RESUMO
Podophyllotoxin, a cyclolignan natural product, has been the object of extensive chemomodulation to obtain better chemotherapeutic agents. Among the obtained podophyllotoxin derivatives, podophyllic aldehyde showed very interesting potency and selectivity against several tumoral cell lines, so it became our lead compound for further modifications, as described in this work, oriented toward the enlargement of the cyclolignan skeleton. Thus, modifications performed at the aldehyde function included nucleophilic addition reactions and the incorporation of the aldehyde carbon into several five-membered rings, such as thiazolidinones and benzo-fused azoles. The synthesized derivatives were evaluated against several types of cancer cells, and although some compounds were cytotoxic at the nanomolar range, most of them were less potent and less selective than the parent compound podophyllic aldehyde, with the most potent being those having the lactone ring of podophyllotoxin. In silico ADME evaluation predicted good druggability for most of them. The results indicate that the γ-lactone ring is important for potency, while the α,ß-unsaturated aldehyde is necessary to induce selectivity in these cyclolignans.
Assuntos
Antineoplásicos , Podofilotoxina , Humanos , Podofilotoxina/farmacologia , Esqueleto , Hipertrofia , Aldeídos , Lactonas , Compostos RadiofarmacêuticosRESUMO
The cytotoxic and antiproliferative properties of many natural sesquiterpene-quinones and -hydroquinones from sponges offer promising opportunities for the development of new drugs. A review dealing with different strategies for obtaining bioactive terpenyl quinones/hydroquinones is presented. The different synthetic approches for the preparation of the most relevant quinones/hydroquinones are described.
Assuntos
Hidroquinonas/síntese química , Quinonas/síntese química , Terpenos/síntese química , Animais , Anti-Infecciosos/síntese química , Anti-Inflamatórios não Esteroides/síntese química , Antineoplásicos/síntese química , Química Farmacêutica , HumanosRESUMO
The 1,4-benzoquinone moiety is a common structural feature in a large number of compounds that have received considerable attention owing to their broad spectrum of biological activities. The cytotoxic and antiproliferative properties of many natural sesquiterpene quinones and hydroquinones from sponges of the order Dictyoceratida, such as avarol, avarone, illimaquinone, nakijiquinone and bolinaquinone, offer promising opportunities for the development of new antitumor agents. The present review summarizes the structure and cytotoxicity of natural terpenequinones/hydroquinones and their bioactive analogues and derivatives.
Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Poríferos/química , Quinonas/química , Quinonas/farmacologia , Terpenos/química , Animais , Antineoplásicos/isolamento & purificação , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Hidroquinonas/química , Hidroquinonas/isolamento & purificação , Hidroquinonas/farmacologia , Estrutura Molecular , Quinonas/isolamento & purificação , Relação Estrutura-Atividade , Terpenos/isolamento & purificação , Terpenos/farmacologiaRESUMO
Agelasines, asmarines and related compounds are natural products with a hybrid terpene-purine structure isolated from numerous genera of sponges (Agela sp., Raspailia sp.). Some agelasine analogs and related structures have displayed high general toxicity towards protozoa, and have exhibited broad-spectrum antimicrobial activity against a variety of species, including Mycobacterium tuberculosis, and also an important cytotoxic activity against several cancer cell lines, including multidrug-resistant ones. Of particular interest in this context are the asmarines (tetrahydro[1,4]diazepino[1,2,3-g,h]purines), which have shown potent antiproliferative activity against several types of human cancer cell lines. This review summarizes the sources of isolation, chemistry and bioactivity of marine alkylpurines and their bioactive derivatives.
