The Masked Polar Group Incorporation (MPGI) Strategy in Drug Design: Effects of Nitrogen Substitutions on Combretastatin and Isocombretastatin Tubulin Inhibitors.

Colchicine site ligands suffer from low aqueous solubility due to the highly hydrophobic nature of the binding site. A new strategy for increasing molecular polarity without exposing polar groups-termed masked polar group incorporation (MPGI)-was devised and applied to nitrogenated combretastatin analogues. Bulky ortho substituents to the pyridine nitrogen hinder it from the hydrophobic pocket while increasing molecular polarity. The resulting analogues show improved aqueous solubilities and highly potent antiproliferative activity against several cancer cell lines of different origin. The more potent compounds showed moderate tubulin polymerization inhibitory activity, arrested the cell cycle of treated cells at the G2/M phase, and subsequently caused apoptotic cell death represented by the cells gathered at the subG0/G1 population after 48 h of treatment. Annexin V/Propidium Iodide (PI) double-positive cells observed after 72 h confirmed the induction of apoptosis. Docking studies suggest binding at the colchicine site of tubulin in a similar way as combretastatin A4, with the polar groups masked by the vicinal substituents. These results validate the proposed strategy for the design of colchicine site ligands and open a new road to increasing the aqueous solubility of ligands binding in apolar environments.

Unexpected Reaction Pathways Leading to Thiodiglycol During the Degradation of Long-Chain Sulfur Mustards.

Degradation of long-chain sulfur mustards with various commercial decontaminants unexpectedly forms thiodiglycol (TDG) through unreported reaction pathways. Chemical warfare agents (CWAs) degradation products have to be unambiguously related to their reference compounds in order to fulfill international verification protocols. Thus, the formation of TDG using water-based decontaminants introduces an uncertainty in the origin of this chemical that has been systematically used to unambiguously demonstrate the presence of yperite in environmental and biomedical samples. Therefore, these novel and unprecedented degradation pathways will result either in modifications of the international verification protocols for forensic purposes or in the exclusion of TDG as an exclusive marker of yperite.

GC-MS Study of Mono- and Bishaloethylphosphonates Related to Schedule 2.B.04 of the Chemical Weapons Convention: The Discovery of a New Intramolecular Halogen Transfer.

A new class of compounds, mono- and bis-haloethylphosphonates (HAPs and bisHAPs, respectively), listed in Schedule 2.B.04 of the Chemical Weapons Convention (CWC), has been synthesized and studied by GC-MS with two aims. First, to improve the identification of this type of chemicals by the Organization for the Prohibition of Chemical Weapons, (OPCW). Second, to study the synergistic effect of halogen and silicon atoms in molecules undergoing mass spectrometry. Fragmentation patterns of trimethylsilyl derivatives of HAPs were found to depend on the nature of the halogen atom; this was in agreement with DFT-calculations. The data suggest that a novel intramolecular halogen transfer takes place during the fragmentation process. Graphical Abstract ᅟ.

Exploring the size adaptability of the B ring binding zone of the colchicine site of tubulin with para-nitrogen substituted isocombretastatins.

We have synthesized and assayed dimethylaminophenyl, pyrrolidin-1-ylphenyl and carbazole containing phenstatins and isocombretastatins as analogues of the highly potent indoleisocombretastatins with extended or reduced ring sizes. This is an attempt to explore beyond the structural constraints of the X-ray crystal structures the zone of the colchicine site where the tropolone ring of colchicine binds to tubulin (zone 1). The isocombretastatins display up to 30 fold increased water solubility when compared with combretastatin A-4, potent inhibition of tubulin polymerization, and nanomolar cytotoxicities against several human cancer cell lines irrespective of the size of the B ring. On the other hand, substitutions ortho to the nitrogen cause an important reduction in potency. We have also shown that representative compounds inhibit autophagy. These results show that zone 1 can adapt to systems of different size as far as they stay in a common plane, but does not tolerate substituents protruding above or below it. These results can help in the understanding of the binding modes of structures with similar systems and in the design of new colchicine site ligands.

Oxazolo[3,2-a]pyridine. A new structural scaffold for the reversal of multi-drug resistance in Leishmania.

