RESUMEN
BACKGROUND: Collinin is a secondary plant metabolite belonging to the class of geranyloxycoumarins. We explored the potential beneficial impact of collinin on periodontal health by investigating its effect on Porphyromonas gingivalis (P. gingivalis), lipopolysaccharide (LPS)-induced inflammatory response of macrophages, and osteoclastogenesis. METHODS: Collinin was synthesized from pyrogallol and propiolic acid. A microdilution assay was used to determine antibacterial activity of collinin. The effect of collinin on collagenase activity of P. gingivalis was determined using fluorescent collagen. Macrophages were treated with collinin before being stimulated with LPS. The secretion of interleukin-6, chemokine (C-C motif) ligand 5, and prostaglandin E2 was assessed by enzyme-linked immunosorbent assays (ELISA). The inhibitory effect of collinin on differentiation of human preosteoclastic cells was assessed by tartrate-resistant acid phosphatase staining, whereas the secretion of matrix metalloproteinase-9 (MMP-9) was measured by ELISA. Bone resorption activity was investigated by using a human bone plate coupled with an immunoassay that detected the release of collagen fragments. RESULTS: Collinin inhibited the growth of P. gingivalis. The effect was more pronounced under iron-restricted conditions. Collinin dose dependently inhibited the degradation of type I collagen by P. gingivalis. It was also a potent inhibitor of the LPS-induced inflammatory response in macrophages and completely inhibited receptor activator of nuclear factor κB ligand-dependent osteoclast differentiation and MMP-9 secretion. Last, collinin affected bone degradation mediated by mature osteoclasts by significantly decreasing the release of collagen helical peptides. CONCLUSION: Although clinical trials are required, data from these in vitro analyses support the potential of collinin as a therapeutic agent for treating inflammatory periodontitis associated with bone breakdown.
Asunto(s)
Colagenasas/metabolismo , Cumarinas/farmacología , Proteínas Inflamatorias de Macrófagos/antagonistas & inhibidores , Osteoclastos/efectos de los fármacos , Proteínas de Plantas/farmacología , Porphyromonas gingivalis/efectos de los fármacos , Remodelación Ósea/efectos de los fármacos , Diferenciación Celular/efectos de los fármacos , Células Cultivadas , Colagenasas/biosíntesis , Humanos , Lipopolisacáridos/antagonistas & inhibidores , Metaloproteinasa 9 de la Matriz/biosíntesis , FN-kappa B/metabolismo , Porphyromonas gingivalis/metabolismo , Ligando RANK/antagonistas & inhibidoresRESUMEN
Bisphosphonate drugs are well known to inhibit osteoclastic activity and have been proposed for the management of bone diseases, including periodontitis which is associated with alveolar bone destruction. In this study, we evaluated the effects of four arylsulfonamide bisphosphonates on growth of the periodontopathogenic bacterium Porphyromonas gingivalis as well as their capacity to reduce cytokine secretion by lipopolysaccharide (LPS)-stimulated oral epithelial cells. The growth of P. gingivalis was inhibited by (4'-Chloro-biphenyl-4-sulfonylamino)methyl-1,1- bisphosphonic acid while the three other arylsulfonamide bisphosphonates ((4-Methoxy-phenylsulfonylamino)methyl-1,1- bisphosphonic acid, (4-Nitro-phenylsulfonylamino)methyl-1,1-bisphosphonic acid, and (Biphenyl-4-sulfonylamino) methyl-1,1-bisphosphonic acid) had no effect. Growth inhibition was more pronounced under an iron-restricted condition. All four arylsulfonamide bisphosphonates decreased the production of the pro-inflammatory cytokines IL-6 and IL-8 by Aggregatibacter actinomycetemcomitans LPS-stimulated oral epithelial cells. In conclusion, we uncovered additional properties of bisphosphonates that may be beneficial for the treatment of periodontal diseases. In particular, (4'-Chlorobiphenyl- 4-sulfonylamino)methyl-1,1-bisphosphonic acid combines the already disclosed antiresoptive activity with antiinflammatory and antibacterial properties.
