Structure-Antitumor Activity Relationships of Aza- and Diaza-Anthracene-2,9,10-Triones and Their Partially Saturated Derivatives.

The 1,8-Diazaanthracene-2,9,10-triones, their 5,8-dihydro derivatives, and 1,8-diazaanthracene-2,7,9,10-tetraones, structurally related to the diazaquinomycin family of natural products, were synthesized in a regioselective fashion employing Diels-Alder strategies. These libraries were studied for their cytotoxicity in a variety of human cancer cell lines in order to establish structure-activity relationships. From the results obtained, we conclude that some representatives of the 1,8-diazaanthracene-2,9,10-trione framework show potent and selective cytotoxicity against solid tumors. Similar findings were made for the related 1-azaanthracene-2,9,10-trione derivatives, structurally similar to the marcanine natural products, which showed improved activity over their natural counterparts. An enantioselective protocol based on the use of a SAMP-related chiral auxiliary derived was developed for the case of chiral 5-substituted 1,8-diazaanthracene-2,9,10-triones, and showed that their cytotoxicity was not enantiospecific.

Descubrimiento y manipulación de los Genes. Conexión con la Biología y la Medicina / Discovery and handling of Genes. Connetions with Biology and Medicine

En esta revisión se analiza el avance que han experimentado los conocimientos biológicos como consecuencia del descubrimiento y manipulación de los genes, las interacciones de la genética y la medicina, y las perspectivas de la edición genómica

This review analyses the advances of biological knowledge derived from the discovery and handling of genes, the connections between genetics and medicine and the perspectives of genomic editing

Reflexiones sobre el proceso científico / Reflections about the scientific process

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La resistencia antimicrobiana. Algunos aspectos de un grave problema / Antimicrobial resistance. Some aspects of a big problem

En esta mini-revisión se analiza la emergencia, diseminación, caracterización y tratamiento de las bacterias multirresistentes, el peligro del abuso y mal uso de los antibióticos, las dificultades para el descubrimiento de nuevos antibacterianos,y el estudio de otros enfoques como la modulación del metabolismo bacteriano para combatir la resistencia a los antibióticos (AU)

We comment here the emergency, dissemination, characterization and treatment of several multidrug-resistant bacteria, the danger of anibiotics overuse and bad use, the challenges of antibacterial discovery, and the study of other appoaches such as modulation of bacterial metabolism to combat antibiotic resistance (AU)

Las compañías farmacéuticas británicas y el desarrollo de las ciencias de la vida tras el Brexit / British pharmaceutical companies and the development of the life sciences after the Brexit

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La tuberculosis no es una enfermedad del pasado / Tuberculosis is not an illness of the past

La búsqueda de una cura para la tuberculosis a lo largo de la historia se ha visto amenazada por la explosión del número de enfermos de VIH y la aparición continuada de resistencias a los fármacos antituberculosos. En esta revisión se comenta el desarrollo de distintos métodos de diagnóstico, vacunas y fármacos, haciendo énfasis en los modos de superar las resistencias, los mecanismos de acción de los fármacos, y las dianas más conocidas o más vulnerables

The search for a cure for tuberculosis throughout history has been menaced by the increasing number of people with HIV and the continuous appearence of antituberculosis drug resistance. The development of diagnosis procedures, vaccines and drugs is updated in this review, emphasizing the methods to overcome resistances, the mechanisms of drugs action, and the best known or more vulnerable targets

Inhibidores BET. El singular compuesto (+)-JQ1 / BET inhibitors. The odd compound (+)-JQ1

El descubrimiento fortuito de los inhibidores BET (bromodomain extra-terminal), y en especial de los inhibidores del bromodominio BRD4, ha permitido modular con fármacos epigenéticos la transcripción del protooncogén c-MY C, entre otros genes implicados en la carcinogénesis y otras disfunciones. Estos fármacos, entre los que se encuentra el compuesto (+)-JQ1, han mostrado su potencial como anticancerosos, inmunomoduladores, anticonceptivos masculinos, antivirales, o agentes preventivos del fallo cardíaco. En esta revisión se analiza su descubrimiento, estructura, mecanismo de acción y sus perspectivas futuras

The serendipitous discovery of (bromodomain extra-terminal) (BET) inhibitors, especially of the BRD4 bromodomain inhibitors, has allowed modulation of gene transcription with epigenetic drugs. This is the case of protooncogen c- MY C and other genes involved in carcinogenesis and different disfunctions. These drugs, that include the compound (+)-JQ1, have shown their potencial as anticancer agents, immunomodulators, male contraceptives, antiviral, or heart failure chemopreventive agents, among others. In this review we analyze their discovery, structure, mechanism of action and future perspectives

Teixobactina, un nuevo antibiótico que difícilmente podría originar resistencias / Teixobactine, a new antibiotic that would hardly produce resistance

