Carmelo Daquino - Academia.edu (original) (raw)
Papers by Carmelo Daquino
The biological properties and possible pharmacological applications of benzo[kl]xanthene lignans,... more The biological properties and possible pharmacological applications of benzo[kl]xanthene lignans, rare among natural products and synthetic compounds, are almost unexplored. In the present contribution, the possible interaction of six synthetic benzo[kl]xanthene lignans and the natural metabolite rufescidride with DNA has been investigated through a combined STD-NMR and molecular docking approach, paralleled by in vitro biological assays on their antiproliferative activity towards two different cancer cell lines: SW 480 and HepG2. Our data suggest that the benzo[kl]xanthene lignans are suitable lead compounds for the design of DNA selective ligands with potential antitumour properties.
![Research paper thumbnail of Phenethyl caffeate benzo[kl]xanthene lignan with DNA interacting properties induces DNA damage and apoptosis in colon cancer cells](https://attachments.academia-assets.com/107143929/thumbnails/1.jpg)
](Life Sciences, 2012
Phenethyl caffeate benzoxanthene lignan (PCBL) is a synthetic compound with DNA interacting, anti... more Phenethyl caffeate benzoxanthene lignan (PCBL) is a synthetic compound with DNA interacting, antiangiogenic, antiproliferative and tumor cell death inducing abilities. Though PCBL exhibits the qualities of a prospective antitumor agent, the basic mechanism of PCBL induced cell death remains unknown. This study aims to analyze the molecular mechanisms of PCBL induced cell death in tumor cells to further substantiate its antitumor abilities. Main methods: MTT assay was used for finding cell proliferation inhibition, flow cytometric analysis for the detection of cell cycle arrest, comet assay for DNA break detection and immunofluorescence for analyzing H2AX phosphorylation. Western blot analysis was used to detect the activation of different proteins related to DNA damage response and apoptosis. Key findings: PCBL inhibited proliferation of WiDr cells more efficiently than its analog, MCBL. Comet analysis of PCBL treated WiDr cells and activity of various DNA damage response proteins such as γ-H2AX, BRCA1, ATR and Chk1 in PCBL treated cells demonstrated the DNA damaging property of PCBL. Effector molecules of apoptosis such as caspase-3, caspase-7 and caspase-9 were found activated along with PARP cleavage in PCBL treated cells, suggesting apoptosis as the main mode of cell death. PCBL induced cell death was found associated with the activation of MAPK signaling. Inhibition of ERK, one of the MAPKs, by U0126 improved the apoptosis inducing ability of PCBL. Significance: In vitro findings suggest that PCBL works by initiating DNA damage and inducing apoptosis in cancer cells and thus could be considered for further preclinical studies.
Organic & Biomolecular Chemistry, 2013
Org. Biomol. Chem., 2011
The biological properties and possible pharmacological applications of benzo[kl]xanthene lignans,... more The biological properties and possible pharmacological applications of benzo[kl]xanthene lignans, rare among natural products and synthetic compounds, are almost unexplored. In the present contribution, the possible interaction of six synthetic benzo[kl]xanthene lignans and the natural metabolite rufescidride with DNA has been investigated through a combined STD-NMR and molecular docking approach, paralleled by in vitro biological assays on their antiproliferative activity towards two different cancer cell lines: SW 480 and HepG2. Our data suggest that the benzo[kl]xanthene lignans are suitable lead compounds for the design of DNA selective ligands with potential antitumour properties.
![Research paper thumbnail of Antiangiogenic properties of an unusual benzo[k,l]xanthene lignan derived from CAPE (Caffeic Acid Phenethyl Ester)](https://attachments.academia-assets.com/107143917/thumbnails/1.jpg)
](Investigational New Drugs, 2010
Angiogenesis is normally a highly regulated process that occurs during development, reproduction,... more Angiogenesis is normally a highly regulated process that occurs during development, reproduction, and wound repair. However, angiogenesis can also become a fundamental pathogenic process in cancer and several other diseases. To date, the synthesis of angiogenesis inhibitors has been researched in several ways also starting from bioactive plant compounds. In the present study, we tested both in an angiogenesis bioassay and in ovarian cell culture, the potential antiangiogenic effect of a natural-derived benzo[k,l]xanthene lignan (5). This unusual compound was synthesized through the biomimetic dimerization of CAPE (Caffeic Acid Phenetyl Ester), a bioactive component of honeybee propolis. The lignan showed a significant, dose-related inhibitory effect on new vessel growth in the angiogenesis bioassay and it inhibited Vascular Endothelial Growth Factor secretion in ovarian cell culture. Therefore, we indicate the natural-derived benzo[k,l]xanthene lignan 5 as a potential new angiogenesis inhibitor.