Asunto(s)
Compuestos de Bifenilo/síntesis química , Citocinas/metabolismo , Difosfonatos/síntesis química , Mucosa Bucal/efectos de los fármacos , Mucosa Bucal/metabolismo , Porphyromonas gingivalis/efectos de los fármacos , Sulfonamidas/síntesis química , Antibacterianos/farmacología , Compuestos de Bifenilo/química , Compuestos de Bifenilo/farmacología , Células Cultivadas , Difosfonatos/química , Difosfonatos/farmacología , Humanos , Sulfonamidas/química , Sulfonamidas/farmacologíaRESUMEN
BACKGROUND: Periodontal diseases are bacterial infections leading to chronic inflammation disorders that are frequently observed in adults. In the present study, we evaluated the effect of auraptene and lacinartin, two natural oxyprenylated coumarins, on the growth, adherence properties, and collagenase activity of Porphyromonas gingivalis. We also investigated the capacity of these compounds to reduce cytokine and matrix metalloproteinase (MMP) secretion by lipopolysaccharide (LPS)-stimulated macrophages and to inhibit MMP-9 activity. METHODS: Microplate dilution assays were performed to determine the effect of auraptene and lacinartin on P. gingivalis growth as well as biofilm formation stained with crystal violet. Adhesion of FITC-labeled P. gingivalis to oral epithelial cells was monitored by fluorometry. The effects of auraptene and lacinartin on LPS-induced cytokine and MMP secretion by macrophages were determined by immunological assays. Fluorogenic assays were used to evaluate the capacity of the two coumarins to inhibit the activity of P. gingivalis collagenase and MMP-9. RESULTS: Only lacinartin completely inhibited P. gingivalis growth in a complex culture medium. However, under iron-limiting conditions, auraptene and lacinartin both inhibited the growth of P. gingivalis. Lacinartin also inhibited biofilm formation by P. gingivalis and promoted biofilm desorption. Both compounds prevented the adherence of P. gingivalis to oral epithelial cells, dose-dependently reduced the secretion of cytokines (IL-8 and TNF-α) and MMP-8 and MMP-9 by LPS-stimulated macrophages, and inhibited MMP-9 activity. Lacinartin also inhibited P. gingivalis collagenase activity. CONCLUSIONS: By acting on multiple targets, including pathogenic bacteria, tissue-destructive enzymes, and the host inflammatory response, auraptene and lacinartin may be promising natural compounds for preventing and treating periodontal diseases.
Asunto(s)
Cumarinas/farmacología , Enfermedades Periodontales/tratamiento farmacológico , Extractos Vegetales/farmacología , Adhesión Bacteriana/efectos de los fármacos , Biopelículas/efectos de los fármacos , Línea Celular , Células Epiteliales/efectos de los fármacos , Células Epiteliales/microbiología , Humanos , Macrófagos/efectos de los fármacos , Macrófagos/inmunología , Enfermedades Periodontales/inmunología , Enfermedades Periodontales/microbiología , Porphyromonas gingivalis/efectos de los fármacos , Porphyromonas gingivalis/crecimiento & desarrollo , Porphyromonas gingivalis/fisiologíaRESUMEN
The compounds 2',6'-dihydroxy-4'-geranyloxyacetophenone (1) and 2',6'-dihydroxy-4'-farnesyloxy-acetophenone (2) are oxyprenylated secondary metabolites extracted from plants belonging to the Rutaceae family. In this study, 1 and 2 were synthesized and tested for their antimicrobial activity toward major oral pathogens. Compounds 1 and 2 were synthesized by selective prenylation of 2,4,6-trihydroxyacetophenone at the 4' position with geranyl and farnesyl bromide, respectively. Compound 1 showed stronger antimicrobial activity than 2 against major oral pathogens, including Gram positive bacteria (Streptococcus mutans, Streptococcus sobrinus), Gram negative bacteria (Prevotella intermedia, Porphyromonas gingivalis) and Candida albicans. Evidences were obtained that the mode of action of 1 and 2 may be related to their iron-chelating property. This study suggests that 1 and 2 may represent potential natural molecules for the prevention/treatment of common oral infections, including dental caries, periodontal disease, and candidiasis.
