RESUMEN

N-heterocyclic compounds are important molecular scaffolds in the search for new drugs, since most drugs contain heterocyclic moieties in their molecular structure, and some of these classes of heterocycles are able to provide ligands for two or more biological targets. Ketene dithioacetals are important building blocks in organic synthesis and are widely used in the synthesis of N-heterocyclic compounds. In this work, we used double vinylic substitution reactions on ketene dithioacetals to synthesize a small library of heterocyclic derivatives and evaluated their cytotoxic activity in breast and ovarian cancer cells, identifying two benzoxazoles with good potency and selectivity. In silico predictions indicate that the two most active derivatives exhibit physicochemical properties within the range of drug-like compounds and showed potential to interact with HDAC8 and ERK1 cancer-related targets.

Asunto(s)

Antineoplásicos , Etilenos , Compuestos Heterocíclicos , Cetonas , Humanos , Línea Celular Tumoral , Etilenos/química , Etilenos/farmacología , Compuestos Heterocíclicos/química , Compuestos Heterocíclicos/farmacología , Compuestos Heterocíclicos/síntesis química , Antineoplásicos/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Cetonas/química , Cetonas/farmacología , Cetonas/síntesis química , Relación Estructura-Actividad , Histona Desacetilasas/metabolismo , Simulación del Acoplamiento Molecular , Ensayos de Selección de Medicamentos Antitumorales , Acetales/química , Acetales/farmacología , Acetales/síntesis química , Proteínas Represoras

RESUMEN

Chagas disease and Leishmaniasis are neglected endemic protozoan diseases recognized as public health problems by the World Health Organization. These diseases affect millions of people around the world however, efficient and low-cost treatments are not available. Different steroid molecules with antimicrobial and antiparasitic activity were isolated from diverse organisms (ticks, plants, fungi). These molecules have complex structures that make de novo synthesis extremely difficult. In this work, we designed new and simpler compounds with antiparasitic potential inspired in natural steroids and synthesized a series of nineteen steroidal arylideneketones and thiazolidenehydrazines. We explored their biological activity against Leishmania infantum, Leishmania amazonensis, and Trypanosoma cruzi in vitro and in vivo. We also assayed their genotoxicity and acute toxicity in vitro and in mice. The best compound, a steroidal thiosemicarbazone compound 8 (ID_1260) was active in vitro (IC50 200 nM) and in vivo (60% infection reduction at 50 mg/kg) in Leishmania and T. cruzi. It also has low toxicity in vitro and in vivo (LD50 >2000 mg/kg) and no genotoxic effects, being a promising compound for anti-trypanosomatid drug development.

Asunto(s)

Enfermedad de Chagas/tratamiento farmacológico , Leishmaniasis/tratamiento farmacológico , Esteroides/uso terapéutico , Tiosemicarbazonas/uso terapéutico , Tripanocidas/química , Tripanocidas/uso terapéutico , Animales , Desarrollo de Medicamentos , Humanos , Hidrazinas/síntesis química , Hidrazinas/química , Hidrazinas/farmacología , Cetonas/síntesis química , Cetonas/química , Cetonas/farmacología , Leishmania infantum/efectos de los fármacos , Leishmania mexicana/efectos de los fármacos , Macrófagos/efectos de los fármacos , Macrófagos/parasitología , Ratones , Pruebas de Sensibilidad Parasitaria , Esteroides/síntesis química , Esteroides/química , Relación Estructura-Actividad , Tiosemicarbazonas/síntesis química , Tiosemicarbazonas/química , Tiosemicarbazonas/toxicidad , Tripanocidas/síntesis química , Tripanocidas/farmacología , Trypanosoma cruzi/efectos de los fármacos

RESUMEN

The useful synthons sugar enones (2-benzyloxypyran-3-ones) derived from pentoses have been prepared starting from 2-acetoxyglycals or benzyl pentopyranosides. The glycals were glycosylated with benzyl alcohol in the presence of a Lewis acid (SnCl4 or InCl3) to give enantioenriched enones (ee = 80-90%). Under catalysis with InCl3, benzyl 2-enopyranosides gave also the enones (ee = 87%). On the other hand, enantiomerically pure enones were synthesized via an improved straightforward and high yielding sequence (70% overall) from benzyl pentopyranosides. However, the yields of both, the glycosylation of glycals as well as some specific reactions of the sequence from glycosides, were lowered when a p-nitro substituent was introduced into the benzyl group. These routes became impractical in the case of p-acetamidobenzyl derivatives, because of the large extent of decomposition. Therefore, alternative sequences have been developed for the synthesis of 2-(p-acetamidobenzyloxy)pyran-3-ones.

