Cytotoxic Cyclolignans Obtained by the Enlargement of the Cyclolignan Skeleton of Podophyllic Aldehyde, a Selective Podophyllotoxin-Derived Cyclolignan.

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.

Synthetic strategies to terpene quinones/hydroquinones.

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.

Traditional plant-based remedies to control insect vectors of disease in the Arribes del Duero (western Spain): an ethnobotanical study.

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.

Química Farmacéutica de las Acilaminometilpiridinas / Pharmaceutical Chemistry of Acylaminomethylpyridines

Se han sintetizado una nueva familia de depresores del Sistema Nervioso Central, basado en un sistema denominado actualmente la 'utilización de fragmentos'. A uno de los fármacos obtenidos por este procedimiento la OMS le asignó el nombre de picobenzida. Al tratarse de una benzamida sustituida se prepararon análogos modificando los sustituyentes del anillo aromático y se llevó a cabo un estudio QSAR de la serie, que condujo a la optimización de la misma. Un ensayo para modificar el anillo de piridina condujo a una nueva reacción de dimerización para esta clase de compuestos (AU)

A new family of central nervous system depressants has been synthesized, applying the methodology now known as the 'use of fragments'. One of the drugs produced by this process was assigned the name picobencide by WHO. Being a substituted benzamide, analogues were prepared modifying the substituents of the aromatic ring. A QSAR study was carried out which led to the optimization of the series. A test to modify the pyridine ring led to a new dimerization reaction of this kind of compounds (AU)

Cytotoxic terpene quinones from marine sponges.

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.

Terpenyl-purines from the sea.

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.

Thiols oxidation and covalent binding of BSA by cyclolignanic quinones are enhanced by the magnesium cation.

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.

Synthesis and cytotoxic evaluation of C-9 oxidized podophyllotoxin derivatives.

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.

Synthesis and cytotoxicity of new heterocyclic terpenylnaphthoquinones.

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.

Synthesis and cytotoxicity of new aminoterpenylquinones.

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.

Synthesis and biological evaluation of new selective cytotoxic cyclolignans derived from podophyllotoxin.

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.

Synthesis, cytotoxicity and antiviral activity of podophyllotoxin analogues modified in the E-ring.

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.

Synthesis and cytotoxicity of podophyllotoxin analogues modified in the A ring.

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.

Synthesis and biological evaluation of cytotoxic 6(7)-alkyl-2-hydroxy-1, 4-naphthoquinones.

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.

Reductive activation of terpenylnaphthoquinones.

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.

Cytotoxic-antineoplastic activity of hydroquinone derivatives.

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.