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1.
J Public Health Res ; 12(2): 22799036231175480, 2023 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-37251415

RESUMEN

Background: Occupational hazards believed to cause musculoskeletal disorders in rope workers are traditionally associated with maintaining incongruous postures for prolonged periods of time. Design and methods: A cross-sectional survey was conducted on 132 technical operators in the wind energy and acrobatic construction sectors, who work on ropes, analysing the ergonomic characteristics of the environments, the way in which tasks are carried out, the strain perceived by individual workers, and assessing the presence of any musculoskeletal disorders (MSDs) by means of an objective examination focused on the anatomical districts that were the object of our study. Results: Analysis of the data obtained showed that there were differences in the perception of the level of physical intensity and perceived exertion between the groups of workers. Statistical analysis also revealed a significant association between the frequency of MSDs analysed and perceived exertion. Discussion: The most significant finding to emerge from this study is the high prevalence of MSDs of the cervical spine (52.94%), the upper limbs (29.41%), and the dorso-lumbar spine (17.65%). These values differ from those classically found in those exposed to the risk of conventional manual handling of loads. Conclusions: The high prevalence of disorders of the cervical spine, the scapulo-humeral girdle and the upper limbs, indicates the need to consider the forced position to be assumed for a large part of the work activity, staticity, and the inability to move the lower limbs for long periods as the predominant risk in rope work.

2.
Eur J Med Chem ; 213: 113070, 2021 Mar 05.
Artículo en Inglés | MEDLINE | ID: mdl-33309162

RESUMEN

The quinazolinone nucleus represents, among the class of fused heterocycles, a very important scaffold to obtain molecules with biological activities. A review of literature revealed how such kind of fused heterocycles, coming from natural or synthetic source, are associated with a wide range of biological activities. This review is mainly directed towards the 4-(3H)-quinazolinones N-3 substituted with a five membered heterocycle in which all the possible combinations of nitrogen, sulfur and oxygen atoms are present.


Asunto(s)
Quinazolinonas/química , Animales , Antiinfecciosos/química , Antiinfecciosos/farmacología , Antiinflamatorios/química , Antiinflamatorios/farmacología , Anticonvulsivantes/química , Anticonvulsivantes/farmacología , Antineoplásicos/química , Antineoplásicos/farmacología , Antioxidantes/química , Antioxidantes/farmacología , Antituberculosos/química , Antituberculosos/farmacología , Benzotiazoles/química , Broncodilatadores/química , Broncodilatadores/farmacología , Humanos , Estructura Molecular , Nitrógeno/química , Oxígeno/química , Quinazolinonas/farmacología , Azufre/química , Tiazoles/química
3.
Bioorg Chem ; 101: 103989, 2020 08.
Artículo en Inglés | MEDLINE | ID: mdl-32563004

RESUMEN

Polycyclic or O-glycoconiugate polycyclic compounds 1a-g were previously tested for their in vitro antiproliferative activity. In this series of compounds, activity increases as log P decreases. Specifically, compounds 1d and 1g showed lower log P values together with the best antiproliferative profiles. With the aim of extending our understanding of the structure-activity relationship (SAR) of this class of compounds, we prepared new polycyclic derivatives 2a-c, which bear on each of the two phenyl rings hydrophilic substituents (OH, SO2NH2 or NHCOCH3). These substituents are able to form hydrogen bonds and to decrease the partition coefficient value as compared with compound 1d. Compound 2a was slightly more active than 1d, while 2b and 2c had antiproliferative activity comparable to that of 1d. Finally, the role of the two phenyl groups of polycycle derivatives 1 was also investigated. The analog 3, which bears two methyls instead of the two phenyls had a lower log P value (2.94 ± 1.22) than all the other compounds, but it had negligible antiproliferative activity at 10 µM. The analysis of the most active derivative 2a revealed a significant antiproliferative activity against the triple-negative breast cancer cell line MDA-MB231. After a 24 h treatment, an autophagic process was activated, as demonstrated by an increase in monodansylcadaverine-positive cells as well as by the appearance of the autophagic markers Beclin and LC3II. Prolonging the treatment to 48 h, 2a caused cytotoxicity through the activation of caspase-dependent apoptosis.


