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1.
Eur J Med Chem ; 62: 98-110, 2013 Apr.
Article in English | MEDLINE | ID: mdl-23353747

ABSTRACT

Naphthoquinones have been found to have a wide range of biological activities, including cytotoxicity to cancer cells. The secondary metabolites lapachol, α- and ß-lapachone and a series of 25 related synthetic 1,4-naphthoquinones were screened against the oesophageal cancer cell line (WHCO1). Most of the compounds exhibited enhanced cytotoxicity (IC50 1.6-11.7 µM) compared to the current drug of choice cisplatin (IC50 = 16.5 µM). This study also established that the two new synthetic halogenated compounds 12a and 16a (IC50 = 3.0 and 7.3 µM) and the previously reported compound 11a (IC50 = 3.9 µM), were non-toxic to NIH3T3 normal fibroblast cells. Cell death of oesophageal cancer cells by processes involving PARP cleavage caused by 11a was shown to be associated with elevated c-Jun levels, suggesting a role for this pathway in the mechanism of action of this cohort of naphthoquinone compounds.


Subject(s)
Antineoplastic Agents/pharmacology , Esophageal Neoplasms/drug therapy , Naphthoquinones/pharmacology , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Death/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Crystallography, X-Ray , Dose-Response Relationship, Drug , Esophageal Neoplasms/pathology , Humans , Mice , Models, Molecular , Molecular Structure , NIH 3T3 Cells , Naphthoquinones/chemical synthesis , Naphthoquinones/chemistry , Structure-Activity Relationship
2.
Bioorg Med Chem ; 20(16): 4995-5000, 2012 Aug 15.
Article in English | MEDLINE | ID: mdl-22795899

ABSTRACT

New oxirane derivatives were synthesized using six naphthoquinones as the starting materials. Our biological results showed that these oxiranes acted as trypanocidal agents against Trypanosoma cruzi with minimal cytotoxicity in the VERO cell line compared to naphthoquinones. In particular, oxirane derivative 14 showed low cytotoxicity in a mammalian cell line and exhibited better activity against epimastigote forms of T.cruzi than the current drug used to treat Chagas disease, benznidazole.


Subject(s)
Ethylene Oxide/pharmacology , Naphthoquinones/chemistry , Naphthoquinones/pharmacology , Trypanocidal Agents/chemistry , Trypanocidal Agents/pharmacology , Trypanosoma cruzi/drug effects , Animals , Cell Death/drug effects , Cell Survival/drug effects , Chlorocebus aethiops , Dose-Response Relationship, Drug , Drug Evaluation, Preclinical , Ethylene Oxide/analogs & derivatives , Ethylene Oxide/chemistry , Models, Molecular , Molecular Structure , Parasitic Sensitivity Tests , Structure-Activity Relationship , Trypanocidal Agents/chemical synthesis , Trypanosoma cruzi/cytology , Trypanosoma cruzi/growth & development , Vero Cells
3.
4.
Curr Microbiol ; 62(2): 684-9, 2011 Feb.
Article in English | MEDLINE | ID: mdl-20882284

ABSTRACT

A broad-spectrum antibiotic therapy has led to medical complications and emergence of multiresistant bacteria including Enterococcus faecalis. In this study, we designed, synthesized, and evaluated the antibacterial activity of 13 nor-ß-lapachone derivatives against a drug resistant E. faecalis strain. Two triazole substituted compounds (1e = 8 µg/ml and 1c = 16 µg/ml) and the non-substituted derivative (1a = 8 µg/ml) were promising compared to chloramphenicol (12 µg/ml), an antibiotic currently available in the market. We also performed a structure-activity relationship analysis using a molecular modeling approach that pointed the low HOMO energy values; HOMO density concentrated on the nor-ß-lapachone ring, lipophilicity, solubility and number HBA as important stereoelectronic features for the antibacterial profile. In addition the triazole compounds presented low theoretical toxicity profile, and drug-score higher than commercial antibiotics also fulfilling the Lipinski "Rule of Five", which pointed them as promising candidates for further studies in infections caused by multiresistant E. faecalis hospital strains.


