What do we see when we do not see the bladder? Review of the main urinary diversion techniques and their complications.

OBJECTIVE: To review the different types of urinary diversion surgeries (UDS) in order to recognize the expected findings in a postoperative study, using different imaging techniques. To recognize the main postoperative complications, both early and late. CONCLUSION: UDS are surgical procedures whose purpose is to redirect urine flow after cystectomy, generally in an oncologic context. The imaging evaluation of urological surgeries is often a radiological challenge, with CT being the most commonly used image modality. Therefore, it is essential to know the main surgical techniques, the expected postoperative findings and the optimization of imaging techniques for early diagnosis and correct evaluation of postoperative complications.

Synthetic approaches towards the marine alkyl purines.

Agelasines, asmarines and related compounds are natural products with a hybrid terpene-purine structure isolated from numerous genera of sponges (Agela sp, Raspailia sp). Nuttingins and malonganenones are tetraprenylated purine alkaloids from gordonian (Eplexura sp, Leptogorgia sp). Some of these alkaloids displayed broad spectrum activity including cytotoxic activity against several cancer cells. The review summarizes the synthesis of mono- or bi-cyclic diterpenoids usually having a 9-methyladenine moiety.

Natural products as leads to anticancer drugs.

Throughout history, natural products have afforded a rich source of compounds that have found many applications in the fields of medicine, pharmacy and biology. Within the sphere of cancer, a number of important new commercialised drugs have been obtained from natural sources, by structural modification of natural compounds, or by the synthesis of new compounds, designed following a natural compound as model. The search for improved cytotoxic agents continues to be an important line in the discovery of modern anticancer drugs. The huge structural diversity of natural compounds and their bioactivity potential have meant that several products isolated from plants, marine flora and microorganisms can serve as "lead" compounds for improvement of their therapeutic potential by molecular modification. Additionally, semisynthesis processes of new compounds, obtained by molecular modification of the functional groups of lead compounds, are able to generate structural analogues with greater pharmacological activity and with fewer side effects. These processes, complemented with high-throughput screening protocols, combinatorial chemistry, computational chemistry and bioinformatics are able to afford compounds that are far more efficient than those currently used in clinical practice. Combinatorial biosynthesis is also applied for the modification of natural microbial products. Likewise, advances in genomics and the advent of biotechnology have improved both the discovery and production of new natural compounds.

Natural products as leads to anticancer drugs

Throughout history, natural products have afforded a rich source of compounds that have found many applications in the fields of medicine, pharmacy and biology. Within the sphere of cancer, a number of important new commercialised drugs have been obtained from natural sources, by structural modification of natural compounds, or by the synthesis of new compounds, designed following a natural compound as model. The search for improved cytotoxic agents continues to be an important line in the discovery of modern anticancer drugs. The huge structural diversity of natural compounds and their bioactivity potential have meant that several products isolated from plants, marine flora and microorganisms can serve as "lead" compounds for improvement of their therapeutic potential by molecular modification. Additionally, semisynthesis processes of new compounds, obtained by molecular modification of the functional groups of lead compounds, are able to generate structural analogues with greater pharmacological activity and with fewer side effects. These processes, complemented with high-throughput screening protocols, combinatorial chemistry, computational chemistry and bioinformatics are able to afford compounds that are far more efficient than those currently used in clinical practice. Combinatorial biosynthesis is also applied for the modification of natural microbial products. Likewise, advances in genomics and the advent of biotechnology have improved both the discovery and production of new natural compounds (AU)

[Nodular alveolar pattern of presentation for amiodarone pulmonary toxicity]. / Patrón alveolar nodular como forma de presentación de la toxicidad pulmonar por amiodarona.