Assuntos
Antibacterianos/síntese química , Antineoplásicos/síntese química , Purinas/síntese química , Terpenos/síntese química , Agelas , Animais , Antibacterianos/química , Antibacterianos/farmacologia , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Resistência a Múltiplos Medicamentos , Resistencia a Medicamentos Antineoplásicos , Humanos , Biologia Marinha , Poríferos , Purinas/química , Purinas/farmacologia , Terpenos/química , Terpenos/farmacologiaRESUMO
A novel cyclolignanic quinone, 7-acetyl-3',4'-didemethoxy-3',4'-dioxopodophyllotoxin (CLQ), inhibits topoisomerase II (TOPO II) activity. The extent of this inhibition was greater than that produced by the etoposide quinone (EQ) or etoposide. Glutathione (GSH) reduces EQ and CLQ to their corresponding semiquinones under anaerobic conditions. The latter were detected by EPR spectroscopy in the presence of MgCl(2) but not in its absence. Semiquinone EPR spectra change with quinone/GSH mol ratio, suggesting covalent binding of GSH to the quinones. Quinone-GSH covalent adducts were isolated and identified by ESI-MS. These orthoquinones also react with nucleophilic groups from BSA to bind covalently under anaerobic conditions. BSA thiol consumption and covalent binding by these quinones are enhanced by MgCl(2). Complex formation between the parent quinones and Mg(+2) was also observed. Density functional calculations predict the observed blue-shifts in the absorption spectra peaks and large decreases in the partial negative charge of electrophilic carbons at the quinone ring when the quinones are complexed to Mg(+2). These observations suggest a possible role of Mg(+2) chelation by these quinones in increasing TOPO II thiol and/or amino/imino reactivity with these orthoquinones.
Assuntos
Antineoplásicos/química , Quelantes/química , Inibidores Enzimáticos/química , Cloreto de Magnésio/química , Podofilotoxina/química , Quinonas/química , Soroalbumina Bovina/química , Compostos de Sulfidrila/química , Antineoplásicos/metabolismo , Antineoplásicos/farmacologia , Benzoquinonas/química , Cátions Bivalentes , Quelantes/metabolismo , Quelantes/farmacologia , DNA Topoisomerases Tipo II/química , Espectroscopia de Ressonância de Spin Eletrônica , Inibidores Enzimáticos/metabolismo , Inibidores Enzimáticos/farmacologia , Etoposídeo/análogos & derivados , Etoposídeo/química , Glutationa/química , Modelos Moleculares , Estrutura Molecular , Oxirredução , Podofilotoxina/análogos & derivados , Podofilotoxina/metabolismo , Podofilotoxina/farmacologia , Ligação Proteica , Quinonas/metabolismo , Quinonas/farmacologia , Soroalbumina Bovina/metabolismo , Espectrometria de Massas por Ionização por Electrospray , Compostos de Sulfidrila/metabolismo , Inibidores da Topoisomerase IIRESUMO
Podophyllotoxin and some of its derivatives are cyclolignans currently used for removing warts and in the clinical treatment of malign neoplasms. As such, they have been an objective of the scientific community for decades, in the search for more potent and more selective anticancer agents. Our interest in the chemoinduction of drug selectivity led us to the design and preparation of new podophyllotoxin derivatives by reaction of podophyllic aldehyde with aliphatic, aromatic, and heteroaromatic amines. Several of the resulting imines displayed a significant selectivity against human colon carcinoma cells, even higher than that of the starting aldehyde. Additional biological studies indicate that these derivatives induce microtubule depolymerization, arrest cells at the G2/M phase of cell cycle, and are able to induce a delayed apoptosis after 48 h of treatment, characterized by caspase-3 activation.