Compounds belonging to three different classes of fused heterocyclic systems, structurally related to Calcium-channel blockers of the 1,4-dihydropyridine family, were evaluated in their ability to overcome leishmanial resistance to common drugs in a MDR Leishmania tropica strain. Compounds with the skeletal basis of oxazolo[3,2-a]pyridine displayed significant reversion of resistance to daunomycin and miltefosine, with reversion indexes up to 6.7-fold and 8.7-fold, respectively. Most interestingly, the enantiopure compound 20S attained to revert the resistance to both drugs and fairly more significantly than its enantiomer 20R.

Constituents and biological activities of Schinus polygamus.

The folk medicine employs Schinus polygamus to treat arthritic pain and cleansing of wounds. As no reports of pharmacological studies supporting its anti-inflammatory and analgesic properties, extracts of increasing polarity were assayed on the base of fever, pain and inflammation, together with its antimicrobial activity. All the extracts showed pharmacological activities. From the most active extracts different metabolites were isolated that can in part explain the antipyretic, anti-inflammatory, and analgesic activity: beta-sitosterol, shikimic acid together with quercetin, previously reported. Also, the essential oil of leaves and fruits was obtained and compared with the oil obtained from Schinus polygamus collected in Argentine. Oils differed in composition and in antibacterial activity, where the Chilean species exhibited a wide spectrum of activity against Gram-positive and Gram-negative bacteria, and the most abundant compound found in leaves and fruits was beta-pinene, meanwhile the Argentine species showed high activity against Bacillus cereus, and the main components resulted to be alpha-phellandrene and limonene.

Reactivity of 4-tert-butyldimethylsiloxy-1,2,3,6-tetrahydropyridines with hydrazines.

The reactivity of 6-(nitrophenyl or trimethoxyphenyl)-4-tert-butyldimethyl- siloxy-1,2,3,6-tetrahydropyridine derivatives with hydrazines under acid conditions is described. The structure of the products isolated - hydrazones, pyrazolines or pyridazinones - depended on the conditions used. In addition, a systematic study of the reaction outcomes was carried out by introducing variations on the substituents of the tetrahydropyridine ring.

New naphthylcombretastatins. Modifications on the ethylene bridge.

Compounds with three aromatic systems, carrying a 2-naphthalene and a 3,4,5-trimethoxyphenyl moieties bonded to five-membered, six-membered or fused heterocycles display potent cytotoxic effect and inhibition of tubulin polymerization, in agreement with their structural similarity to combretastatins and their heterocyclic analogues.

Further naphthylcombretastatins. An investigation on the role of the naphthalene moiety.

By synthesis and biological studies of new naphthalene analogues of combretastatins, we have found that the naphthalene is a good surrogate for the isovanillin moiety (3-hydroxy-4-methoxyphenyl) of combretastatin A-4, always generating highly cytotoxic analogues when combined with the 3,4,5-trimethoxyphenyl or related systems. On the other hand, when the naphthalene replaces the 3,4,5-trimethoxyphenyl moiety, the cytotoxic activity is largely decreased. The most cytotoxic naphthalene analogues of combretastatins, which also produce inhibition of tubulin polymerization, exerted their antimitotic effects through microtubule network disruption and subsequent G(2)/M arrest of the cell cycle in human cancer cells.

A new family of quinoline and quinoxaline analogues of combretastatins.

The 3-hydroxy-4-methoxyphenyl ring of combretastatin A-4 can be replaced by a 2-naphthyl moiety without significant loss of cytotoxicity and inhibition of tubulin polymerization potency. In this paper we show that the 6- or 7-quinolyl systems can in turn replace both cyclic moieties, keeping in the first case most of the potency as cytotoxic agent and in the second case as inhibitor of tubulin polymerization, related to the activities displayed by model compounds.

Synthesis and cytotoxic activity of different open indolocarbazole alkaloid analogues.

An array of 4-(aryl or indolyl)pyrrolo[3,4-c]carbazole-1,3-diones (open analogues of indolocarbazole alkaloids), 10-(aryl or indolyl)pyrrolo[3,4-b]carbazole-1,3-diones, and different derivatives have been prepared using a Diels-Alder plus Fischer indolization approach and tested as cytotoxic agents. Some representative compounds display interesting cytotoxic profiles.