Asunto(s)
Acetofenonas/farmacología , Antibacterianos/farmacología , Antifúngicos/farmacología , Boca/microbiología , Extractos Vegetales/farmacología , Rutaceae/química , Acetofenonas/síntesis química , Acetofenonas/química , Acetofenonas/uso terapéutico , Antibacterianos/síntesis química , Antibacterianos/uso terapéutico , Antifúngicos/síntesis química , Antifúngicos/uso terapéutico , Bacterias/efectos de los fármacos , Candida albicans/efectos de los fármacos , Candidiasis/tratamiento farmacológico , Quelantes/síntesis química , Quelantes/farmacología , Quelantes/uso terapéutico , Caries Dental/tratamiento farmacológico , Hierro/metabolismo , Pruebas de Sensibilidad Microbiana , Enfermedades Periodontales/tratamiento farmacológico , Fitoterapia , Extractos Vegetales/química , Extractos Vegetales/uso terapéutico , Porphyromonas/efectos de los fármacos , Prenilación , Prevotella/efectos de los fármacos , Streptococcus/efectos de los fármacosRESUMEN
The translational diffusion coefficients of various helicates have been determined by using NMR diffusion spectroscopy (Diffusion Ordered SpectroscopY, DOSY), in order to investigate the individual behaviour of the helicates according to their length (different nuclearities; 1-5 metals), to the nature of the metal involved (CuI or AgI), as well to their bulkiness due to the presence of substituents on the periphery of the assembly. Furthermore, the spectrum of a mixture of helicates belonging to the same series, but with different lengths and nuclearities, showed the signals of each component, with no observable cross-linking, confirming the self-recognition properties of the helicates.
RESUMEN
Double helicates are known to exhibit self-recognition characteristics determined by the coordination geometry of the metal involved as well as by the topicity of the ligands. Combining tridentate (terpyridine, T) or bidentate (bipyridine, B) subunits in a tritopic strand affords a set of ligands able to assemble by pairs to form double helicates, homo- or heterostranded, homo- or heterotopic, depending on the coordination properties of the metals involved. The four ligand strands, BBB, TTT, BBT, and TBT form constitutionally dynamic sets of double helicates with the metal ions Cu(I), Cu(II), and Zn(II); these helicates correspond to the correct coding of the BB, BT, and TT pairs for tetra-, penta-, and hexacoordinate Cu(I), Cu(II), and Zn(II) cations, respectively.
RESUMEN
Connecting two facially-protected porphyrins was expected to lead to an equal mixture of laterally-bridged doubly-protected bis-porphyrins; one in which the two porphyrin units were protected on the same face (syn) and one with the two prophyrin units protected on opposite faces (anti). Addition of a co-factor (bidentate ligand) was expected to lead predominantly to the syn-bis-porphyrin by a templated self-replication process. This concept was explored using Baldwin's capped porphyrin. Bis(capped porphyrins) were synthesised in several steps starting from zinc(II) capped porphyrin 2. Nitration of 2 followed by reduction and photo-oxidation yields a mixture of zinc(II) porphyrindiones 7 and 8 that can separated by HPLC. The condensation of 2 molar eq. of zinc(II) porphyrin-7,8-dione 8 with 1,2,4,5-benzenetetramine leads to the formation of a 1:1 mixture of syn- and anti-dizinc(II) bis(7,8-capped porphyrins), 11 and 12, respectively, that have almost identical spectroscopic properties. These two geometric isomers were distinguished by significant differences in their molecular recognition properties. Likewise the syn- and anti-dizinc(II) bis(2,3-capped porphyrins), 9 and 10, respectively, are synthesised from the related zinc(II) capped porphyrin-2,3-dione 7, and were also identified using molecular recognition studies. The molecular recognition properties of these bis(capped porphyrins) were utilised in studies of self-replicating porphyrin systems. The results show that tetraazaanthraceno-bis-porphyrins 9-12 can catalyse their own formation but self-replication was not observed. These results highlight the potential that these interesting hosts have as templates in supramolecular chemistry, synthesis and catalysis.