Amiodarone is a triiodinated antiarrhythmic drug that accumulates in alveolar macrophages. Its use is limited by its high rate of associated pulmonary toxicity, estimated at 5-7%. Radiologic findings for pulmonary toxicity caused by amiodarone are unspecific and varied. The most common finding is subpleural reticular-type interstitial thickening, predominately in the bases of the lungs. However, the presence of parenchymal nodules is an uncommon presentation. We report the case of a woman treated with amiodarone that presented multiple nodular lesions at plain-film radiography and high-resolution CT that were compatible with pulmonary toxicity caused by amiodarone at pathologic examination.

Patrón alveolar nodular como forma de presentación de la toxicidad pulmonar por amiodarona / Nodular alveolar pattern of presentation for amiodarone pulmonary toxicity

La amiodarona es un antiarrítmico triyodado que se deposita en los macrófagos alveolares, cuyo uso se ve limitado por su toxicidad pulmonar que presenta una incidencia estimada del 5-7%. Los hallazgos radiológicos de la toxicidad pulmonar por amiodarona son inespecíficos y variados, siendo el más frecuente un engrosamiento intersticial de tipo reticular subpleural de predominio en bases. La presencia de nódulos parenquimatosos es, sin embrago, una forma infrecuente de presentación de esta entidad. Exponemos el caso de una mujer en tratamiento con amiodarona que presentaba en la radiología simple de tórax y tomografía computarizada (TC) de alta resolución múltiples lesiones nodulares cuyo posterior estudio anatomopatológico confirmaba su compatibilidad con toxicidad pulmonar por amiodarona

Amiodarone is a triiodinated antiarrhythmic drug that accumulates in alveolar macrophages. Its use is limited by its high rate of associated pulmonary toxicity, estimated at 5-7%. Radiologic findings for pulmonary toxicity caused by amiodarone are unspecific and varied. The most common finding is subpleural reticular-type interstitial thickening, predominately in the bases of the lungs. However, the presence of parenchymal nodules is an uncommon presentation. We report the case of a woman treated with amiodarone that presented multiple nodular lesions at plain-film radiography and high-resolution CT that were compatible with pulmonary toxicity caused by amiodarone at pathologic examination

Podophyllotoxin: distribution, sources, applications and new cytotoxic derivatives.

Several podophyllotoxin derivatives modified in the A, B, C, D and E rings were prepared from podophyllotoxin and methyl isoxazopodophyllic acid and evaluated for their cytotoxicity on several neoplastic cell lines. Chemical transformations performed on these compounds have yielded derivatives more potent and more selective that the parent compound. Most of the compounds maintained their cytotoxicity at the microM level. Distribution, biosynthesis, production, biotechnology, applications and synthesis have also been reviewed.

Cytotoxic cyclolignans related to podophyllotoxin.

The cyclolignan family of natural products includes compounds with important antineoplastic and antiviral properties such as podophyllotoxin and two of their semisynthetic derivatives, etoposide and teniposide. The latter are included in a wide variety of cancer chemotherapy protocols. Due to these biological activities, cyclolignans have been the objective of numerous studies focused to prepare better and safer anticancer drugs. Several cyclolignans related to podophyllotoxin have been prepared and evaluated for their cytotoxic activities on four neoplastic cell lines (P-388, A-549, HT-29 and MEL-28); some of them have antiviral and immunosuppressive activities.

New selective cytotoxic diterpenylquinones and diterpenylhydroquinones.

A new series of diterpenylquinone/hydroquinones has been prepared by Diels-Alder cycloaddition between three labdanic diterpenoids (myrceocommunic acid, methyl myrceocommunate, and myrceocommunyl acetate) and p-benzoquinone or 1,4-naphthoquinone. Influences of the quinone/hydroquinone fragment and other structural features, such as the different functionalities in the terpenic core, are considered in relation to the cytotoxicity toward neoplastic cells and the selectivity of these diterpenylnaphthoquinones/hydroquinones and anthraquinones. Several compounds showed IC50 values under the micromolar level, and four of these derivatives were evaluated at the NCI screening panel. The results showed an important selectivity toward renal cancer lines, identifying these compounds as a very promising group of antineoplastics.

Antitumor properties of podophyllotoxin and related compounds.