Asunto(s)

Cetonas/química , Cetonas/síntesis química , Pentosas/química , Catálisis , Técnicas de Química Sintética , Glicosilación , Estereoisomerismo

RESUMEN

The cytotoxic activity of the pimarane diterpene annonalide (1) and nine of its semisynthetic derivatives (2-10) was investigated against the human tumor cell lines HL-60 (leukemia), PC-3 (prostate adenocarcinoma), HepG2 (hepatocellular carcinoma), SF-295 (glioblastoma) and HCT-116 (colon cancer), and normal mouse fibroblast (L929) cells. The preparation of 2-10 involved derivatization of the side chain of 1 at C-13. Except for 2, all derivatives are being reported for the first time. Most of the tested compounds presented IC50s below 4.0 µM, being considered potential antitumor agents. The structures of all new compounds were elucidated by spectroscopic analyses including 2D NMR and HRMS. Additionally, the interaction of annonalide (1) with ctDNA was evaluated using spectroscopic techniques, and the formation of a supramolecular complex with the macromolecule was confirmed. Competition assays with fluorescent probes (Hoechst and ethidium bromide) and theoretical studies confirmed that 1 interacts preferentially via DNA intercalation with stoichiometric ratio of 1:1 (1:ctDNA). The ΔG value was calculated as -28.24 kJ mol-1, and indicated that the interaction process occurs spontaneously. Docking studies revealed that van der Walls is the most important interaction in 1-DNA and EB-DNA complexes, and that both ligands (1 and EB) interact with the same DNA residues (DA6, DA17 and DT19).

Asunto(s)

Ciclooctanos/química , ADN/química , Cetonas/química , Animales , Sitios de Unión , Bovinos , Línea Celular Tumoral , Supervivencia Celular , Ciclooctanos/síntesis química , Ciclooctanos/toxicidad , ADN/metabolismo , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Cetonas/síntesis química , Cetonas/toxicidad , Simulación del Acoplamiento Molecular , Conformación de Ácido Nucleico , Espectrofotometría , Electricidad Estática , Termodinámica , Temperatura de Transición

RESUMEN

Secondary and tertiary alcohols synthesized via allylation of aldehydes and ketones are important compounds in bioactive natural products and industry, including pharmaceuticals. Development of a mechanochemical method using potassium allyltrifluoroborate salt and water, to successfully perform the allylation of aromatic and aliphatic carbonyl compounds is reported for the first time. By controlling the grinding parameters, the methodology can be selective, namely, very efficient for aldehydes and ineffective for ketones, but by employing lanthanide catalysts, the reactions with ketones can become practically quantitative. The catalyzed reactions can also be performed under mild aqueous stirring conditions. Considering the allylation agent and its by-products, aqueous media, energy efficiency and use of catalyst, the methodology meets most of the green chemistry principles.

Asunto(s)

Aldehídos/química , Tecnología Química Verde , Cetonas/química , Alcoholes/química , Aldehídos/síntesis química , Catálisis , Cetonas/síntesis química , Elementos de la Serie de los Lantanoides , Solventes/química

RESUMEN

In this paper we present the convenient syntheses of six new guanylhydrazone and aminoguanidine tetrahydropyran derivatives 2-7. The guanylhydrazone 2, 3 and 4 were prepared in 100% yield, starting from corresponding aromatic ketones 8a-c and aminoguanidine hydrochloride accessed by microwave irradiation. The aminoguanidine 5, 6 and 7 were prepared by reduction of guanylhydrazone 2-4 with sodium cyanoborohydride (94% yield of 5, and 100% yield of 6 and 7). The aromatic ketones 8a-c were prepared from the Barbier reaction followed by the Prins cyclization reaction (two steps, 63%-65% and 95%-98%). Cytotoxicity studies have demonstrated the effects of compounds 2-7 in various cancer and normal cell lines. That way, we showed that these compounds decreased cell viabilities in a micromolar range, and from all the compounds tested we can state that, at least, compound 3 can be considered a promising molecule for target-directed drug design.