European Journal of Organic Chemistry, Dec 1, 2009
The metal-mediated oxidative coupling of caffeic acid esters has been employed in the biomimetic ... more The metal-mediated oxidative coupling of caffeic acid esters has been employed in the biomimetic synthesis of dimeric lignans and neolignans. Phenethyl and methyl caffeate esters were used as substrates and MnO 2 , Mn(OAc) 3 and Ag 2 O as oxidative coupling agents. The manganese-mediated reactions afforded in good yields the unusual benzo[kl]xanthene lignans 6 and 15 as the major products accompanied by minor amounts of the aryldihydronaphthalene lignans [a]
Tetrahedron Letters, 2006
Novel hydroxycinnamic acid-calix[4]arene hybrids 4 and 5 were synthesized. Their radical scavengi... more Novel hydroxycinnamic acid-calix[4]arene hybrids 4 and 5 were synthesized. Their radical scavenging and antioxidant activities were determined by using DPPH Å radical and AIBN Å -induced linoleic acid peroxidation test, respectively. Preliminary studies showed that compounds 4 and 5 possess enhanced activity with respect to the corresponding hydroxycinnamic acid and phenetidine derivative. Kinetic solvent effects were taken in account to understand the different antioxidative behaviour of the synthesized compounds.
Tetrahedron, 2006
The reaction at room temperature of 3,5-di-tert-butyl-and 3,5-di-methoxy-4-hydroxycinnamic acids ... more The reaction at room temperature of 3,5-di-tert-butyl-and 3,5-di-methoxy-4-hydroxycinnamic acids 1 and 2 with the dpph % radical in acetone or other non-hydroxylic polar solvents yields interesting dimeric p-quinomethanes 10-16 characterized by a broad and strong absorption in the visible region. Although the yields appear to be low to moderate (10-40%), this simple synthesis affords quinones not otherwise obtainable, which contain an unsaturated g-lactone ring (14-16). The structures have been elucidated by interpretation of ESI-MS, FT-IR and NMR spectral data. In particular, FT-IR spectra in a KBr matrix demonstrate the quinone nature of these compounds because of the presence of strong absorption bands at 1604-1640 cm K1 and allows excluding the presence of carboxylic acid groups in the molecules. Kinetic evidence and molecular structures suggest that the formation of these p-quinomethanes is best explained through an 8-8 C-C coupling of the aryloxyl radicals derived from 1 and 2 and a subsequent fast mono-or di-decarboxylation of the initial dimer by an S E 1-type mechanism. Further oxidation of the phenolic intermediates by dpph % yields the final quinones. q
Organic Letters, 2011
In methanol/water, dpph(•) bleaching (519 nm) by quercetin, QH(2), exhibits biphasic kinetics. Th... more In methanol/water, dpph(•) bleaching (519 nm) by quercetin, QH(2), exhibits biphasic kinetics. The dpph(•) reacts completely with the quercetin anion within 100 ms. Subsequent slower bleaching involves solvent and QH(2) addition to quinoid products. The fast reaction is first-order in dpph(•) but only ca. 0.38 order in [QH(2)]. This extraordinary nonintegral order is attributed to reversible formation of π-stacked {QH(-)/dpph(•)} complexes in which electron transfer to products, {QH(•)/dpph(-)}, is slow (k(ET) ≈ 10(5) s(-1)).