The lignan family of natural products includes compounds with important antineoplastic and antiviral properties such as podophyllotoxin and two of their semisynthetic derivatives, etoposide and teniposide. The latter are included in a wide variety of cancer chemotherapy protocols. Due to these biological activities, lignans, and especially cyclolignans, have been the objective of numerous studies focused to prepare better and safer anticancer drugs. The mechanism by which podophyllotoxin blocks cell division is related to its inhibition of microtubule assembly in the mitotic apparatus. However, etoposide and teniposide were shown not to be inhibitors of microtubule assembly which suggested that their antitumor properties were due to another mechanism of action, via their interaction with DNA and inhibition of DNA topoisomerase II. Other podophyllotoxin derivatives has also been reported which retained or even improved the cytotoxic activity, but these were weak inhibitors of topoisomerase II in vitro; the data revealed that such analogs exhibit a different, as yet unknown, mechanism of action. The main deficiency of these compounds is their cytotoxicity for normal cells and hence side effects derived from their lack of selectivity against tumoral cells. In this regard it is necessary to investigate and prepare new more potent and less toxic analogs, that is, with better therapeutic indices. It is well accepted from structure-activity studies in this field that the trans-lactones are more potent as antineoplastics than the cis-lactones. Not only the configuration of the D ring is an important factor for high cytotoxic activity, but also a quasi-axial arrangement of the E ring is necessary. On this basis, studies on lignans have been addressed to modify the lactone moiety and prepare analogs with heteroatoms at different positions of the cyclolignan skeleton. Our group has been working during the last few years on chemical transformations of podophyllotoxin and analogs and we have prepared a large number of cyclolignan derivatives some of which display potent antiviral, immunosuppressive and cytotoxic activities. We have reported several new cytotoxic agents with nitrogen atoms at C-7 or C-9 or at both C-7 and C-9: imine derivatives, oxime derivatives, pyrazoline-, pyrazo- and isoxazoline-fused cyclolignans. At present, we are preparing mainly new compounds by modifications of the A and E cyclolignan-rings. They are being tested on cultures of different tumoral cell lines (P-388 murine leukemia, A-549 human lung carcinoma, HT-29 human colon carcinoma and MEL-28 human melanoma) and some of them have shown an interesting and selective cytotoxicity.

Structure- and species-dependent insecticidal effects of neo-clerodane diterpenes.

Several natural neo-clerodane diterpenoids isolated from Linaria saxatilis and some semisynthetic derivatives were tested against several insect species with different feeding adaptations. The antifeedant tests showed that the oliphagous Leptinotarsa decemlineata was the most sensitive insect, followed by the aphid Myzus persicae. The polyphagous Spodoptera littoralis was not deterred by these diterpenoids; however, following oral administration, some of these compounds did have postingestive antifeedant effects on this insect. In general terms, the antifeedant effects of these compounds were species-dependent and more selective than their toxic/postingestive effects. The study of their structure-activity relationships showed that both the decalin moiety and the chain at C-9 determined their bioactivity. Furthermore, the presence of a 4,18-epoxy/diol moiety was an important feature for both the antifeedant and the toxic/postingestive effects.

Synthesis and antineoplastic activity of cyclolignan aldehydes.

Several aldehydes related to methyl 9-deoxy-9-oxo-alpha-apopicropodophyllate, a selective antitumour agent against the HT-29 colon carcinoma, have been prepared and evaluated for their cytotoxic activities on four neoplastic cell lines (P-388, A-549, HT-29 and MEL-28). All of them lacked the lactone ring but maintained their cytotoxicity at, or under, the microM level.

New antineoplastic prenylhydroquinones. Synthesis and evaluation.

Several prenylhydroquinones have been prepared through Diels-Alder condensation, further functionalized or degraded chemically and then evaluated for their cytotoxic activity against some neoplastic cultured cell lines. A number of them have shown IC50 values under the microM level.

Structure-antifeedant activity relationship of clerodane diterpenoids. Comparative study with withanolides and azadirachtin.