Assuntos
Antineoplásicos/síntese química , Podofilotoxina/análogos & derivados , Podofilotoxina/síntese química , Animais , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Iminas/síntese química , Iminas/farmacologia , Camundongos , Podofilotoxina/farmacologia , Relação Estrutura-AtividadeRESUMO
Four terpenylnaphthoquinones were found to enhance the rate of superoxide production in the presence of ascorbate as detected from the superoxide dismutase (SOD)-inhibitable initial oxygen consumption rates. Initial rates of oxygen consumption in the presence of ascorbate plus quinone increase with an increase in the half-wave reduction potentials of the quinones. These quinones also enhance the rate of Cyt(III)c reduction by xanthine/xanthine oxidase (X/XO) in both air- and nitrogen-saturated aqueous solutions at pH 7.4. Maximum rates of Cyt(III)c reduction in nitrogen and oxygen-saturated solutions (V(max)), in the presence of X/XO, increase with an increase in the half-wave reduction potentials of the quinones. SOD inhibits Cyt(III)c reduction rates in the presence of these quinones and X/XO in a manner which is also dependent on the quinone half-wave redox potential. The relative antineoplastic activity of two of these quinones follows the order in rates of oxygen consumption or Cyt(III)c reduction. This is consistent with an antineoplastic action of these quinones through the mechanism of redox cycling or possible interference or inhibition of mitochondrial respiration.
Assuntos
Ácido Ascórbico/química , Naftoquinonas/química , Terpenos/química , Animais , Grupo dos Citocromos c/química , Espectroscopia de Ressonância de Spin Eletrônica , Cavalos , Cinética , Oxirredução , Superóxido Dismutase/química , Superóxidos/química , Xantina/química , Xantina Oxidase/químicaRESUMO
Several podophyllotoxin derivatives lacking the methylenedioxy group or with different functionalization of the A-ring of the cyclolignan skeleton have been prepared and evaluated for their cytotoxic activities on four neoplastic cell lines (P-388, A-549, HT-29 and MEL-28). Most of them maintained their cytotoxicity at the microM level.
Assuntos
Antineoplásicos/síntese química , Lignanas/síntese química , Podofilotoxina/análogos & derivados , Animais , Antineoplásicos/farmacologia , Linhagem Celular Tumoral/efeitos dos fármacos , Dioxanos/síntese química , Dioxanos/farmacologia , Dioxóis/síntese química , Dioxóis/química , Dioxóis/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Lignanas/farmacologia , Espectroscopia de Ressonância Magnética , Camundongos , Modelos Químicos , Estrutura Molecular , Podofilotoxina/farmacologia , Relação Estrutura-AtividadeRESUMO
Several myrcenylhydroquinone derivatives have been evaluated for their cytotoxic activity against three neoplastic cell line cultures and compared with the activity previously observed on other neoplastic systems. Also a new series of this type of compounds has been prepared and the compounds synthesised have been evaluated by their GI(50) values.
Assuntos
Antineoplásicos/farmacologia , Hidroquinonas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/toxicidade , Avaliação Pré-Clínica de Medicamentos , Humanos , Hidroquinonas/síntese química , Hidroquinonas/química , Hidroquinonas/toxicidade , Concentração Inibidora 50 , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Relação Estrutura-Atividade , Células Tumorais CultivadasRESUMO
Several podophyllotoxin derivatives modified in the E-ring were prepared and evaluated for their cytotoxicity on four neoplastic cell lines (P-388, A-549, HT-29 and MEL-28) and for their antiherpetic activity against Herpes simplex virus type II. The trimethoxyphenyl moiety was oxidized to ortho-quinone and further condensed with diamines and enamines to form different heterocycles. Most of the compounds maintained their cytotoxicity at the muM level and some of them showed antiherpetic activity.