Subject(s)
Anti-Bacterial Agents/pharmacology , Enterococcus faecalis/drug effects , Naphthoquinones/pharmacology , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/toxicity , Enterococcus faecalis/isolation & purification , Gram-Positive Bacterial Infections/microbiology , Humans , Microbial Sensitivity Tests , Naphthoquinones/chemistry , Naphthoquinones/toxicity , Structure-Activity Relationship
5.
Eur J Med Chem ; 46(1): 399-410, 2011 Jan.
Article in English | MEDLINE | ID: mdl-21115213

ABSTRACT

Thirty two compounds were synthesized in moderate to high yields and showed activity against cancer cells HL-60 (leukemia), MDA-MB435 (melanoma), HCT-8 (colon) and SF295 (central nervous system), with IC(50) below 2 µM for some compounds. The ß-lapachone-based 1,2,3-triazoles showed the best cytoxicity profile and emerge as promising anticancer prototypes. Insights about the reactive oxygen species (ROS) mechanism of anticancer action for some compounds were obtained by addition of 1-bromoheptane that deplete reduced glutathione (GSH) content and by using N-acetylcysteine that protects cells against apoptotic cellular death, as well by analysis of thiobarbituric acid reactive substances (TBARS) formation, and oxidative DNA damage after treatment detected by the comet assay with the bacterial enzymes formamidopyrimidine DNA-glycosylase (FPG) and endonuclease III (ENDOIII).


Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Benzoquinones/chemical synthesis , Benzoquinones/pharmacology , Antineoplastic Agents/chemistry , Apoptosis/drug effects , Benzoquinones/chemistry , Cell Line, Tumor , Cell Survival/drug effects , DNA Breaks/drug effects , Drug Screening Assays, Antitumor , Humans , Inhibitory Concentration 50
6.
Tuberculosis (Edinb) ; 90(5): 293-7, 2010 Sep.
Article in English | MEDLINE | ID: mdl-20663716

ABSTRACT

The increase of incidence of tuberculosis (TB) with resistant strains and HIV co-infection has reinforced the necessity of developing new drugs for its treatment. The reaction of naphthoquinones with aromatic or aliphatic aldehydes in the presence of ammonium acetate led to the synthesis of the three ß-lapachone derivatives (naphthoimidazoles) that were tested in this study. Phenazines were prepared by the reaction of the respective naphtoquinone with o-phenylenediamine in acetic acid under reflux. The antimicrobial activity of the derivatives was evaluated in vitro against Mycobacterium tuberculosis H37Rv (ATCC 27294) and the rifampicin-resistant strain (ATCC 35338) containing a His-526-Tir mutation in the rpoB gene. Using the Resazurin Microtiter Assay (REMA) method, bioactive molecules were observed in the susceptible and resistant strains with MICs ranging from 2.2 µM to 17 µM. The naphthoimidazoles with p-toluyl and indolyl group attached to the imidazole ring were more active against the H37Rv strain (MIC 9.12 µM and 4.2 µM, respectively) than the rifampicin-resistant strain (MIC 8.3 µM and 17 µM, respectively). The phenazine with the allyl-pyran group was most active among the two strains and had an MIC of 2.2 mM. These results show the potential of these molecules as prototypes for future drugs used in treating TB.


Subject(s)
Antitubercular Agents/pharmacology , Drug Resistance, Microbial/drug effects , Mycobacterium tuberculosis/drug effects , Naphthoquinones/pharmacology , Rifampin/pharmacology , Cell Line , Humans , Microbial Sensitivity Tests , Phenazines/pharmacology
7.
J Proteomics ; 73(12): 2306-15, 2010 Nov 10.
Article in English | MEDLINE | ID: mdl-20621210

ABSTRACT

Chagas' disease, caused by the protozoan Trypanosoma cruzi, is endemic in Latin America, which current treatment presents variable efficacy and serious side effects. A previous screening of naphthoquinone derivatives pointed to the naphthoimidazoles N1, N2 and N3 as the most active compounds against T. cruzi. In this study, a proteomic approach was employed to identify proteins involved in the N1, N2 and N3 trypanocidal activity. In epimastigotes, the naphthoimidazoles are involved in multiple mechanisms: (a) redox metabolism; (b) energy production; (c) ergosterol biosynthesis; (d) cytoskeleton assembly; (e) protein metabolism and biosynthesis; and (f) chaperones modulation. They induce an imbalance in crucial pathways of the parasite, leading to the loss of metabolic homeostasis and T. cruzi death.