Asunto(s)
Proliferación Celular/efectos de los fármacos , Compuestos Policíclicos/síntesis química , Compuestos Policíclicos/farmacología , Apoptosis/efectos de los fármacos , Autofagia/efectos de los fármacos , Línea Celular Tumoral , Cristalografía por Rayos X , Humanos , Enlace de Hidrógeno , Compuestos Policíclicos/química , Relación Estructura-Actividad
4.
Bioorg Chem ; 83: 367-379, 2019 03.
Artículo en Inglés | MEDLINE | ID: mdl-30408649

RESUMEN

Based on some common structural features of known compounds interfering with p53 pathways and our previously synthesized benzamides, we synthesized new ethyl 5-(4-substituted benzamido)-1-phenyl-1H-pyrazole-4-carboxylates 26a-c, ethyl 5-(4-substituted benzamido)-1-(pyridin-2-yl)-1H-pyrazole-4-carboxylates 27a-c and N-(1H-indazol-6-yl)-4-substituted benzamides 31a,b bearing in the 4 position of the benzamido moiety the 2-phenylpropanamido or 2-phenoxyacetamido or cinnamamido groups. A preliminary test to evaluate the antiproliferative activity against human lung carcinoma H292 cells highlighted how compound 26c showed the best activity. This last was therefore selected for further studies with the aim to find the mechanism of action. Compound 26c induces intrinsic apoptotic pathway by activating p53 and is also able to activate TRAIL-inducing death pathway by promoting increase of DR4 and DR5 death receptors, downregulation of c-FLIPL and caspase-8 activation.


Asunto(s)
Antineoplásicos/farmacología , Benzamidas/farmacología , Indazoles/farmacología , Pirazoles/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/toxicidad , Apoptosis/efectos de los fármacos , Benzamidas/síntesis química , Benzamidas/toxicidad , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Indazoles/síntesis química , Indazoles/toxicidad , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Pirazoles/síntesis química , Pirazoles/toxicidad
5.
Pharmacol Rep ; 70(6): 1124-1132, 2018 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-30317127

RESUMEN

BACKGROUND: Compounds acting on endocannabinoid system regulate different neuronal processes through the cannabinoid receptors activation. The main aim of this study was determining whether the 2-styrylquinazolin-4(3H)-one 5, a structural analogue of rimonabant, was able to counteract the behavioural signs of the activation of the endocannabinoidergic system induced by CP 55.940. METHODS: Behavioural assessment was carried out using the tetrad task and the novel object recognition test. The endocannabinoidergic system activation was possible by the administration of CP 55.940 and 30min after rats were tested in the tetrad task for the evaluation of the antinociceptive-, cataleptic-, hypothermic- and locomotor- effects. The evaluation of the declarative memory was carried out through the novel object recognition test. The administration of the new compound was made at three different doses, 30min before CP 55.940 administration on a separate group of animals. RESULTS: Our results demonstrated that compound 5, at the highest dose, was able to counteract the effects exerted by CP 55.940, shown by an increase in body temperature, total distance travelled, latency to fall and decrease in tail flick latency, interfering conjointly in memory impairment. CONCLUSION: This study shows that compound 5 is able to counteract the cannabinoid activation induced by the agonist CP 55.940. Further investigations on its pharmacological profile are mandatory before considering it as a potential candidate for clinical studies and its possible employment as pharmacological agent for the management of different pathological conditions such as motor incoordination, obesity and brain related disorders.


Asunto(s)
Cannabinoides/farmacología , Ciclohexanoles/farmacología , Locomoción/efectos de los fármacos , Quinazolinas/farmacología , Reconocimiento en Psicología/efectos de los fármacos , Estirenos/farmacología , Animales , Cannabinoides/química , Ciclohexanoles/química , Relación Dosis-Respuesta a Droga , Locomoción/fisiología , Proyectos Piloto , Quinazolinas/química , Ratas , Ratas Wistar , Reconocimiento en Psicología/fisiología , Estirenos/química
6.
Eur J Med Chem ; 142: 213-228, 2017 Dec 15.
Artículo en Inglés | MEDLINE | ID: mdl-28793973

RESUMEN

In this review we report the recent advances in anticancer activity of the family of natural occurring flavonoids, covering the time span of the last five years. The bibliographic data will be grouped, on the basis of biological information, in two great categories: reports in which the extract plants bioactivity is reported and the identification of each flavonoid is present or not, and reports in which the anticancer activity is attributable to purified and identified flavonoids from plants. Wherever possible, the targets and mechanisms of action as well as the structure-activity relationships of the molecules will be reported. Also, in the review it was thoroughly investigated the recent discovery on flavonoids containing the 2-phenyl-4H-chromen-4-one system even if some examples of unusual flavonoids, bearing a non-aromatic B-ring or other ring condensed to the base structure are reported.


