtho[2,3-d]isoxazole-4,9-dione system containing a EWG in position 3 using the readily available 2,3-dichloro-1,4-naphthoquinone and nitromethyl derivatives in the presence of base. Antifungal activity of synthesised naphthoquinones was evaluated against ATCC and PYCC reference strains of Candida. The results suggest that the naphtho[2,3-d]isoxazole-4,9-dione scaffold has the potential to be developed into novel and safe therapeutic antifungal agents., (Copyright 2009 Elsevier Ltd. All rights reserved.)

2-Piperazinyl naphthoquinones (2) and 2-piperidinyl naphthoquinones (3) were designed and synthesized as new cytotoxic and apoptosis inducing agents by utilizing the anti-parasite drug atovaquone as lead compound. Several compounds displayed significantly improved cytotoxic activities against a panel of cancer cell lines than that of atovaquone. These compounds also induced apoptosis through activating pro-apoptotic caspases 9 and 3.

A series of shikonin analogues with side chain variants have been synthesized and evaluated for antitumor activity. These novel analogues show a broad spectrum of in vitro cytotoxicity against various cancer cell lines. Additionally, some analogues were also found to have the ability to decrease the expression level of HIF-1alpha in breast cancer cells MDA-MB-231 under hypoxia. The features of these analogues suggest their potential in cancer therapy.

Ozonolysis of lapachol (1), resulting in an unusual formation of a potent antitumor agent 2-acetylfuranonaphthoquinone (3) along with the expected aldehyde 6, is described. The reaction of lapachol (1) with CAN in dry acetonitrile leading to biologically active furanonaphthoquinones is also reported. The antitumoral activity of the tested compounds on human DU-145 prostate carcinoma cells was evaluated following XTT assay. The results revealed that 2-(1-methylethenyl)-2,3-dihydronaphtho[2,3-b]furan-4,9-dione (5), beta-lapachone (10) and dehydro-beta-lapachone diacetate (11) showed 100% inhibition at 25 microg/ml. All the tested samples showed dose-dependent activity.

FlexX-based molecular docking study was employed to identify 2-hydroxy-1,4-naphthoquinone as a new 'acidic head group' for the design of a novel series of PPARgamma ligands. To provide the proof of concept, designed molecules were synthesized and evaluated in a standard radioligand-binding assay. Out of eight molecules, four were found to bind to the murine PPARgamma with IC(50) ranging from 0.2 to 56.2 microM as compared to standard pioglitazone, with IC(50) of 0.7 microM.

Taking advantage of the structural features of natural products showing anti-trypanosomatid activity, we designed and synthesized a small library of 2-phenoxy-1,4-naphthoquinone and 2-phenoxy-1,4-anthraquinone derivatives. The library was obtained following a parallel approach and using readily available synthons. All the derivatives showed inhibitory activity toward either Trypanosoma or Leishmania species, with 8, 10, and 16 being the most active compounds against Trypanosoma brucei rhodesiense, Leishmania donovani, and Trypanosoma cruzi cells (IC(50)=50nM, IC(50)=0.28microM, and IC(50)=1.26microM, respectively).

Stereoselective synthesis of 1, one of biologically active naphthoquinones from a Brazilian traditional medicine Tabebuia avellanedae, was achieved by utilizing Noyori reduction as a key step. Compound 1 displayed potent cytotoxicity against several human tumor cell lines, whereas it showed lower cytotoxicity against some human normal cell lines compared with that of mitomycin. On the other hand, its enantiomer was less active toward the tumor cell lines than 1.

Two series of azanaphthoquinone annelated pyrrolo oximes have been synthesized. The antiproliferative activities of 10 compounds were evaluated on at least four different cell lines. One series of pyrrolo derivatives showed high cytotoxic activity. The effects on cell cycle and caspase activity were investigated. Compounds 9a and 9b showed an accumulation of cells in G2/M phase. Substantial and dose-dependent caspase activity was found after treatment of cells with 9a and 9b. This indicates an apoptosis inducing property of these compounds.

A series of 3-substituted-1,4-dioxo-1,4-dihydronaphthalen-2-yl-thio-alkanoate derivatives 3-21 and naphtho[2,3-b][1,4]-thiazine-5,10-diones 24 were synthesized and evaluated for their antibacterial and antifungal activities. The structure-activity relationships of these compounds were studied and the results show that the compound 24a exhibited better antibacterial activity than Gentamycin in vitro against Staphylococcus aureus. In addition 24a also imparted marked antifungal activity in vitro against Cryptococcus neoformans, Sporothrix schenckii, and Trichophyton mentagraphytes when compared with Fluconazole. Compounds 15, 18, 19, and 21 also exhibited significant antibacterial activity in vitro against S. aureus.