Asunto(s)

Guanidinas/síntesis química , Hidrazonas/síntesis química , Neoplasias/tratamiento farmacológico , Piranos/síntesis química , Borohidruros/síntesis química , Borohidruros/química , Línea Celular Tumoral , Ciclización , Guanidinas/administración & dosificación , Guanidinas/química , Humanos , Hidrazonas/administración & dosificación , Hidrazonas/química , Cetonas/síntesis química , Cetonas/química , Estructura Molecular , Piranos/administración & dosificación , Piranos/química

RESUMEN

The interface between synthetic organic chemistry and natural products was explored in order to unravel the structure of coibacin A, a metabolite isolated from the marine cyanobacterium cf. Oscillatoria sp. that exhibits selective antileishmanial activity and potent anti-inflammatory properties. Our synthetic plan focused on a convergent strategy that allows rapid access to the desired target by coupling of three key fragments involving E-selective Wittig and modified Julia olefinations. CD measurements and comparative HPLC analyses of the natural product and four synthetic stereoisomers led to determination of its absolute configuration, thus correcting the original assignment at C-5 and unambiguously establishing those at C-16 and C-18. Additionally, we synthesized coibacin B on the basis of the assignment of configuration for coibacin A.

Asunto(s)

Cetonas/química , Cetonas/síntesis química , Lactonas/química , Lactonas/síntesis química , Oscillatoria/química , Cetonas/aislamiento & purificación , Lactonas/aislamiento & purificación , Conformación Molecular , Estereoisomerismo

RESUMEN

The stereoselective preparation of α,ß-unsaturated diazoketones with Z geometry is described from aldehydes and a new olefination reagent. When prepared from amino aldehydes, these diazoketones could be converted to substituted dihydropyridin-3-ones in just one step, after an intramolecular N-H insertion reaction. The straightforward synthesis of a natural trihydroxylated piperidine demonstrates the utility of these unsaturated diazoketones for the rapid construction of piperidines.

Asunto(s)

Aldehídos/química , Compuestos Azo/síntesis química , Cetonas/síntesis química , Piridonas/síntesis química , Compuestos Azo/química , Cetonas/química , Estructura Molecular , Piridonas/química

RESUMEN

The solvent-free indium-promoted reaction of alkanoyl chlorides with sterically and electronically diverse arylstannanes is a simple and direct method for the regioselective synthesis of primary, secondary and tertiary alkyl aryl ketones in good to excellent isolated yields (42-84%) under mild and neutral conditions. The protocol is also adequate for the synthesis of aryl vinyl ketones. Reaction times are drastically reduced (from 3-32h to 10-70min) under ultrasonic irradiation. Evidences for the involvement of a homolytic aromatic ipso-substitution mechanism, in which indium metal acts as radical initiator, are presented. It is possible the transference of two aryl groups from tin, thus improving effective mass yield, working with diarylstannanes as starting substrates.

Asunto(s)

Indio/química , Cetonas/síntesis química , Sonicación , Compuestos de Estaño/química , Catálisis , Hidrocarburos Clorados/química , Cetonas/química , Cetonas/efectos de la radiación , Estructura Molecular , Sonido , Compuestos de Estaño/efectos de la radiación

RESUMEN

The Weinreb amides 2a,b were prepared from the α,α-dimethoxyacetic acids 1c,d. A number of representative nucleophilic additions (RMgX and RLi) on 2 afforded α-ketoacetals 3a-j in 70-99% yield. These compounds represent a versatile arrangement of functional groups of significant synthetic value, as demonstrated in the synthesis of (±)-salbutamol.

Asunto(s)

Albuterol/síntesis química , Amidas/síntesis química , Cetonas/síntesis química , Estructura Molecular , Estereoisomerismo

RESUMEN

The mechanism of the Dakin-West reaction has been thoroughly investigated by monitoring the reaction using ESI-MS/MS techniques in combination with M06-2X/6-311++G(d,p) calculations. Several of the key intermediates in the previously proposed "azlactone" mechanism have been experimentally detected and characterized. In particular, interception of the mixed anhydrides involved in the early and late stages of the mechanistic scheme, as well as of the cyclic acyl-oxazolone intermediate, supports the original pathway suggested by Dakin and West. All intermediates and transition structures involved in several competing mechanisms have been calculated. The theoretical calculations support the experimental results and corroborate the proposed "azlactone" mechanism. The pathway involving the cyclic oxazolone ("azlactone") intermediate represents an energy barrier more than 3 kcal mol(-1) lower than for the competing aldol-type mechanism, thus ruling out this alternative mechanism. The DFT calculations explain the observed ESI-MS data and assess those intermediates which the experiments cannot fully elucidate.

Asunto(s)

Aminoácidos/química , Cetonas/química , Cetonas/síntesis química , Teoría Cuántica , Anhídridos/química , Modelos Moleculares , Conformación Molecular , Oxazolona/química

RESUMEN

Cellulose-derived chiral pyrrolidines were synthesized in excellent yields, regioselectivities, and stereoselectivities via a 1,3-dipolar cycloaddition reaction between levoglucosenone and azomethine ylides. An unprecedented isomerization event led to a new family of pyrrolidines with an unusual relative stereochemistry. Preliminary results showed that these compounds are promising organocatalysts for iminium ion-based asymmetric Diels-Alder reactions.