Assuntos
Antivirais/síntese química , Podofilotoxina/análogos & derivados , Podofilotoxina/farmacologia , Animais , Antivirais/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Chlorocebus aethiops , Herpesvirus Humano 2/efeitos dos fármacos , Humanos , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Podofilotoxina/síntese química , Relação Estrutura-Atividade , Células VeroRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: In several Spanish rural communities, simple and effective plant-based remedies are employed for the control of vector-borne diseases. Hence, the aim of this study was to assess the knowledge and usage custom of traditional insect control in the Arribes del Duero-ARD-(Salamanca-Zamora, W Spain). MATERIALS AND METHODS: Between 2005 and 2009, 116 semi-structured interviews of 80 non-specialist people (44 men and 36 women; mean age, 72) were conducted. This community was located in the Arribes del Duero Natural Park, representative of a highly heterogeneous Mediterranean landscape with a strong decline in the population and a significant proportion (almost 40%) age 65 or greater. We calculated the cultural importance for each species cited. To analyze how traditional ecological knowledge (TEK) varies with the characteristics of the informants, we performed an ANCOVA. RESULTS AND CONCLUSIONS: We documented the traditional use of 22 vascular plants as remedies to prevent or treat external parasites, and control mosquitoes, flies and other nuisance insects. There were described 27 plant remedies, of which 16 (59%) continue to be in use, including basil (Ocimum basilicum L. and Ocimum minimum L.) as a repellent for mosquitoes and houseflies. Most of the plant species contain phenols and/or terpenoids, and in several investigations bioassays have been performed to test their repellent and/or insecticidal properties. Three taxa (Ballota nigra L., Cicer arietinum L. and Ocimum minimum) have not been tested and these may offer excellent natural remedies. As well as allowing the discovery of new chemical compounds with insecticidal activity, this traditional knowledge may be paramount in the control of potential populations of vectors of emerging diseases in the Mediterranean region without harming the environment.
Assuntos
Etnobotânica , Insetos Vetores , Medicina Tradicional , Plantas Medicinais , Idoso , Animais , Feminino , Humanos , Masculino , Espanha , Especificidade da EspécieRESUMO
A series of podophyllotoxin and podophyllic aldehyde derivatives, lacking the lactone ring and oxidized at C-9 position, has been prepared. The functionalities considered at C-9 were carboxylic acids and several derivatives such as esters, amides, nitriles or anhydrides. The synthesized compounds were cytotoxic at the micromolar level, though less potent and selective than the parent compounds, revealing the influence of the C-9 electrophilic character on the potency and selectivity of these cyclolignans.
Assuntos
Antineoplásicos/síntese química , Podofilotoxina/análogos & derivados , Podofilotoxina/farmacologia , Aldeídos , Animais , Antineoplásicos/farmacologia , Ácidos Carboxílicos , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Podofilotoxina/síntese química , Relação Estrutura-AtividadeRESUMO
Several 2-arylamino-, 2-aryloxy- and 2-arylsulfanyl-6(7)-alkyl-1,4-naphthoquinones (NQ) have been prepared and further transformed into the corresponding heterocyclic-fused naphthoquinones by palladium (II)-catalyzed oxidative cyclization. The compounds synthesized have been evaluated against neoplastic cell lines. The extension of the polycyclic system clearly decreased the cytotoxic potency of the 2-substituted terpenylnaphthoquinones.
Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Naftoquinonas/síntese química , Naftoquinonas/farmacologia , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Espectroscopia de Ressonância Magnética , Espectrometria de Massas de Bombardeamento Rápido de ÁtomosRESUMO
Several 6(7)-alkyl-1,4-naphthoquinones (NQ) have been prepared by cycloaddition reactions between the monoterpene alpha-myrcene and p-benzoquinones and halogen and nitrogen-containing functional groups have been introduced at the C-2 position of the naphthoquinone ring via nucleophilic addition or substitution reactions. These substituents at positions 2/3 of the NQ clearly influence the cytotoxic potency of this type of compound. Of particular interest is substitution by arylamino, specifically p-oxyarylamino, groups, which considerably enhance their bioactivity and selectivity.
Assuntos
Quinonas/síntese química , Terpenos/química , Espectroscopia de Ressonância Magnética , Quinonas/toxicidade , Espectrofotometria InfravermelhoRESUMO
Various Diels Alder cycloaddition conditions have been used to optimise the preparation of cytotoxic 6-alkyl-1, 4-naphthoquinones, which were subsequently transformed into 6(7)-alkyl-2-hydroxy-1, 4-naphthoquinones. The compounds thus prepared were evaluated for their cytotoxic activity against several neoplastic cultured cell lines and some of them showed IC50 values below the microM level.