Life Sciences, 2012
Phenethyl caffeate benzoxanthene lignan (PCBL) is a synthetic compound with DNA interacting, anti... more Phenethyl caffeate benzoxanthene lignan (PCBL) is a synthetic compound with DNA interacting, antiangiogenic, antiproliferative and tumor cell death inducing abilities. Though PCBL exhibits the qualities of a prospective antitumor agent, the basic mechanism of PCBL induced cell death remains unknown. This study aims to analyze the molecular mechanisms of PCBL induced cell death in tumor cells to further substantiate its antitumor abilities. MTT assay was used for finding cell proliferation inhibition, flow cytometric analysis for the detection of cell cycle arrest, comet assay for DNA break detection and immunofluorescence for analyzing H2AX phosphorylation. Western blot analysis was used to detect the activation of different proteins related to DNA damage response and apoptosis. PCBL inhibited proliferation of WiDr cells more efficiently than its analog, MCBL. Comet analysis of PCBL treated WiDr cells and activity of various DNA damage response proteins such as γ-H2AX, BRCA1, ATR and Chk1 in PCBL treated cells demonstrated the DNA damaging property of PCBL. Effector molecules of apoptosis such as caspase-3, caspase-7 and caspase-9 were found activated along with PARP cleavage in PCBL treated cells, suggesting apoptosis as the main mode of cell death. PCBL induced cell death was found associated with the activation of MAPK signaling. Inhibition of ERK, one of the MAPKs, by U0126 improved the apoptosis inducing ability of PCBL. In vitro findings suggest that PCBL works by initiating DNA damage and inducing apoptosis in cancer cells and thus could be considered for further preclinical studies.
Organic & Biomolecular Chemistry, 2013
Benzo[kl]xanthene lignans, promising bioactive polyphenols obtained by biomimetic oxidative coupl... more Benzo[kl]xanthene lignans, promising bioactive polyphenols obtained by biomimetic oxidative coupling of caffeic acid derivatives, react efficiently with peroxyl radicals in both polar and non-polar solvents, thanks to the simultaneous presence of guaiacol-like and catechol-like OH-groups.
Organic & Biomolecular Chemistry, 2011
The biological properties and possible pharmacological applications of benzo[kl]xanthene lignans,... more The biological properties and possible pharmacological applications of benzo[kl]xanthene lignans, rare among natural products and synthetic compounds, are almost unexplored. In the present contribution, the possible interaction of six synthetic benzo[kl]xanthene lignans and the natural metabolite rufescidride with DNA has been investigated through a combined STD-NMR and molecular docking approach, paralleled by in vitro biological assays on their antiproliferative activity towards two different cancer cell lines: SW 480 and HepG2. Our data suggest that the benzo[kl]xanthene lignans are suitable lead compounds for the design of DNA selective ligands with potential antitumour properties.
The Journal of Organic Chemistry, 2004
The kinetic behavior of cinnamic acids, their methyl esters, and two catechols 1-10 (ArOH) in the... more The kinetic behavior of cinnamic acids, their methyl esters, and two catechols 1-10 (ArOH) in the reaction with DPPH(*) in methanol and ethanol is not compatible with a reaction mechanism that involves hydrogen atom abstraction from the hydroxyl group of 1-10 by DPPH(*). The rate of this reaction at 25 degrees C is, in fact, comparatively fast despite that the phenolic OH group of ArOH is hydrogen bonded to solvent molecules. The observed rate constants (k(1)) relative to DPPH(*) + ArOH are 3-5 times larger for the methyl esters than for the corresponding free acids and, for the latter, decrease as their concentration is increased according to the relation k(1) = B/[ArOH](0)(m), where k(1) is given in units of M(-1) s(-1), m is ca. 0.5, and B ranges from 0.02 (p-coumaric acid) to ca. 3.48 (caffeic acid) in methanol and from 0.04 (p-coumaric acid) to ca. 13 (sinapic acid) in ethanol. Apparently, the reaction mechanism of DPPH(*) + ArOH involves a fast electron-transfer process from the phenoxide anion of 1-10 to DPPH(*). Kinetic analysis of the reaction sequence for the free acids leads to an expression for the observed rate constant, k(1), proportional to [ArOH](0)(-1/2) in excellent agreement with the experimental behavior of these phenols. The experimental results are also interpreted in terms of the influence that adventitious acids or bases present in the solvent may have. These impurities dramatically influence the ionization equilibrium of phenols and cause a reduction or an enhancement, respectively, of the measured rate constants.