Stereodifferentiation of chiral compounds using reversed-phase liquid chromatography coupled with capillary gas chromatography.

A method is described for the enantiomeric quantitation of some chiral compounds via online coupling of reversed-phase liquid chromatography-gas chromatography. The evaluation of some variables affecting the experimentation (i.e., the packing material used in the interface, volume of the transferred fraction, desorption time, initial temperature of the interface, and purge time) makes it possible to optimize the recoveries obtained for some chiral terpenes and lactones using a capillary column of beta-cyclodextrin dissolved in OV-1701. The proposed method allows the enantiomeric analysis of aqueous matrices obtaining relative standard deviations lower than 9% and detection limits ranging from 0.26-0.93 ppm for the investigated compounds.

Naphthalene analogues of lignans.

The methodology for the synthesis of podophyllotoxin and thuriferic acid-type lignans has been applied to derivatives carrying a naphthalene moiety. Starting from the 1,3-dithiane of 2-naphthaldehyde afforded the expected analogues in the 2,1-naphthalene series. The preferred conformations of these compounds are influenced by the bulky naphthalene system. By contrast, 1,8-bridged products were obtained from the 1,3-dithiane of 1-naphthaldehyde. In this series, polycyclic naphthalene lignan analogues were isolated after deprotection and/or desulfurization reactions. The cyclizations produced in this process are due to the proximity between the 3,4,5-trimethoxyphenyl moiety and the reacting C-2 of the 1,3-dithiane ring.

Inotropic activity of hydroindene amidinohydrazones.

Several hydroindenic derivatives (7a-methyl-2,3,5,6,7,7a-hexahydro-1H-indenes), bearing an amidinohydrazone at C-5 and different moieties at C-1, have been synthesized and evaluated for their inotropic and chronotropic effects on right- and left-guinea-pig-atria activity. Three of them showed the same profile as digoxin, although with lower potency. The effect on Na(+),K(+)-ATPase (NKA) was also evaluated for these three compounds, observing that two of them, with the same absolute configuration as natural cardenolides, are also NKA inhibitors, while the compound with the opposite configuration lacks such an effect. More interestingly, both active compounds act without affecting the cardiac rhythm. This could be related to the selective inhibition of the human alpha2beta1 isozyme (associated with the inotropic effect) with respect to the alpha1beta1 isozyme (associated with the maintenance of basal ionic levels in the cell and the toxic effect of cardenolides).

Synthesis and cytotoxic activities of analogues of thuriferic acid.

Several analogues of thuriferic acid and derivatives, with the 3,4-methylenedioxyphenyl ring replaced by naphthalene, furan, thiophene and carbazole ring systems, have been prepared. The synthetic strategy is based on a conjugate addition-alkylation methodology followed by cationic cyclization in order to obtain the isopodophyllone analogues, which are transformed in the thuriferic acids. Their cytotoxic activities against several tumour cells lines are also described.

Obstrucción intestinal mecánica y embarazo en el Hospital Regional Honorio Delgado 1970 a 1994

Se estudia la obstrucción intestinal mecánica durante el embarazo o puerperio en el Hospital Honorio Delgado en los años de 1970-1994, se encontraron 23 casos que determinó una incidencia de un caso en 5229 partos. Se determino como causas más frecuentes bridas y adherencias en un 39.13 por ciento, vólvulo de sigmoides 34.78 por ciento, que el antecedente de cirugía previa por la formación de bridas y adherencias juega un papel importante en la génesis de la obstrucción intestinal, siendo mayor en el primer embarazo que sigue a la cirugía en un 77 por ciento. Se encontró una mayor frecuencia entre el segundo y el tercer trimestre de gestación, que el cuadro clínico pese a ser similar al de pacientes no embarazadas puede presentar dificultad diagnóstica, se consideran aspectos como la edad, procedencia, examenes auxiliares, tratamiento y complicaciones. La mortalidad materna encontrada fue de 8.7 por ciento y la fetal 56.22 por ciento