La resistencia a los antibióticos se ha desarrollado más eficazmente que la introducción de nuevas estructuras, lo que ha provocado un importante problema de salud pública. En una reciente publicación se ha descrito el hallazgo de un nuevo antibiótico denominado teixobactina por cribado de bacterias del suelo no cultivadas hasta el momento (1). Este compuesto es un depsipéptido que inhibe la síntesis de la pared celular enlazándose a un motivo muy conservado del lípido II (precursor de péptidoglicano) y al lípido III (precursor del ácido teicoico). Tanto el método desarrollado en su descubrimiento como la aparente capacidad de teixobactina para evitar resistencias, podrían dar lugar a otros antibióticos clínicamente útiles

Antibiotic resistance is spreading faster than the introduction of new compounds into clinical practice, causing a public health crisis. In a recent publication has been described a new antibiotic of depsipeptide nature named teixobactin that was discovered in a screen of uncultured soil bacteria (1). This compound inhibits cell wall synthesis by binding to a highly conserved motif of lipid II (precursor f peptidoglycan) and lipid III (precursor of cell wall teichoic acid). The method developed in its discovery and the apparent ability of teixobactin to avoid resistances, may open a path towards the development of other clinicaly useful antibiotics

1,3-dipolar cycloadditions from tricyclic hemiaminals. Synthesis of the quinocarcin core through catalyst-free generation of azomethine ylides.

The generation of azomethine ylides from the readily accessible hemiaminals 3 and 8 or from iminium salt 10 was studied. Compounds 8 gave anti- and syn-cycloadducts containing the quinocarcin core through a catalyst-free dehydration process.

Cytotoxicity of new pyrazino[1,2-b]isoquinoline and 6,15-iminoisoquino[3,2-b]3-benzazocine compounds.

Looking for optimised analogues of compound 2 that might be useful in colon cancer therapy, we here explore the in vitro cytotoxicity against MDA-MB 231 human breast carcinoma, A-549 human lung carcinoma and HT-29 human colon carcinoma cell lines of several analogues and derivatives. The effect of the R2-substituent and/or the introduction of an arylmethyl side-chain at C-3, as well as the presence of a double bond in the skeleton or a methoxy group at C-1 have been investigated. New 6,15-iminoisoquino[3,2-b]3-benzazocine compounds, related to the saframycin family, in which the C(7)-N(8)-C(9)-substructure contains a lactam function, a fused oxazolidine or an aminonitrile function were also studied, and many of them showed low micromolar GI50 values.

Recent synthetic approaches to 6,15-iminoisoquino[3,2-b]3-benzazocine compounds.

Saframycins, safracins, renieramycins, cribrostatins, and esteinascidins are 6,15-iminoisoquino[3,2-b]3-benzazocine compounds that constitute the largest subgroup among the antitumor antibiotics belonging to the tetrahydroisoquinoline family. Their structural complexity has led to widespread synthetic attention to obtain them in both racemic and enantiopure forms. Publication in 1996 of the first total synthesis of ecteinascidin 743 by Corey's group was an important milestone, but the development of preparative protocols for these structures has continued, offering new possibilities to exploit the biological activity of the above-mentioned natural products and their analogues. This minireview is intended to update this progress following a methodological rather than a chronological organization. Besides of a brief description of the different strategies evolved from retrosynthetic analyses, which have been organized according to the order of bonding events that will link the precursors, semisynthetic approaches and a brief account of the total syntheses of ecteinascidin 743, have been analyzed.

Cytotoxicity mechanisms of pyrazino[1,2-b]isoquinoline-4-ones and SAR studies.

The cytotoxicity showed by 1b, an interesting representant of the title compounds, for HT-29 human colon cancer cells (CI(50) value of 1.95 x 10(-7)M) has been related to the induced cell death at the G2 phase and not to DNA damage. This compound promotes the degradation of components of the G2/M checkpoint machinery, in particular cdc2, Cyclin B1 and Wee1, which represents a novel mechanism of cytotoxicity. Degradation of Wee1 seems to be mediated by proteasome activity but degradation of cdc2 has to occur through a different mechanism. The activity of 1b on G2 cell cycle components suggests that tumor cells that are arrested in G2/M by anticancer drugs like cisplatin could be targeted by compound 1b, increasing the apoptosis induction, and that their optimized analogs might be useful in the treatment of colon cancer through combination therapies with cisplatin or other anticancer drugs that affect the cytoskeleton integrity such as taxol and taxotere. SAR studies with compounds obtained by manipulation of the N(2) and C(4)-functional groups and the C(6)-chain of compound 1b have confirmed the importance of these structural features in the in vitro antitumor activity. Fused oxazolidine derivatives as compound 5 were inactive, and the lack of activity found in the replacement of the C(4)-lactam by a cyanoamine function, as in compounds 8-10, could be explained considering that their all-syn relative configuration makes them too stable to generate alkylating iminium species.

Pyrazino[1,2-b]isoquinolines: synthesis and study of their cytostatic and cytotoxic properties.