The Journal of Organic Chemistry, 2008
The formal H-atom abstraction by the 2,2-diphenyl-1-picrylhydrazyl (dpph • ) radical from 27 phen... more The formal H-atom abstraction by the 2,2-diphenyl-1-picrylhydrazyl (dpph • ) radical from 27 phenols and two unsaturated hydrocarbons has been investigated by a combination of kinetic measurements in apolar solvents and density functional theory (DFT). The computed minimum energy structure of dpph • shows that the access to its divalent N is strongly hindered by an ortho H atom on each of the phenyl rings and by the o-NO 2 groups of the picryl ring. Remarkably small Arrhenius pre-exponential factors for the phenols [range (1.3-19) × 10 5 M -1 s -1 ] are attributed to steric effects. Indeed, the entropy barrier accounts for up to ca. 70% of the freeenergy barrier to reaction. Nevertheless, rate differences for different phenols are largely due to differences in the activation energy, E a,1 (range 2 to 10 kcal/mol). In phenols, electronic effects of the substituents and intramolecular H-bonds have a large influence on the activation energies and on the ArO-H BDEs. There is a linear Evans-Polanyi relationship between E a,1 and the ArO-H BDEs: E a,1 /kcal × mol -1 ) 0.918 BDE(ArO-H)/kcal × mol -1 -70.273. The proportionality constant, 0.918, is large and implies a "late" or "product-like" transition state (TS), a conclusion that is congruent with the small deuterium kinetic isotope effects (range 1.3-3.3). This Evans-Polanyi relationship, though questionable on theoretical grounds, has profitably been used to estimate several ArO-H BDEs. Experimental ArO-H BDEs are generally in good agreement with the DFT calculations. Significant deviations between experimental and DFT calculated ArO-H BDEs were found, however, when an intramolecular H-bond to the O • center was present in the phenoxyl radical, e.g., in ortho semiquinone radicals. In these cases, the coupled cluster with single and double excitations correlated wave function technique with complete basis set extrapolation gave excellent results. The TSs for the reactions of dpph • with phenol, 3-and 4-methoxyphenol, and 1,4-cyclohexadiene were also computed. Surprisingly, these TS structures for the phenols show that the reactions cannot be described as occurring exclusively by either a HAT or a PCET mechanism, while with 1,4-cyclohexadiene the PCET character in the reaction coordinate is much better defined and shows a strong π-π stacking interaction between the incipient cyclohexadienyl radical and a phenyl ring of the dpph • radical. 9275 FIGURE 6. Plot of activation energy for reaction 1 vs ArO-H BDE for those phenols shown in Chart 1 for which reliable BDEs were available (see ). Blue circles are for 16 of phenols 1-26. Phenols 15 and 23 were considered outliers and were excluded from the solid correlation line: E a,1 ) 0.918(O-H BDE) -70.27 (r 2 ) 0.95, eq X). The red square is for 2,4,6-tritertbutylphenol, 27.
The Journal of Organic Chemistry, 2008
The Journal of Organic Chemistry, 2010
Journal of Allergy and Clinical Immunology, 1993
Background: Various means of monitoring asthma severity have been proposed to reduce morbidity an... more Background: Various means of monitoring asthma severity have been proposed to reduce morbidity and mortality rates. We compared two means of assessing asthma flare-ups: monitoring peak expiratory flow rate (PEFR) and keeping a symptom diary.
Journal of Allergy and Clinical Immunology, 1992
It is unknown whether factors such as the nature of the agent, gender, uge, atopy, smoking habits... more It is unknown whether factors such as the nature of the agent, gender, uge, atopy, smoking habits, continuous or noncontinuous exposure, and puttern qf' asthmatic reaction can itzfiuencl~ the rute of development of symptoms in subjects with occupational asthma. We compared .severt>l clinical and functional parameters among three groups of subjects with occupational asthmtr caused by Western red cedar (group I, n = 433). isocynnates (group 2. n = 1071, and high molecular weight agents acting through an IgE-mediated mechanism (group 3, n = IZl). Survival analysis showed that the three curves relating years of exposure before onset o/ symptoms to the proportion of subjects without symptoms were sign@-antly different in two respects: (I) almost 40% of subjects in groups I and 2 as compared with 200/c of sut$ect.j in group 3 became symptomatic within 1 year of exposure; (2 i qfter 5 years qf exposure, the r<tte of sensitization was slower for subjects in groups 2 and 3 as compared with those in group I.