Subject(s)
Chagas Disease/drug therapy , Imidazoles/therapeutic use , Naphthoquinones/therapeutic use , Trypanocidal Agents/therapeutic use , Trypanosoma cruzi/drug effects , Animals , Down-Regulation , Protozoan Proteins/biosynthesis , Trypanosoma cruzi/metabolism
8.
Bioorg Med Chem ; 18(9): 3224-30, 2010 May 01.
Article in English | MEDLINE | ID: mdl-20378360

ABSTRACT

In continuing our screening program of naphthoquinone activity against Trypanosoma cruzi, the aetiological agent of Chagas' disease, new beta-lapachone-based 1,2,3-triazoles, 3-arylamino-nor-beta-lapachones, 3-alkoxy-nor-beta-lapachones and imidazole anthraquinones were synthesised and evaluated against bloodstream trypomastigote forms of the parasite. Compounds 2,2-dimethyl-3-(2,4-dibromophenylamino)-2,3-dihydro-naphtho[1,2-b]furan-4,5-dione, IC(50)/24h 24.9+/-7.4 and 4-azido-3-bromo-2,2-dimethyl-3,4-dihydro-2H-benzo[h]chromene-5,6-dione with 23.4+/-3.8 microM showed a trypanosomicidal activity higher than benznidazole. These results demonstrate the potential of naphthoquinone derivatives as novel structures for the development of alternative drugs for Chagas' disease.


Subject(s)
Anthraquinones , Antiparasitic Agents , Naphthoquinones , Triazoles , Trypanosoma cruzi/drug effects , Animals , Anthraquinones/chemical synthesis , Anthraquinones/chemistry , Anthraquinones/pharmacology , Antiparasitic Agents/chemical synthesis , Antiparasitic Agents/chemistry , Antiparasitic Agents/pharmacology , Crystallography, X-Ray , Imidazoles/chemical synthesis , Imidazoles/chemistry , Imidazoles/pharmacology , Mice , Molecular Structure , Naphthoquinones/chemical synthesis , Naphthoquinones/chemistry , Naphthoquinones/pharmacology , Parasitic Sensitivity Tests , Quinones/chemical synthesis , Quinones/chemistry , Quinones/pharmacology , Triazoles/chemical synthesis , Triazoles/chemistry , Triazoles/pharmacology
9.
J Med Chem ; 53(1): 504-8, 2010 Jan 14.
Article in English | MEDLINE | ID: mdl-19947600

ABSTRACT

Several 3-arylamino and 3-alkoxy-nor-beta-lapachone derivatives were synthesized in moderate to high yields and found to be highly potent against cancer cells SF295 (central nervous system), HCT8 (colon), MDA-MB435 (melanoma), and HL60 (leukemia), with IC(50) below 2 microM. The arylamino para-nitro and the 2,4-dimethoxy substituted naphthoquinones showed the best cytoxicity profile, while the ortho-nitro and the 2,4-dimethoxy substituted ones were more selective than doxorubicin and similar to the precursor lapachones, thus emerging as promising new lead compounds in anticancer drug development.