Asunto(s)
Antineoplásicos Fitogénicos/química , Antineoplásicos Fitogénicos/farmacología , Descubrimiento de Drogas , Flavonoides/química , Flavonoides/farmacología , Neoplasias/tratamiento farmacológico , Animales , Benzopiranos/química , Benzopiranos/farmacología , Descubrimiento de Drogas/métodos , Humanos , Plantas/química , Relación Estructura-Actividad
7.
Eur J Med Chem ; 132: 262-273, 2017 May 26.
Artículo en Inglés | MEDLINE | ID: mdl-28365319

RESUMEN

Several anthranilamide-based 2-phenylcyclopropane-1-carboxamides 13a-f, 1,1'-biphenyl-4-carboxamides 14a-f and 1,1'-biphenyl-2-carboxamides 17a-f were obtained by a multistep procedure starting from the (1S,2S)-2-phenylcyclopropane-1-carbonyl chloride 11, the 1,1'-biphenyl-4-carbonyl chloride 12 or the 1,1'-biphenyl-2-carbonyl chloride 16 with the appropriate anthranilamide derivative 10a-f. Derivatives 13a-f, 14a-f and 17a-f showed antiproliferative activity against human leukemia K562 cells. Among these derivatives 13b, 14b and 17b exerted a particular cytotoxic effect on tumor cells. Derivative 17b showed a better antitumoral effect on K562 cells than 13b and 14b. Analyses performed to explore 17b mode of action revealed that it induced an arrest in G2/M phase of cell cycle which was consequent to DNA lesions as demonstrated by the increase in phospho-ATM and γH2AX, two known markers of DNA repair response system. The effect of 17b was also related to ROS generation, activation of JNK and induction of caspase-3 dependent apoptosis.


Asunto(s)
Antineoplásicos/síntesis química , ortoaminobenzoatos/farmacología , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Puntos de Control del Ciclo Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Daño del ADN/efectos de los fármacos , Reparación del ADN , Fase G2 , Humanos , Células K562 , ortoaminobenzoatos/síntesis química
8.
Eur J Med Chem ; 122: 247-256, 2016 Oct 21.
Artículo en Inglés | MEDLINE | ID: mdl-27372287

RESUMEN

A natural like O-glycoconjugate polycyclic compound 4 was obtained by a multistep procedure starting from N-(3-methyl-1-(4-nitrophenyl)-1H-pyrazol-5-yl)acetamide. The glycosyl derivative 4 showed antiproliferative activity against all the tumoral cell lines of the NCI panel in the range 0.47-5.43 µM. Cytofluorimetric analysis performed on MDA-MB231, a very aggressive breast cancer cell line, which does not express estrogen, progesterone and HER-2/neu receptors, showed that 4 is able to induce prolonged cell cycle arrest at G2/M phase and morphological signs of differentiation. These events are correlated with down-regulation of both cyclin B1 and cdc2, the cyclins involved in G2/M transition, as well as up-regulation of cyclin-dependent kinase (CDK) inhibitor p21 Cip1/Waf1.


Asunto(s)
Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Productos Biológicos/química , Diseño de Fármacos , Glicoconjugados/síntesis química , Glicoconjugados/farmacología , Compuestos Policíclicos/química , Antineoplásicos/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Técnicas de Química Sintética , Puntos de Control de la Fase G2 del Ciclo Celular/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Glicoconjugados/química , Humanos , Puntos de Control de la Fase M del Ciclo Celular/efectos de los fármacos , Receptor ErbB-2/metabolismo , Receptores de Progesterona/metabolismo
9.
Eur J Med Chem ; 123: 58-68, 2016 Nov 10.
Artículo en Inglés | MEDLINE | ID: mdl-27474923