The biological properties and possible pharmacological applications of benzo[kl]xanthene lignans,... more The biological properties and possible pharmacological applications of benzo[kl]xanthene lignans, rare among natural products and synthetic compounds, are almost unexplored. In the present contribution, the possible interaction of six synthetic benzo[kl]xanthene lignans and the natural metabolite rufescidride with DNA has been investigated through a combined STD-NMR and molecular docking approach, paralleled by in vitro biological assays on their antiproliferative activity towards two different cancer cell lines: SW 480 and HepG2. Our data suggest that the benzo[kl]xanthene lignans are suitable lead compounds for the design of DNA selective ligands with potential antitumour properties.
Life Sciences, 2012
Phenethyl caffeate benzoxanthene lignan (PCBL) is a synthetic compound with DNA interacting, anti... more Phenethyl caffeate benzoxanthene lignan (PCBL) is a synthetic compound with DNA interacting, antiangiogenic, antiproliferative and tumor cell death inducing abilities. Though PCBL exhibits the qualities of a prospective antitumor agent, the basic mechanism of PCBL induced cell death remains unknown. This study aims to analyze the molecular mechanisms of PCBL induced cell death in tumor cells to further substantiate its antitumor abilities. Main methods: MTT assay was used for finding cell proliferation inhibition, flow cytometric analysis for the detection of cell cycle arrest, comet assay for DNA break detection and immunofluorescence for analyzing H2AX phosphorylation. Western blot analysis was used to detect the activation of different proteins related to DNA damage response and apoptosis. Key findings: PCBL inhibited proliferation of WiDr cells more efficiently than its analog, MCBL. Comet analysis of PCBL treated WiDr cells and activity of various DNA damage response proteins such as γ-H2AX, BRCA1, ATR and Chk1 in PCBL treated cells demonstrated the DNA damaging property of PCBL. Effector molecules of apoptosis such as caspase-3, caspase-7 and caspase-9 were found activated along with PARP cleavage in PCBL treated cells, suggesting apoptosis as the main mode of cell death. PCBL induced cell death was found associated with the activation of MAPK signaling. Inhibition of ERK, one of the MAPKs, by U0126 improved the apoptosis inducing ability of PCBL. Significance: In vitro findings suggest that PCBL works by initiating DNA damage and inducing apoptosis in cancer cells and thus could be considered for further preclinical studies.
Organic & Biomolecular Chemistry, 2013
Org. Biomol. Chem., 2011
The biological properties and possible pharmacological applications of benzo[kl]xanthene lignans,... more The biological properties and possible pharmacological applications of benzo[kl]xanthene lignans, rare among natural products and synthetic compounds, are almost unexplored. In the present contribution, the possible interaction of six synthetic benzo[kl]xanthene lignans and the natural metabolite rufescidride with DNA has been investigated through a combined STD-NMR and molecular docking approach, paralleled by in vitro biological assays on their antiproliferative activity towards two different cancer cell lines: SW 480 and HepG2. Our data suggest that the benzo[kl]xanthene lignans are suitable lead compounds for the design of DNA selective ligands with potential antitumour properties.
Investigational New Drugs, 2010
Angiogenesis is normally a highly regulated process that occurs during development, reproduction,... more Angiogenesis is normally a highly regulated process that occurs during development, reproduction, and wound repair. However, angiogenesis can also become a fundamental pathogenic process in cancer and several other diseases. To date, the synthesis of angiogenesis inhibitors has been researched in several ways also starting from bioactive plant compounds. In the present study, we tested both in an angiogenesis bioassay and in ovarian cell culture, the potential antiangiogenic effect of a natural-derived benzo[k,l]xanthene lignan (5). This unusual compound was synthesized through the biomimetic dimerization of CAPE (Caffeic Acid Phenetyl Ester), a bioactive component of honeybee propolis. The lignan showed a significant, dose-related inhibitory effect on new vessel growth in the angiogenesis bioassay and it inhibited Vascular Endothelial Growth Factor secretion in ovarian cell culture. Therefore, we indicate the natural-derived benzo[k,l]xanthene lignan 5 as a potential new angiogenesis inhibitor.