Asunto(s)

Compuestos Azo/química , Compuestos Bicíclicos Heterocíclicos con Puentes/química , Celulosa/química , Glucosa/análogos & derivados , Cetonas/química , Pirrolidinas/síntesis química , Tiosemicarbazonas/química , Catálisis , Reacción de Cicloadición , Glucosa/química , Cetonas/síntesis química , Estructura Molecular , Pirrolidinas/química , Estereoisomerismo

RESUMEN

Three polyhydroxylated ketones bearing the 5α-hydroxy-6-oxo moiety were obtained from cholesterol. Two of them show plant growth promoting activity in the bean's second internode bioassay. The obtained results indicate that the presence of the 5α-hydroxy-6-oxo moiety may be capable to induce plant growth promotion even the absence oxygenated functions in the side chain.

Asunto(s)

Colestanos/química , Fabaceae/crecimiento & desarrollo , Cetonas/síntesis química , Modelos Químicos , Relación Dosis-Respuesta a Droga , Fabaceae/efectos de los fármacos , Hidroxilación , Cetonas/química , Cetonas/farmacología , Estructura Molecular , Relación Estructura-Actividad

RESUMEN

Bulky arylstannanes and bulky aroyl chlorides are good reaction partners for the synthesis of two-, three-, and even four-ortho-substituted benzophenones, in good to excellent isolated yields (47-91%). Three simple and direct routes, with differential advantages, are proposed: (i) a catalyst-free protocol, in o-dichlorobenzene (ODCB) at 180 °C; (ii) a room temperature protocol, using AlCl(3) (0.5 equiv), in dichloromethane (DCM); and (iii) a solvent-free, indium-promoted procedure. A radical mechanism is proposed for the indium-mediated reactions.

Asunto(s)

Cetonas/química , Cetonas/síntesis química , Compuestos de Estaño/química , Catálisis , Clorobencenos/química , Indicadores y Reactivos/química , Indio/química , Especificidad por Sustrato

RESUMEN

This paper describes a new method for the preparation of 1,5-bis(4-hydroxy-3-methoxyphenyl)-1,4-pentadien-3-one 1 and its derivatives 2-5. This set of synthetic compounds exhibited high antitumoral activities regarding in vitro screening against several human tumor cell lines as lung carcinoma NCI-460, melanoma UACC-62, breast MCF-7, colon HT-29, renal 786-O, ovarian OVCAR-03 and ovarian expressing the resistance phenotype for adriamycin NCI-ADR/RES, prostate PC-3, and leukemia K-562. Compounds were also tested against murine tumor cell line B16F10 melanoma and lymphocytic leukemia L1210 as well as to their effect toward normal macrophages. Specific activity against colon cancer cells HT-29 was observed for all tested compounds and suggests further studies with models of colon cancer. Compounds 1, 2, and 4 showed significant cytotoxic activity with IC(50) values 2.3 microM for all human cancer cell lines. Intraperitoneal acute administration of compound 1 and 2 showed very low toxicity rate.

Asunto(s)

Anisoles/farmacología , Antineoplásicos/farmacología , Cetonas/farmacología , Animales , Anisoles/síntesis química , Anisoles/química , Antineoplásicos/síntesis química , Antineoplásicos/química , Línea Celular Tumoral , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Cetonas/síntesis química , Cetonas/química , Ratones , Relación Estructura-Actividad

RESUMEN

This work describes the synthesis and anti-inflammatory properties of a pentadienone derivative, HB2. The treatment with HB2 produced anti-oedematogenic, anti-inflammatory and antinociception without change locomotors performance. Finally, HB2 reduced the nitric oxide and prostaglandin E(2) production on RAW 264.7 cells stimulated with LPS without changing the cell viability. Taken together, our results show, for the first time, that HB2 can modulate the inflammatory response when administered to mice.