RESUMEN

The ability of several N-phenyl-1H-pyrazole-4-carboxamide derivatives and other pyrazoles opportunely modified at the positions 3, 4 and 5, to reduce the formation of the biofilm in some Staphylococcus aureus strains (ATCC 29213, ATCC 25923 and ATCC 6538) were investigated. All the tested compounds were able, although to a different extent, to reduce the biofilm formation of the three bacterial strains considered. Among these, the 1-(2,5-dichlorophenyl)-5-methyl-N-phenyl-1H-pyrazole-4-carboxamide 14 resulted as the best inhibitor of biofilm formation showing an IC50 ranging from 2.3 to 32 µM, against all the three strains of S. aureus. Compound 14 also shows a good protective effect in vivo by improving the survival of wax moth larva (Galleria mellonella) infected with S. aureus ATCC 29213. These findings indicate that 14d is a potential lead compound for the development of new anti-virulence agents against S. aureus infections.


Asunto(s)
Biopelículas/efectos de los fármacos , Hidrazinas/farmacología , Pirazoles/farmacología , Infecciones Estafilocócicas/tratamiento farmacológico , Staphylococcus aureus/efectos de los fármacos , Animales , Antibacterianos/síntesis química , Antibacterianos/farmacología , Hidrazinas/síntesis química , Larva/efectos de los fármacos , Mariposas Nocturnas/microbiología , Pirazoles/síntesis química , Staphylococcus aureus/fisiología , Relación Estructura-Actividad , Virulencia/efectos de los fármacos
10.
Molecules ; 21(2): 241, 2016 Feb 19.
Artículo en Inglés | MEDLINE | ID: mdl-26907235

RESUMEN

A FRET-based random screening assay was used to generate hit compounds as sortase A inhibitors that allowed us to identify ethyl 3-oxo-2-(2-phenylhydrazinylidene)butanoate as an example of a new class of sortase A inhibitors. Other analogues were generated by changing the ethoxycarbonyl function for a carboxy, cyano or amide group, or introducing substituents in the phenyl ring of the ester and acid derivatives. The most active derivative found was 3-oxo-2-(2-(3,4dichlorophenyl)hydrazinylidene)butanoic acid (2b), showing an IC50 value of 50 µM. For a preliminary assessment of their antivirulence properties the new derivatives were tested for their antibiofilm activity. The most active compound resulted 2a, which showed inhibition of about 60% against S. aureus ATCC 29213, S. aureus ATCC 25923, S. aureus ATCC 6538 and S. epidermidis RP62A at a screening concentration of 100 µM.


Asunto(s)
Aminoaciltransferasas/antagonistas & inhibidores , Proteínas Bacterianas/antagonistas & inhibidores , Inhibidores Enzimáticos/química , Fenilhidrazinas/química , Aminoaciltransferasas/química , Antiinfecciosos/química , Antiinfecciosos/farmacología , Proteínas Bacterianas/química , Biopelículas/efectos de los fármacos , Cisteína Endopeptidasas/química , Inhibidores Enzimáticos/farmacología , Concentración 50 Inhibidora , Fenilhidrazinas/farmacología , Staphylococcus aureus/efectos de los fármacos , Staphylococcus epidermidis/efectos de los fármacos
11.
Bioorg Med Chem ; 23(19): 6305-16, 2015 Oct 01.
Artículo en Inglés | MEDLINE | ID: mdl-26344588

RESUMEN

Several new 2-(2-phenoxyacetamido)benzamides 17a-v, 21 and 22 were synthesized by stirring in pyridine the acid chlorides 16a-e and the appropriate5-R-4-R1-2-aminobenzamide 15a-e and initially evaluated in vitro for antiproliferative activity against the K562 (human chronic myelogenous leukemia) cell line. Some of synthesized compounds were evaluated for their in vitro antiproliferative activity against the full NCI tumor cell line panel derived from nine clinically isolated cancer types (leukemia, non-small cell lung, colon, CNS, melanoma, ovarian, renal, prostate and breast). The most active compounds caused an arrest of K562 cells in the G0-G1 phase of cell cycle and induction of apoptosis, which was mediated by caspase activation.