European Journal of Organic Chemistry, Dec 1, 2009
The metal-mediated oxidative coupling of caffeic acid esters has been employed in the biomimetic ... more The metal-mediated oxidative coupling of caffeic acid esters has been employed in the biomimetic synthesis of dimeric lignans and neolignans. Phenethyl and methyl caffeate esters were used as substrates and MnO 2 , Mn(OAc) 3 and Ag 2 O as oxidative coupling agents. The manganese-mediated reactions afforded in good yields the unusual benzo[kl]xanthene lignans 6 and 15 as the major products accompanied by minor amounts of the aryldihydronaphthalene lignans [a]
Tetrahedron Letters, 2006
Novel hydroxycinnamic acid-calix[4]arene hybrids 4 and 5 were synthesized. Their radical scavengi... more Novel hydroxycinnamic acid-calix[4]arene hybrids 4 and 5 were synthesized. Their radical scavenging and antioxidant activities were determined by using DPPH Å radical and AIBN Å -induced linoleic acid peroxidation test, respectively. Preliminary studies showed that compounds 4 and 5 possess enhanced activity with respect to the corresponding hydroxycinnamic acid and phenetidine derivative. Kinetic solvent effects were taken in account to understand the different antioxidative behaviour of the synthesized compounds.
Tetrahedron, 2006
The reaction at room temperature of 3,5-di-tert-butyl-and 3,5-di-methoxy-4-hydroxycinnamic acids ... more The reaction at room temperature of 3,5-di-tert-butyl-and 3,5-di-methoxy-4-hydroxycinnamic acids 1 and 2 with the dpph % radical in acetone or other non-hydroxylic polar solvents yields interesting dimeric p-quinomethanes 10-16 characterized by a broad and strong absorption in the visible region. Although the yields appear to be low to moderate (10-40%), this simple synthesis affords quinones not otherwise obtainable, which contain an unsaturated g-lactone ring (14-16). The structures have been elucidated by interpretation of ESI-MS, FT-IR and NMR spectral data. In particular, FT-IR spectra in a KBr matrix demonstrate the quinone nature of these compounds because of the presence of strong absorption bands at 1604-1640 cm K1 and allows excluding the presence of carboxylic acid groups in the molecules. Kinetic evidence and molecular structures suggest that the formation of these p-quinomethanes is best explained through an 8-8 C-C coupling of the aryloxyl radicals derived from 1 and 2 and a subsequent fast mono-or di-decarboxylation of the initial dimer by an S E 1-type mechanism. Further oxidation of the phenolic intermediates by dpph % yields the final quinones. q
Organic Letters, 2011
In methanol/water, dpph(•) bleaching (519 nm) by quercetin, QH(2), exhibits biphasic kinetics. Th... more In methanol/water, dpph(•) bleaching (519 nm) by quercetin, QH(2), exhibits biphasic kinetics. The dpph(•) reacts completely with the quercetin anion within 100 ms. Subsequent slower bleaching involves solvent and QH(2) addition to quinoid products. The fast reaction is first-order in dpph(•) but only ca. 0.38 order in [QH(2)]. This extraordinary nonintegral order is attributed to reversible formation of π-stacked {QH(-)/dpph(•)} complexes in which electron transfer to products, {QH(•)/dpph(-)}, is slow (k(ET) ≈ 10(5) s(-1)).