Subject(s)
Naphthoquinones/chemical synthesis , Naphthoquinones/pharmacology , Cell Line, Tumor , Cell Proliferation/drug effects , Crystallography, X-Ray , Drug Screening Assays, Antitumor , Humans , Models, Molecular , Molecular Structure , Naphthoquinones/chemistry , Naphthoquinones/toxicity , Stereoisomerism , Structure-Activity Relationship
10.
Free Radic Biol Med ; 47(5): 644-53, 2009 Sep 01.
Article in English | MEDLINE | ID: mdl-19501647

ABSTRACT

Despite ongoing efforts, the current treatment for Chagas disease is still unsatisfactory, mainly because of the severe side effects and variable efficacy of the available nitroheterocycles. Our group has been assaying natural quinones isolated from Brazilian flora, and their derivatives, as alternative chemotherapeutic agents against Trypanosoma cruzi. From C-allyl lawsone three naphthofuranquinones were synthesized, which were active against trypomastigotes and epimastigotes. Here, we further investigated the activity and the mechanisms of action of these quinones. They exhibited powerful effects on intracellular amastigotes, presenting low toxicity to the host cells. Ultrastructural analyses of treated epimastigotes and trypomastigotes indicated a potent effect of the three naphthofuranquinones on the parasite mitochondrion, which appeared drastically swollen and with a washed-out matrix profile. Fluorescence-activated cell sorting analysis of rhodamine 123-stained T. cruzi showed that the three naphthofuranquinones caused a potent dose-dependent collapse of the mitochondrial membrane potential, especially in the epimastigote form. Naphthofuranquinones also decreased specifically mitochondrial complex I-III activity in both epimastigotes and trypomastigotes, parallel to a reduction in succinate-induced oxygen consumption. Mitochondrial hydrogen peroxide formation was also increased in epimastigotes after treatment with the naphthofuranquinones. Our results indicate that the trypanocidal action of the naphthofuranquinones is associated with mitochondrial dysfunction, leading to increased reactive oxygen species generation and parasite death.


Subject(s)
Mitochondria/drug effects , Naphthoquinones/pharmacology , Trypanosoma cruzi/drug effects , Trypanosoma cruzi/ultrastructure , Animals , Cells, Cultured , DNA Damage/drug effects , Dose-Response Relationship, Drug , Drug Evaluation, Preclinical , Electron Transport/drug effects , Hydrogen Peroxide/metabolism , Life Cycle Stages/drug effects , Membrane Potential, Mitochondrial/drug effects , Mitochondria/metabolism , Mitochondria/physiology , Models, Biological , Naphthoquinones/chemical synthesis , Oxidative Stress/drug effects , Oxygen Consumption/drug effects , Trypanocidal Agents/pharmacology , Trypanosoma cruzi/growth & development , Trypanosoma cruzi/metabolism
11.
Eur J Med Chem ; 44(5): 2334-7, 2009 May.
Article in English | MEDLINE | ID: mdl-18662840

ABSTRACT

We report here an alternative to the MCPBA or ozonolysis-based oxidation methods of quinoxaline-featuring compounds prepared from beta-lapachones. The use of peracetic acid allowed a simple preparation of the corresponding macrolactones by cleavage of the ring system. These lactones were evaluated for their antimycobacterial potential and compound 4 turned out to have an MIC of 0.62 microg per mL on Mycocabteriumtuberculosis H37Rv. These results justify further research into its value as a potential lead for an original treatment of tuberculosis.


Subject(s)
Antitubercular Agents/chemical synthesis , Lactones/chemical synthesis , Mycobacterium tuberculosis/drug effects , Phenazines/chemistry , Microbial Sensitivity Tests , Oxidation-Reduction , Quinoxalines , Structure-Activity Relationship
12.
Acta Crystallogr Sect E Struct Rep Online ; 65(Pt 5): o1063, 2009 Apr 18.
Article in English | MEDLINE | ID: mdl-21583879

ABSTRACT

In the title compound, C(22)H(14)N(2)O(2), the five rings of the mol-ecule are not coplanar. There is a significant twist between the four fused rings, which have a slightly arched conformation, and the pendant aromatic ring, as seen in the dihedral angle of 13.16 (8)° between the anthraquinonic ring system and the pendant aromatic ring plane.