A structure-antifeedant activity relationship (SAR) study of clerodane diterpenoids was carried out. Attention was focused on the feeding-deterrent activities exhibited toward Tenebrio molitor by clerodane diterpenoids and withanolides. Azadirachtin was chosen as a reference compound. SAR studies on the clerodane compounds indicate that the stereoelectronic factors are more important than the hydrophobic aspects as determinants of antifeedant activity. A furan ring in the side chain and a carbonyl alpha,beta-unsaturated (or spiro-epoxide) group appear to be indispensable for the biological response. A conformational study indicate that the optimum interatomic distance between these moieties is a range between 9.5 and 10.5 A. In addition, a similar stereoelectronic response was found among withanolides and azadirachtin. On the basis of these results it is reasonable to imagine a closely related chemical mechanism for these compounds.

Inhibition of human sPLA2 and 5-lipoxygenase activities by two neo-clerodane diterpenoids.

The inhibitory effect of two neo-clerodane diterpenoids, E-isolinaridial (EI) and its methylketone derivative (EIM), isolated from Linaria saxatilis var. glutinosa, on PLA2 and other enzyme activities involved in the inflammatory process was studied. Both compounds inhibited human synovial sPLA2 in a concentration-dependent manner with IC50 values of 0.20 and 0.49 microM, respectively, similar to scalaradial. Besides, these compounds decreased the cell-free 5-lipoxygenase activity and A23187-induced neutrophil LTB4 biosynthesis. Another function of human neutrophils, such as receptor-mediated degranulation, was also significantly reduced. In contrast, none of the compounds affected superoxide generation in leukocytes, or cyclooxygenase-1, cyclooxygenase-2 and inducible nitric oxide synthase activities in cell-free assays.

Further antineoplastic terpenylquinones and terpenylhydroquinones.

Influences of the quinone/hydroquinone fragment and other structural features are considered in relation with the antineoplastic activity and selectivity of terpenylquinones/hydroquinones. Several compounds have shown IC50 values under the microM level.

Immunosuppressive cyclolignans.

The immunosuppressive activity of several lactonic, nonlactonic, and heterocycle-fused cyclolignans has been demonstrated for the first time by use of a T-cell-mediated immune response. Of the compounds tested, 4'-demethyldeoxypodophyllotoxin (8), beta-apopicropodophyllin (6), and the isoxazoline-fused cyclolignan 15 are the most potent with respect to their suppression of activated splenocytes.

[A multivariate analysis approach to antineoplastic and antiviral structure-activity relationships to a series of podophyllotoxins]. / Approche par analyse multivariée des relations structure-activités antitumorale et antivirale dans la série de la podophyllotoxine.

In this work, the authors have used technics of multivariate analysis to determine the structure-activity relationships of 46 podophyllotoxin derivatives and analogs studied for their antineoplastic and antiviral activities. The obtained results allow to envisage the possible synthesis of more specific molecules by making modifications in the structure of the model molecular archetype.

Synthesis and evaluation of pyrazolignans. A new class of cytotoxic agents.

A series of fused pyrazole derivatives of cyclolignans have been prepared through simple chemical routes and evaluated for their cytotoxic activities in culture cells of P-388 murine leukemia, A-549 lung carcinoma and HT-29 colon carcinoma. Despite the lack of the lactone moiety in their structures, they show IC50 values at microM levels.

Methyl ethers of podophyllotoxin-related cyclolignans.

Methyl ethers of podophyllotoxin [1] and its epimers at positions 7 and 8' were obtained through the corresponding chlorinated or brominated derivatives at position 7. Additionally, the corresponding diol methyl ethers were obtained by reducing the lactone with LiAlH4. 7-O-Methylepipicropodophyllotoxin [12], 7-O-methylpicropodophyllotoxin [13], the diol methyl ethers 15-18 and the corresponding diacetates are described here for the first time. Most of the cyclolignans obtained were evaluated for their cytotoxic activity.