A series of dinaphtho[1,2-b;2',3'-d]furan-7,12-dione derivatives were synthesized and evaluated for inhibitory activities against receptor tyrosine kinases. The naphthofuroquinone compounds with dialkylaminoethoxy group at C(5)-position (7, 8, 10, and 11) manifested strong inhibitory activities against epidermal growth factor receptor and vascular endothelial growth factor receptor. Docking study of 11 with EGFR was also performed.

A series of (S)-N-(1,4-naphthoquinon-2-yl)-alpha-amino acid methyl esters 3-9, 2-N,N-dialkylamino-1,4-naphthoquinones 10-11 and 2-hydroxy-3-(2'-mercaptoimidazolyl)-1,4-naphthoquinones and their cyclic analogs 12-15 were synthesized and evaluated for antifungal and antibacterial activities. The structure-activity relationships of these compounds were studied and the results show that the compounds 9b and 13c exhibited in vitro antifungal activity against Candida albicans, Cryptococcus neoformans, and Sporothrix schenckii, whereas compound 6a showed in vitro antibacterial activity against Streptococcus faecalis, K. pneumoniae, Escherichia coli, and Staphylococcus aureus.

A series of 1,4-naphthoquinone derivatives were synthesized and evaluated for antibacterial and antiviral activities. The structure-activity relationships of these compounds were also studied. The results suggest that compounds 9-22 showed in vitro marked antibacterial activity. Compounds 4c and 7a showed inhibitory effect against RNA dependent RNA polymerase induced poliovirus type 2 infected HeLa cells.

Anti-glycation activity of our anti-oxidant quinone library was measured and several 2,3-dimethoxy-5-methyl-1,4-benzoquinones and 2-methyl-1,4-naphthoquinones were identified as novel inhibitors of glycation, of which 2,3-dimethoxy-5-methyl-1,4-benzoquinones 13b is the most potent glycation inhibitor with around 50 microM of the IC(50) value.

A synthetic benz[f]indole-4,9-dione analog, 2-amino-3-ethoxycarbonyl-N-methylbenz[f]indole-4,9-dione (SME-6), showed a potent growth inhibition of a panel of human cancer cell lines. The mechanism of action study revealed that the growth inhibitory effect of SME-6 was highly related to the induction of G2/M cell cycle arrest and apoptosis in human lung cancer cells (A549). These data may provide new information for understanding the mechanisms by benz[f]indole-4,9-diones-mediated antitumor activity.

Syntheses and excellent anti-MRSA activities of the mansonone F analogs are reported. In addition, the minimal structural requirements for its anti-MRSA activities as well as its structure-activity relationship including the C3 substituents effects on anti-MRSA activity are also described. In particular, this study revealed that both ortho-quinone and tricyclic systems of mansonone F are essential for anti-MRSA activities.

We report on the fluorinated form of Cpd 5 as a cell growth inhibitor. This compound is 3-fold more potent than the parent Cpd 5 and is predicted, using the semi-empirical AM1 method to be only an arylator of cysteine-containing proteins, without generating reactive oxygen species.

The synthesis and evaluation of some 2-substituted-1,4-naphthoquinones 2, S-(1,4-naphthoquinon-2-yl)-mercaptoalkanoic acid amides 4, related benzoquinone and naphthoquinone derivatives 6-9 and 2,3-disubstituted 1,4-naphthoquinones 10-11 were carried out. The antifungal, antibacterial, antiviral and anticancer activities were determined by using the standard assay. The results show that compounds 2b and 10a showed in vitro antiviral activity against Influenza-A Virus and Herpes Simplex Virus and possess pronounced antifungal profile whereas 4a showed anticancer activities against Lymphoid Leukaemia P 388.

A series of 1,4-naphthoquinone derivatives were synthesized and tested for antifungal and antitumor activity against a number of fungal disease causative species and Walker 256 carcinoma cell lines. The results show that the compounds 8a,e and 11b possess pronounced antifungal profile where as 7b and f were found to be active against Walker 256 carcinoma cell lines. Moreover 7c and 11a showed inhibitory effect against reverse transcriptase enzyme from Rauscher Murine Leukemia Virus.

The elaboration and biological activity of 15, containing the proposed pharmacophore for the antibiotic activity of the pyranonaphthoquinones, are reported. The synthetic strategy involved acid-catalyzed lactonization of mandelate 17 for isochroman ring formation, in combination with a Wittig-oxa-Michael functionalization of isochroman-3-ol derivative 20, a lactonization involving configurational inversion of a benzylic alcohol and a final AgO oxidation. Compound 15 showed activity against Staphylococcus aureus and Bacillus subtilis with MIC of 64 and 32 microg/mL, respectively.

We synthesized DL-shikonin, shikonin, alkanin, and their cyclo-derivatives and acyl-derivatives. These compounds have low cytotoxicity, as well as inhibitory activity against the telomerase enzyme, except cyclo-derivatives.