Asunto(s)
Antineoplásicos/síntesis química , Benzamidas/química , Antineoplásicos/química , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Benzamidas/síntesis química , Benzamidas/farmacología , Caspasas/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Puntos de Control de la Fase G1 del Ciclo Celular/efectos de los fármacos , Humanos , Células K562 , Microscopía Fluorescente , Relación Estructura-Actividad
12.
Eur J Med Chem ; 96: 98-104, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-25874335

RESUMEN

Based on the encouraging results found for 3,5-dimethyl-6-phenyl-8-(trifluoromethyl)-5,6-dihydropyrazolo[3,4-f][1,2,3,5]tetrazepin-4-(3H)-one 7 previously tested by us, as well as the consideration that heterocycle fused tetrazepinones bearing the 2-chloroethyl substituent show a better cytotoxic profile than temozolomide and mitozolomide against human cancer cell lines which express the DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT), in this paper we report the multistep synthesis and the biological study of 3-(2-chloroethyl)-5-methyl-6-phenyl-8-(trifluoromethyl)-5,6-dihydropyrazolo[3,4-f][1,2,3,5]tetrazepin-4-(3H)-one 10. Like compound 7, it was active on P-glycoprotein expressing cells (MDR) HL60 and on K562 cell line that are resistant to apoptosis induced by different stimuli, showing GI50 values of 14 and 18 µM respectively. As an antiproliferative agent against the above cells compound 10 was about 2.2 times more active than compound 7. Compound 10 was also tested against WiDR cells which are overexpressing the DNA repair protein MGMT, showing a GI50 value of 2.3 µM. Finally, concerning the effect on cell cycle we observed an evident difference between compounds 7 and 10. In fact, compound 7 induces a block of cell cycle in G0-G1, therefore acting as phase-specific drug, in contrast, compound 10 is a not phase-specific agent. Both the compounds are able to increase the apoptotic sub G0-G1 peak of cell cycle.


Asunto(s)
Antineoplásicos/farmacología , Azepinas/farmacología , Pirazoles/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Azepinas/síntesis química , Azepinas/química , Ciclo Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Células HL-60 , Humanos , Células K562 , Estructura Molecular , Pirazoles/síntesis química , Pirazoles/química , Relación Estructura-Actividad
13.
Eur J Med Chem ; 97: 732-46, 2015 Jun 05.
Artículo en Inglés | MEDLINE | ID: mdl-25549911

RESUMEN

In this review we report the recent advances in bioactive system containing pyrazole fused with a five membered heterocycle, covering the time span of the last decade. All of them are represented around the common structure of the pyrazole ring fused with another five membered heterocycle containing the nitrogen, sulfur and oxygen atoms in all their possible combinations. The classification we have used is based in terms of the therapeutic area providing, when possible, some general conclusions on the targets and mechanisms of action as well as the structure-activity relationships of the molecules.


Asunto(s)
Descubrimiento de Drogas/métodos , Pirazoles/química , Pirazoles/farmacología , Animales , Humanos
14.
Eur J Med Chem ; 72: 1-9, 2014 Jan 24.
Artículo en Inglés | MEDLINE | ID: mdl-24333609

RESUMEN

The reaction under reflux between 1-phenyl-3-R-5-methylaminopyrazoles and 2,5-hexanedione lead to 5,7:7,13-dimethanopyrazolo[3,4-b]pyrazolo[3',4':2,3]azepino[4,5-f]azocine derivatives 3b-g. These unusual molecules show the structural complexity of many biologically active natural products and are endowed with the chemical diversity that is required in drug discovery. The compounds 3b,e were reduced by hydrogen in the presence of Palladium on activated charcoal to give the dihydro derivatives 5b,e. Compounds 3b-f and 5b,e were selected by the NCI to evaluate their in vitro antiproliferative activity against 60 human cell lines derived from nine clinically isolated cancer types (leukaemia, lung, colon, melanoma, renal, ovarian, brain, breast, and prostate). The most active compound of this series, caused a block in G0-G1 phase of cell cycle. Analysis of pRb expression showed that this compound favours pRb dephosphorylation.


Asunto(s)
Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Compuestos Heterocíclicos de 4 o más Anillos/síntesis química , Compuestos Heterocíclicos de 4 o más Anillos/farmacología , Compuestos Policíclicos/farmacología , Antineoplásicos/química , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Células HL-60 , Compuestos Heterocíclicos de 4 o más Anillos/química , Humanos , Células K562 , Células MCF-7 , Modelos Moleculares , Estructura Molecular , Compuestos Policíclicos/síntesis química , Compuestos Policíclicos/química , Relación Estructura-Actividad
15.
Eur J Med Chem ; 58: 64-71, 2012 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-23088933