13.
Magn Reson Chem ; 46(12): 1158-62, 2008 Dec.
Article in English | MEDLINE | ID: mdl-18524015

ABSTRACT

Six new nor-beta-lapachones have been synthesized from reaction of 3-bromo-nor-beta-lapachone with arylamines. These derivatives have potent anticancer properties against several cell lines. Here, we report complete unambiguous assignments of (1)H and (13)C chemical shifts of the new compounds. The assignments were made using a combination of one- and two-dimensional NMR techniques ((1)H, (13)C, (1)H-(1)H COSY, (1)H-(13)C HSQC, and (1)H-(13)C HMBC).


Subject(s)
Magnetic Resonance Spectroscopy/methods , Quinones/chemistry , Amines/chemistry , Antineoplastic Agents/chemistry , Carbon Isotopes , Furans/chemistry , Naphthalenes/chemistry
14.
Bioorg Med Chem ; 16(9): 5030-8, 2008 May 01.
Article in English | MEDLINE | ID: mdl-18378461

ABSTRACT

New naphthoquinone derivatives were synthesized and assayed against bloodstream trypomastigote forms of Trypanosoma cruzi, the etiological agent of Chagas' disease. The compounds were rationalized based on hybrid drugs and appear as important compounds against this parasite. From nor-lapachol were prepared five substituted ortho-naphthofuranquinones, a non-substituted para-naphthofuranquinone, a new oxyrane and an azide and from alpha-lapachone a new non-substituted para-naphthofuranquinone. Other five substituted ortho-naphthofuranquinones recently designed as cytotoxic, were also evaluated. The most active compounds were the ortho naphthofuranquinones 3-(4-methoxyphenylamino)-2,3-dihydro-2,2-dimethylnaphtho[1,2-b]furan-4,5-dione and 3-(3-nitrophenylamino)-2,3-dihydro-2,2-dimethylnaphtho[1,2-b]furan-4,5-dione with trypanocidal activity higher than that of benznidazole, the standard drug. The compounds were rationalized based on hybrid drugs and appear as important compounds against T. cruzi. The trypanocidal activity of these substances endowed with redox properties representing a good starting point for a medicinal chemistry program aiming the chemotherapy of Chagas' disease.


Subject(s)
Antiprotozoal Agents/chemical synthesis , Antiprotozoal Agents/pharmacology , Naphthoquinones/chemical synthesis , Naphthoquinones/pharmacology , Trypanosoma cruzi/drug effects , Animals , Antiprotozoal Agents/chemistry , Crystallography, X-Ray , Models, Molecular , Molecular Structure , Naphthoquinones/chemistry , Parasitic Sensitivity Tests , Stereoisomerism
15.
Acta Crystallogr Sect E Struct Rep Online ; 64(Pt 12): o2348, 2008 Nov 13.
Article in English | MEDLINE | ID: mdl-21581322

ABSTRACT

The title compound, C(20)H(15)Br(2)NO(3), shows the furan ring to adopt a half-chair conformation and the two ring systems to be approximately perpendicular [dihedral angle = 71.0 (2)°]. In the crystal structure, inter-molecular C-H⋯O contacts link the mol-ecules.

16.
Eur J Med Chem ; 43(8): 1774-80, 2008 Aug.
Article in English | MEDLINE | ID: mdl-18045742

ABSTRACT

[1,2,3]-Triazole derivatives of nor-beta-lapachone were synthesized and assayed against the infective bloodstream trypomastigote form of Trypanosoma cruzi, the etiological agent of Chagas disease. All the derivatives were more active than the original quinones, with IC(50)/1 day values in the range of 17 to 359 microM, the apolar phenyl substituted triazole 6 being the most active compound. These triazole derivatives of nor-beta-lapachone emerge as interesting new lead compounds in drug development for Chagas disease.