Life Sciences, 2012
Phenethyl caffeate benzoxanthene lignan (PCBL) is a synthetic compound with DNA interacting, anti... more Phenethyl caffeate benzoxanthene lignan (PCBL) is a synthetic compound with DNA interacting, antiangiogenic, antiproliferative and tumor cell death inducing abilities. Though PCBL exhibits the qualities of a prospective antitumor agent, the basic mechanism of PCBL induced cell death remains unknown. This study aims to analyze the molecular mechanisms of PCBL induced cell death in tumor cells to further substantiate its antitumor abilities. MTT assay was used for finding cell proliferation inhibition, flow cytometric analysis for the detection of cell cycle arrest, comet assay for DNA break detection and immunofluorescence for analyzing H2AX phosphorylation. Western blot analysis was used to detect the activation of different proteins related to DNA damage response and apoptosis. PCBL inhibited proliferation of WiDr cells more efficiently than its analog, MCBL. Comet analysis of PCBL treated WiDr cells and activity of various DNA damage response proteins such as γ-H2AX, BRCA1, ATR and Chk1 in PCBL treated cells demonstrated the DNA damaging property of PCBL. Effector molecules of apoptosis such as caspase-3, caspase-7 and caspase-9 were found activated along with PARP cleavage in PCBL treated cells, suggesting apoptosis as the main mode of cell death. PCBL induced cell death was found associated with the activation of MAPK signaling. Inhibition of ERK, one of the MAPKs, by U0126 improved the apoptosis inducing ability of PCBL. In vitro findings suggest that PCBL works by initiating DNA damage and inducing apoptosis in cancer cells and thus could be considered for further preclinical studies.
Organic & Biomolecular Chemistry, 2013
Benzo[kl]xanthene lignans, promising bioactive polyphenols obtained by biomimetic oxidative coupl... more Benzo[kl]xanthene lignans, promising bioactive polyphenols obtained by biomimetic oxidative coupling of caffeic acid derivatives, react efficiently with peroxyl radicals in both polar and non-polar solvents, thanks to the simultaneous presence of guaiacol-like and catechol-like OH-groups.
Organic & Biomolecular Chemistry, 2011
The biological properties and possible pharmacological applications of benzo[kl]xanthene lignans,... more The biological properties and possible pharmacological applications of benzo[kl]xanthene lignans, rare among natural products and synthetic compounds, are almost unexplored. In the present contribution, the possible interaction of six synthetic benzo[kl]xanthene lignans and the natural metabolite rufescidride with DNA has been investigated through a combined STD-NMR and molecular docking approach, paralleled by in vitro biological assays on their antiproliferative activity towards two different cancer cell lines: SW 480 and HepG2. Our data suggest that the benzo[kl]xanthene lignans are suitable lead compounds for the design of DNA selective ligands with potential antitumour properties.
The Journal of Organic Chemistry, 2004
The kinetic behavior of cinnamic acids, their methyl esters, and two catechols 1-10 (ArOH) in the... more The kinetic behavior of cinnamic acids, their methyl esters, and two catechols 1-10 (ArOH) in the reaction with DPPH(*) in methanol and ethanol is not compatible with a reaction mechanism that involves hydrogen atom abstraction from the hydroxyl group of 1-10 by DPPH(*). The rate of this reaction at 25 degrees C is, in fact, comparatively fast despite that the phenolic OH group of ArOH is hydrogen bonded to solvent molecules. The observed rate constants (k(1)) relative to DPPH(*) + ArOH are 3-5 times larger for the methyl esters than for the corresponding free acids and, for the latter, decrease as their concentration is increased according to the relation k(1) = B/[ArOH](0)(m), where k(1) is given in units of M(-1) s(-1), m is ca. 0.5, and B ranges from 0.02 (p-coumaric acid) to ca. 3.48 (caffeic acid) in methanol and from 0.04 (p-coumaric acid) to ca. 13 (sinapic acid) in ethanol. Apparently, the reaction mechanism of DPPH(*) + ArOH involves a fast electron-transfer process from the phenoxide anion of 1-10 to DPPH(*). Kinetic analysis of the reaction sequence for the free acids leads to an expression for the observed rate constant, k(1), proportional to [ArOH](0)(-1/2) in excellent agreement with the experimental behavior of these phenols. The experimental results are also interpreted in terms of the influence that adventitious acids or bases present in the solvent may have. These impurities dramatically influence the ionization equilibrium of phenols and cause a reduction or an enhancement, respectively, of the measured rate constants.