RESUMEN

Several new 4-diazopyrazole derivatives 6a-g and 9a-c were obtained by the reaction of 1-(R-substituted-phenyl)-3-(1,3-dimethyl-1H-pyrazol-5-yl)ureas 5a-g and N-(1,3-dimethyl-1H-pyrazol-5-yl)-2-(R-substituted-phenyl)acetamides 8a-c respectively with a sevenfold excess of nitrous acid in acetic acid solution. The compounds were assayed for their activity against the Staphylococcus aureus reference strains ATCC 25923, ATCC 29213 and ATCC 6538, as well as six veterinary strains. The best anti-staphylococcal profile was showed by [(R-substituted-phenyl)acetyl](4-diazonio-1,3-dimethyl-1H-pyrazol-5-yl)azanides 9a,c. Compound 9c was also able at 3.1 µg mL(-1) to inhibit of 45.7% the biofilm formation of the strains S. aureus ATCC 29213.


Asunto(s)
Antibacterianos/farmacología , Compuestos Azo/farmacología , Pirazoles/farmacología , Staphylococcus aureus/efectos de los fármacos , Antibacterianos/síntesis química , Antibacterianos/química , Compuestos Azo/síntesis química , Compuestos Azo/química , Biopelículas/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Pirazoles/síntesis química , Pirazoles/química , Relación Estructura-Actividad
16.
Eur J Med Chem ; 46(7): 2786-96, 2011 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-21530013

RESUMEN

Several new 2-{[(2E)-3-phenylprop-2-enoyl]amino}benzamides 12a-s and 17t-v were synthesized by stirring in pyridine the (E)-3-(2-R1-3-R2-4-R3-phenyl)acrylic acid chlorides 11c-k and 11t-v with the appropriate anthranilamide derivatives 10a-c or the 5-iodoanthranilic acid 13. Some of the synthesized compounds were evaluated for their in vitro antiproliferative activity against the full NCI tumor cell line panel derived from nine clinically isolated cancer types (leukemia, non-small cell lung, colon, CNS, melanoma, ovarian, renal, prostate and breast). COMPARE analysis, effects on tubulin polymerization in cells and with purified tubulin, and effects on cell cycle distribution for 17t, the most active of the series, indicate that these new antiproliferative compounds act as antitubulin agents.


Asunto(s)
Antineoplásicos/síntesis química , Benzamidas/síntesis química , Moduladores de Tubulina/síntesis química , Tubulina (Proteína)/metabolismo , Acrilatos/química , Antineoplásicos/farmacología , Benzamidas/farmacología , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Concentración 50 Inhibidora , Polimerizacion/efectos de los fármacos , Piridinas/química , Relación Estructura-Actividad , Moduladores de Tubulina/farmacología , ortoaminobenzoatos/química
17.
Eur J Med Chem ; 46(1): 168-74, 2011 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-21130540

RESUMEN

Several new N-phenyl-1H-indazole-1-carboxamides 1c-h and 4l,m were prepared by reacting phenyl isocyanate derivatives 3a,b with 3-amino-1H-indazole derivatives 2c,e,g or 1H-indazole 2l respectively. Chemical transformations of compounds 1a,b and 1g,h gave 3-acetamido-N-phenyl-1H-indazole-1-carboxamide derivatives 5a,b, and 3,5-diamino-N-phenyl-1H-indazole-1-carboxamide derivatives 4i,j respectively. Finally, 3,5-diacetamido-N-phenyl-1H-indazole-1-carboxamide derivatives 6a,b were prepared by acetylation of 4i,j. Some of synthesized compounds were evaluated for their in vitro antiproliferative activity against the full NCI tumor cell lines panel derived from nine clinically isolated cancer types (leukemia, non-small cell lung, colon, CNS, melanoma, ovarian, renal, prostate and breast). Compound 1c, the most active of the series, was able to inhibit cell growth showing GI(50) values in the 0.041-33.6 µM range, mean GI(50) 1.90 µM, being very effective against colon and melanoma cell lines. Cell cycle analysis in K562 cells showed that 1c causes a marked increase of cells in G0-G1 phase. Moreover, it increases the ratio between hypophosphorylated pRb and total pRb.