The in vitro antitumor potential of novel pyrazino[1,2-b]-isoquinoline-4-ones that contain a half portion of significant natural products was explored in three cancer cell lines: MDA-MB 231 human breast carcinoma, A-549 human lung carcinoma, and HT-29 human colon carcinoma. In general, these compounds show mid to low muM GI(50)s, but LC(50)s over 100 microM with the exceptions of compounds 3b and 31 that are moderately toxic in all cell lines, while compound 4a is highly toxic and selective for HT-29 cells with LC(50) values in the high nanomolar range. Experiments directed to elucidate possible mechanisms of action with compounds 3a, 29, and 31 showed that compound 3a is able to efficiently induce apoptosis triggered directly from the G2/M phase of cell cycle, while compounds 29 and 31 are potentially cytostatic agents that induce the G1/S arrest of cell cycle. All three compounds do not act through DNA damage, since they do not activate this signaling at the level of sensors, transducers, and executers. Furthermore, the apoptosis induction of 3a is not mediated by activation of pro-apoptotic kinases JNK and p38 or by activation of AKT.

The first aza Diels-Alder reaction involving an alpha,beta-unsaturated hydrazone as the dienophile: stereoselective synthesis of C-4 functionalized 1,2,3,4-tetrahydroquinolines containing a quaternary stereocenter.

The reaction between aromatic imines and methacrolein dimethylhydrazone in the presence of 10% indium trichloride affords in good to excellent yields biologically and synthetically relevant 1,2,3,4-tetrahydroquinolines bearing a hydrazone function at C-4 in a one-pot process that involves the formation of two C-C bonds and the stereoselective generation of two stereocenters, one of them quaternary, and this constitutes the first example of an alpha,beta-unsaturated dimethylhydrazone behaving as a dienophile in a hetero Diels-Alder reaction and the first vinylogous aza-Povarov reaction.

Synthesis and cytotoxic activity of pyrazino[1,2-b]-isoquinolines, 1-(3-isoquinolyl)isoquinolines, and 6,15-iminoisoquino[3,2-b]-3-benzazocines.

A series of pyrazino[2,1-b]isoquinoline and 6,15-iminoisoquino[3,2-b]-3-benzazocine compounds related to renieramycins, cribrostatin 4, and phthalascidin was synthesized and their in vitro cytotoxic activities were evaluated against three human cancer cell lines. Pyrazino[2,1-b]isoquinolines, 6,15-iminoisoquino[3,2-b]-3-benzazocines, and other more complex octacyclic compounds have been obtained and derived to precursors of iminium ion species. Hydrogenolysis of the lactam function in pentacyclic compounds gave 1-(3-isoquinolyl)isoquinolines. The micromolar cytotoxic activity of representative structures was apparently uninfluenced by the ability to generate intermediates which would permit covalent bonding to DNA.

Efficient synthesis of N-prenylpyrroloindoline and N-prenylindole alkaloids based on a new four-reaction anionic domino process.

Treatment of 2,5-diketopiperazines or carbamates derived from tryptophan or tryptamine with iodomethyltrimethylsilane followed by lithium hexamethyldisilazane and a prenyl halide produced stereoselectively derivatives of the hexahydropyrrolo[2,3-b]indole system bearing prenyl substituents both at C-3a and at the indoline nitrogen in a one-pot procedure involving a novel four-reaction anionic domino process. The reaction was applied to the preparation of N-prenyltryprostatin B and to achieving a very efficient formal total synthesis of the biologically active marine natural product (+/-)-debromoflustramine B.

Perspectiva de las reacciones de metátesis. El Premio Nobel de Química del año 2005 / Perspective of metathesis reactions. The Nobel Prize in Chemistry 2005

A fin de comentar el premio Nobel de Química del año 2005, se hace un breve resumen de lo que significan las reacciones de metátesis en síntesis orgánica y en la obtención de polímeros. En particular, se hace énfasis en el relevante papel que jugaron las propuestas de Yves Chauvin para explicar su mecanismo y en el desarrollo de los carbenos metálicos hasta conseguir catalizadores eficaces en los grupos liderados por R. R. Schrock y R. H Grubbs

To comment the 2005 Nobel Price of Chemistry the significance of metathesis reactions in organic synthesis and polymer science is summarized here. In particular, the leading role played by the mechanistic proposals of Yves Chauvin and the development of metalic carbenes as efficient catalysts by the groups of R. R. Schrock and R. H. Grubbs is emphasized

La innovación farmacéutica. Comentarios sobre tres noticias / Pharmaceutical innovation. Comments on three news

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Unique Michael addition-initiated domino reaction for the stereoselective synthesis of functionalized macrolactones from alpha-nitroketones in water.

[reaction: see text]. A unique domino reaction of alpha-nitrocycloalkanones with alpha-alkyl alpha,beta-unsaturated aldehydes in aqueous base was discovered, leading to the one-pot synthesis of hitherto unknown functionalized, bridged, bicyclic lactones containing 10-, 11-, 13-, and 15-membered rings. The structures of these heterocyclic compounds, containing also an unusual 6-hydroxy-1,2-oxazine ring, were determined by spectral and single-crystal X-ray diffraction studies.