Subject(s)
Naphthoquinones/chemistry , Triazoles/chemical synthesis , Triazoles/pharmacology , Trypanocidal Agents/chemical synthesis , Trypanocidal Agents/pharmacology , Trypanosoma cruzi/drug effects , Animals , Azides/chemistry , Cations/chemistry , Crystallography, X-Ray , Hydrogen Bonding , Models, Molecular , Molecular Structure , Structure-Activity Relationship , Triazoles/chemistry , Trypanocidal Agents/chemistry
17.
Bioorg Med Chem ; 15(22): 7035-41, 2007 Nov 15.
Article in English | MEDLINE | ID: mdl-17827021

ABSTRACT

Several arylamino derivatives of nor-beta-lapachone were synthesized in moderate to high yields and found to show very potent cytotoxicity against six neoplastic cancer cells: SF-295 (central nervous system), HCT-8 (colon), MDAMB-435 (breast), HL-60 (leukaemia), PC-3 (prostate), and B-16 (murine melanoma), with IC(50) below 1 microg/mL. Their cytotoxicities were compared to doxorubicin and with their synthetic precursors, beta-lapachone and nor-beta-lapachone. The activity against a normal murine fibroblast L-929 showed that some of the compounds were selective against cancer cells. The absence of hemolytic activity (EC(50)>200 microg/mL), performed with erythrocyte suspensions, suggests that the cytotoxicity of the compounds was not related to membrane damage of mouse erythrocytes. For comparison purposes, one isomeric compound based on nor-alpha-lapachone was also synthesized and showed lower activity than the related ortho-derivative. The modified arylamino quinones appear as interesting new lead compounds in anti-cancer drug development.


Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Naphthoquinones/chemical synthesis , Naphthoquinones/pharmacology , Animals , Antineoplastic Agents/chemistry , Cell Line, Tumor , Cell Membrane/drug effects , Cell Proliferation/drug effects , Drug Screening Assays, Antitumor , Humans , Mice , Molecular Structure , Naphthoquinones/chemistry , Stereoisomerism , Structure-Activity Relationship
19.
J Chromatogr A ; 1151(1-2): 197-202, 2007 Jun 01.
Article in English | MEDLINE | ID: mdl-17408681

ABSTRACT

This work describes the application of counter-current chromatography (CCC) as a useful, fast and economic alternative for the isolation and purification of heterocyclic derivatives from lapachol and beta-lapachone, two naturally occurring compounds from Tabebuia species, and nor-beta-lapachone, a synthetic congener of lapachol. The discussed data comprise four examples of purification of synthetic reactions with different solvent systems - the mixture of the oxazole and the imidazole from beta-lapachone; the quinoxaline from nor-beta-lapachone; and the purification of the N-oxides from the quinoxaline and the phenazine from nor-beta-lapachone from their respective not fully reacted substrates by means of aqueous reversed- and normal-phase elution modes and non-aqueous solvent systems. Traditional purification of these reaction products by silica gel column chromatography demanded a large amount of solvent and time and, in some cases, serious degradation of the products occurred, leading to low yield of the reaction. High-speed counter-current chromatography (HSCCC) was used as an alternative to optimize the process and raise the yield of the reactions.


Subject(s)
Activating Transcription Factor 6/metabolism , Countercurrent Distribution/methods , Naphthoquinones/chemistry , Activating Transcription Factor 6/genetics , Chromatography, Thin Layer , Cyclization , Imidazoles/chemistry , Molecular Structure , Naphthoquinones/chemical synthesis , Naphthoquinones/isolation & purification , Oxazoles/chemistry , Quinoxalines/chemistry
20.
An. acad. bras. ciênc ; 79(1): 29-33, Mar. 2007. ilus, tab
Article in English | LILACS | ID: lil-445582

ABSTRACT

The reaction of naphthoquinone-oximes (3) and (4) with diazomethane yields directly, in one step, the oxazoles (5) and (6), respectively.


A reação das naphthoquinona-oximas (3) e (4) com diazometano fornece diretamente, em uma etapa, os oxazóis (5) e (6), respectivamente.


Subject(s)
Combinatorial Chemistry Techniques , Diazomethane/chemistry , Naphthoquinones/chemistry , Oxazoles/chemical synthesis , Oximes/chemistry , Oxidation-Reduction
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