Asunto(s)

Analgésicos/uso terapéutico , Anisoles/uso terapéutico , Antiinflamatorios/uso terapéutico , Inflamación/tratamiento farmacológico , Cetonas/uso terapéutico , Dolor/tratamiento farmacológico , Analgésicos/síntesis química , Analgésicos/farmacología , Animales , Anisoles/síntesis química , Anisoles/farmacología , Antiinflamatorios/síntesis química , Antiinflamatorios/farmacología , Línea Celular , Supervivencia Celular/efectos de los fármacos , Dinoprostona/metabolismo , Edema/inducido químicamente , Edema/tratamiento farmacológico , Inflamación/inducido químicamente , Cetonas/síntesis química , Cetonas/farmacología , Masculino , Ratones , FN-kappa B/metabolismo , Óxido Nítrico/metabolismo , Dolor/inducido químicamente

RESUMEN

Good levels of substrate-controlled, 1,5- syn-stereoinduction are obtained in boron-mediated aldol reactions of beta-trichloromethyl-beta-alkoxy and beta-trifluoromethyl-beta-alkoxy methylketones with achiral aldehydes, independent of the nature of the beta-alkoxy protecting group (TBS or PMB). In the case of boron aldol reactions of beta-aryl-beta-alkoxy methylketones, the 1,5- anti-adducts were obtained with high levels of diastereoselectivity only with a beta-OPMB group.

Asunto(s)

Alcoholes/química , Aldehídos/química , Compuestos de Boro/química , Cetonas/química , Cetonas/síntesis química , Estereoisomerismo

RESUMEN

Synthetic studies on Mansonone F and Biflorin are described. Synthesis of ketone 12 has been achieved by utilizing tetrahydronaphthalene 8 which in turn was prepared from the 5-methoxy-alpha-tetralone 3. The conversion of 8 into ketone 12 was accomplished in four steps (O-alkylation with ethyl bromoacetate, dehydrogenation, alkaline hydrolysis and cyclization with phosponate ester).

Asunto(s)

Naftoquinonas/síntesis química , Sesquiterpenos/síntesis química , Cetonas/síntesis química , Cetonas/química , Espectroscopía de Resonancia Magnética , Espectrometría de Masas , Naftoles/síntesis química , Naftoles/química , Piranos/síntesis química , Piranos/química , Espectrofotometría Infrarroja , Tetralonas/química

RESUMEN

A study on the addition of trineophyltin hydride (1) to alkynones under free radical (AIBN and Et3B) and palladium-catalyzed [(PPh3)2PdCl2] conditions is reported. The results obtained indicate that the addition of 1 to eight ynones catalyzed by bis(triphenylphosphine)palladium(II) chloride led in all cases to addition products in very high yields (80-96%). These additions take place with excellent regio- and stereochemistry, leading to the alpha adducts as major products in seven out of the eight cases studied. Also the E adducts, resulting from a syn attack, were the only (seven cases) or the predominant (one case) products. The radical hydrostannations initiated by AIBN of ynones 2-5 with 1 led to addition products in good yields (60-88%); with the more hindered ketones 6 and 7-9 the yields obtained were lower. The radical additions initiated by triethylboron to ynones 2-6 follow a similar pattern but with lower yields; no addition products in the hydrostannation of ynones 7-9 were detected. The new acyl-substituted vinylstannanes, owing to their greater stability compared with that of their tributyl- and trimethylstannyl analogues, can be purified by column chromatography using neutral alumina (in all cases) or silica gel 60 (in most cases) as adsorbents. Full 1H, 13C, and 119Sn NMR data are given.

Asunto(s)

Alquenos/síntesis química , Cetonas/síntesis química , Compuestos Organometálicos/síntesis química , Estaño/química , Alquinos/química , Catálisis , Radicales Libres/química , Paladio/química , Estereoisomerismo

RESUMEN

A set of structurally related compounds incorporating a carbonyl group in the ortho position with regard to a phenol function were tested against the TA3 mouse carcinoma cell line and its multidrug-resistant variant TA3-MTX-R. The series consists of 2'-hydroxyacetophenone, 4'-hydroxyacetophenone 2',5'-dihydroxyacetophenone, 4-acetyl-3,3-dimethyl-5-hydroxy-2-morpholino-2,3-dihydrobenzobfuran, five 4,4-dimethyl-5,8-dioxygenated naphtalene-1-ones and three 4,4-dimethyl-5,8-dioxygenated tetralones. A tentative structure-activity relationship was found for this family of substances, suggesting that a coplanar ortho-carbonyl-1,4-hydroquinone motif is able to cause inhibition of cellular respiration.

Asunto(s)

Respiración de la Célula/efectos de los fármacos , Fenoles/síntesis química , Animales , Resistencia a Múltiples Medicamentos , Cetonas/síntesis química , Cetonas/farmacología , Ratones , Consumo de Oxígeno/efectos de los fármacos , Fenoles/farmacología , Relación Estructura-Actividad , Células Tumorales Cultivadas