Asunto(s)
Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Indazoles/síntesis química , Indazoles/farmacología , Antineoplásicos/química , Antineoplásicos/toxicidad , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Humanos , Indazoles/química , Indazoles/toxicidad , Proteína de Retinoblastoma/metabolismo
18.
Arch Pharm (Weinheim) ; 343(11-12): 631-8, 2010 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-21110338

RESUMEN

Pyrazolylbenzotriazinones are endowed with a structural analogy with the COX-2 selective inhibitor celecoxib. Considering that our research group has long been interested in the 3-pyrazolyl-substituted benzotriazinones as anti-inflammatory agents, six new pyrazolylbenzotriazinone derivatives 16a-c and 18a-c have been prepared by reacting the opportune ethyl 5-(2-aminobenzamido)-1-(pyridin-2-yl)-1H-pyrazole-4-carboxylate or 5-(2-aminobenzamido)-1-(pyridin-2-yl)-1H-pyrazole-4-carboxyic acid with sodium nitrite in glacial acetic acid. The biological studies revealed a good pharmacological profile for some pyrazolylbenzotriazinones and, in the case of the ethyl 5-(4-oxo-1,2,3-benzotriazin-3(4H)-yl)-1-pyridin-2-yl-1H-pyrazole-4-carboxylate, a good COX-1/COX-2 selectivity. Molecular modeling studies confirmed the obtained biological results.


Asunto(s)
Inhibidores de la Ciclooxigenasa 2/química , Triazinas/farmacología , Antiinflamatorios/síntesis química , Antiinflamatorios/farmacología , Celecoxib , Inhibidores de la Ciclooxigenasa 2/síntesis química , Humanos , Modelos Moleculares , Pirazoles , Relación Estructura-Actividad , Sulfonamidas
19.
Arch Pharm (Weinheim) ; 342(6): 321-6, 2009 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-19479756

RESUMEN

The pyrazolo[3,4-d]pyrimidine system shows a multitude of interesting pharmacological properties. Owing to the potential anti-inflammatory activity of 5-benzamido-pyrazolo[3,4-d]pyrimidin-4-one derivatives and considering the easy synthesis of this class of compounds, a set of new 5-benzamido-1H-pyrazolo[3,4-d]pyrimidin-4-ones has been prepared in 42-80% yields by reacting 5-aminopyrazole-4(N-benzoyl)carbohydrazide derivatives and the opportune triethylorthoesters. Compounds 8a, b, 10a-d, and 11a, b revealed a superior inhibitory profile against COX-2, when compared to that of reference standards NS398 and indomethacin. Molecular modelling studies confirmed the obtained biological results.


Asunto(s)
Antiinflamatorios/farmacología , Inhibidores de la Ciclooxigenasa 2/farmacología , Pirazoles/farmacología , Pirimidinas/farmacología , Animales , Antiinflamatorios/síntesis química , Simulación por Computador , Ciclooxigenasa 1/efectos de los fármacos , Ciclooxigenasa 1/metabolismo , Inhibidores de la Ciclooxigenasa 2/síntesis química , Humanos , Indometacina/farmacología , Modelos Moleculares , Nitrobencenos/farmacología , Pirazoles/síntesis química , Pirimidinas/síntesis química , Ovinos , Relación Estructura-Actividad , Sulfonamidas/farmacología
20.
Eur J Med Chem ; 43(11): 2386-94, 2008 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-18339455

RESUMEN

The multistep synthesis of 3,5-dimethyl-6-phenyl-8-(trifluoromethyl)-5,6-dihydropyrazolo[3,4-f][1,2,3,5]tetrazepin-4(3H)-one 15 has been carried out. The compound showed antiproliferative and apoptotic effects against K562, K562-R (imatinib mesilate resistant), HL60 and multidrug resistant (MDR) HL60 cell lines. Compound 15 showed a pro-apoptotic activity against HL60 and K562 resistant cell lines markedly higher than etoposide and busulfan, respectively. Flow cytometry studies carried out on K562 cells allowed to establish that 15 induces G0-G1 phase arrest followed by apoptosis.


Asunto(s)
Apoptosis/efectos de los fármacos , Azepinas/síntesis química , Azepinas/farmacología , Fase G1/efectos de los fármacos , Pirazoles/síntesis química , Pirazoles/farmacología , Fase de Descanso del Ciclo Celular/efectos de los fármacos , Azepinas/química , Células HL-60 , Humanos , Células K562 , Estructura Molecular , Pirazoles/química
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