The Journal of Organic Chemistry, 2008
The formal H-atom abstraction by the 2,2-diphenyl-1-picrylhydrazyl (dpph • ) radical from 27 phen... more The formal H-atom abstraction by the 2,2-diphenyl-1-picrylhydrazyl (dpph • ) radical from 27 phenols and two unsaturated hydrocarbons has been investigated by a combination of kinetic measurements in apolar solvents and density functional theory (DFT). The computed minimum energy structure of dpph • shows that the access to its divalent N is strongly hindered by an ortho H atom on each of the phenyl rings and by the o-NO 2 groups of the picryl ring. Remarkably small Arrhenius pre-exponential factors for the phenols [range (1.3-19) × 10 5 M -1 s -1 ] are attributed to steric effects. Indeed, the entropy barrier accounts for up to ca. 70% of the freeenergy barrier to reaction. Nevertheless, rate differences for different phenols are largely due to differences in the activation energy, E a,1 (range 2 to 10 kcal/mol). In phenols, electronic effects of the substituents and intramolecular H-bonds have a large influence on the activation energies and on the ArO-H BDEs. There is a linear Evans-Polanyi relationship between E a,1 and the ArO-H BDEs: E a,1 /kcal × mol -1 ) 0.918 BDE(ArO-H)/kcal × mol -1 -70.273. The proportionality constant, 0.918, is large and implies a "late" or "product-like" transition state (TS), a conclusion that is congruent with the small deuterium kinetic isotope effects (range 1.3-3.3). This Evans-Polanyi relationship, though questionable on theoretical grounds, has profitably been used to estimate several ArO-H BDEs. Experimental ArO-H BDEs are generally in good agreement with the DFT calculations. Significant deviations between experimental and DFT calculated ArO-H BDEs were found, however, when an intramolecular H-bond to the O • center was present in the phenoxyl radical, e.g., in ortho semiquinone radicals. In these cases, the coupled cluster with single and double excitations correlated wave function technique with complete basis set extrapolation gave excellent results. The TSs for the reactions of dpph • with phenol, 3-and 4-methoxyphenol, and 1,4-cyclohexadiene were also computed. Surprisingly, these TS structures for the phenols show that the reactions cannot be described as occurring exclusively by either a HAT or a PCET mechanism, while with 1,4-cyclohexadiene the PCET character in the reaction coordinate is much better defined and shows a strong π-π stacking interaction between the incipient cyclohexadienyl radical and a phenyl ring of the dpph • radical. 9275 FIGURE 6. Plot of activation energy for reaction 1 vs ArO-H BDE for those phenols shown in Chart 1 for which reliable BDEs were available (see ). Blue circles are for 16 of phenols 1-26. Phenols 15 and 23 were considered outliers and were excluded from the solid correlation line: E a,1 ) 0.918(O-H BDE) -70.27 (r 2 ) 0.95, eq X). The red square is for 2,4,6-tritertbutylphenol, 27.
The Journal of Organic Chemistry, 2008
The Journal of Organic Chemistry, 2010
Journal of Allergy and Clinical Immunology, 1993
Background: Various means of monitoring asthma severity have been proposed to reduce morbidity an... more Background: Various means of monitoring asthma severity have been proposed to reduce morbidity and mortality rates. We compared two means of assessing asthma flare-ups: monitoring peak expiratory flow rate (PEFR) and keeping a symptom diary.
Journal of Allergy and Clinical Immunology, 1992
It is unknown whether factors such as the nature of the agent, gender, uge, atopy, smoking habits... more It is unknown whether factors such as the nature of the agent, gender, uge, atopy, smoking habits, continuous or noncontinuous exposure, and puttern qf' asthmatic reaction can itzfiuencl~ the rute of development of symptoms in subjects with occupational asthma. We compared .severt>l clinical and functional parameters among three groups of subjects with occupational asthmtr caused by Western red cedar (group I, n = 433). isocynnates (group 2. n = 1071, and high molecular weight agents acting through an IgE-mediated mechanism (group 3, n = IZl). Survival analysis showed that the three curves relating years of exposure before onset o/ symptoms to the proportion of subjects without symptoms were sign@-antly different in two respects: (I) almost 40% of subjects in groups I and 2 as compared with 200/c of sut$ect.j in group 3 became symptomatic within 1 year of exposure; (2 i qfter 5 years qf exposure, the r<tte of sensitization was slower for subjects in groups 2 and 3 as compared with those in group I.