Colon cancer incidence rates are increasing annually, a scenario aggravated by genetic and epigen... more Colon cancer incidence rates are increasing annually, a scenario aggravated by genetic and epigenetic alterations that promote drug resistance. Recent studies showed that novel synthetic selenium compounds are more efficient and less toxic than conventional drugs, demonstrating biocompatibility and pro-oxidant effects on tumor cells. This study aimed to investigate the cytotoxic effect of MRK-107, an imidazo [1,2- a]pyridine derivative, in 2D and 3D cell culture models of colon cancer (Caco-2 and HT-29). Sulforhodamine B results revealed a GI50 of 2.4 µM for Caco-2, 1.1 µM for HT-29, and 22.19 µM for NIH/3T3 in 2D cultures after 48 h of treatment. Cell recovery, migration, clonogenic, and Ki-67 results corroborated that MRK-107 inhibits cell proliferation and prevents cell regeneration and metastatic transition by selectively reducing migratory and clonogenic capacity; non-tumor cells (NIH/3T3) re-established proliferation in less than 18 h. The oxidative stress markers DCFH-DA and ...
3-heptylidene-4,6-dimethoxy-3H-isobenzofuran-1-one (Phthalide 1) is the precursor of three resorc... more 3-heptylidene-4,6-dimethoxy-3H-isobenzofuran-1-one (Phthalide 1) is the precursor of three resorcinol lipids that have been described as potential chemotherapeutic agents and capable of potentiating the effects of cyclophosphamide. In this study, we evaluated the genotoxic potential, cell-killing potential, and interactions with cyclophosphamide and cisplatin of phthalide 1. Twelve groups were created from 120 mice: Negative Control, cyclophosphamide (100 mg/kg), cisplatin (6 mg/kg), Phthalide 1 (5, 10 and 20 mg/kg), and associations of 1 with cyclophosphamide and 1 with cisplatin. The results demonstrate that 1 increases (p < 0.05) the frequency of chromosomal damage, liver and kidney cell death, and splenic phagocytosis. The association of 1 with cyclophosphamide and cisplatin demonstrated a chemopreventive effect and, therefore, a reduction (p < 0.05) in the frequency of chromosomal damage. However, cell death and splenic phagocytosis did not suffer significant variations. ...
O aumento da incidencia de câncer e os altos custos de tratamento estimulam a busca por novo comp... more O aumento da incidencia de câncer e os altos custos de tratamento estimulam a busca por novo compostos para uso na prevencao, tratamento bem como em tratamentos coadjuvantes. Diante do exposto, o presente estudo avaliou o acido (Z) -4-((4-il-1,5-dimetil-3-oxo-2-fenil-2,3-di-hidro-1H-pirazol) amino)-4-oxobut-2-enoico (IR- 001) quanto a integridade genetica, atividade imunomodulatoria e inducao apoptose bem como seus efeitos em associacao com os quimioterapicos comerciais doxorrubicina, cisplatina e ciclofosfamida. Esse composto foi planejado e sintetizado com base em dois radicais, um deles, a 4-aminoantipirina que e descrito como efetivo antioxidante e antinflamatorio e o outro 1,4-dioxo-2butenil que e um efetivo agente citotoxico. Os resultados indicaram que o IR-001 e um efetivo quimioprotetor por nao ser mutagenico e apresentar boa capacidade antigenotoxica (ate 94,15%), antimutagenica (ate 92,49%), imunomodulatoria (aumenta a fagocitose esplenica e a frequencia de linfocitos) e ...
A study of [3 + 2] cycloaddition reactions of a bicyclic nitrone with various cyclopentenes has c... more A study of [3 + 2] cycloaddition reactions of a bicyclic nitrone with various cyclopentenes has clarified the diastereomeric preferences as a function of the olefinic structure. It has also identified an important stereochemical difference between nitrones and the analogous azomethine ylides in [3 + 2] cycloaddition reactions.
Orbital: The Electronic Journal of Chemistry, 2020
Neste trabalho, foi planejada a sintese de lipideos resorcinolicos analogos as citosporonas utili... more Neste trabalho, foi planejada a sintese de lipideos resorcinolicos analogos as citosporonas utilizando metodos classicos de sintese orgânica. O objetivo principal foi a preparacao dos compostos: acido 2,4-dihidroxi-6-octil-benzoico ( 6 ) e 2,4-diidroxi-6-(8-oxooctil)-benzoico ( 7 ). Foram estudadas rotas de sintese visando a producao desses compostos, foi possivel obtencao de tres intermediarios avancados, com sucesso: 2,4 dimetoxi-6-octil-benzoato de etila ( 8 ), 2-hidroxi-4-metoxi-6-octil-benzoato de etila ( 9 ) e acido 2-hidroxi-4-metoxi-6-octil-benzoico ( 10 ), os quais tiveram suas estruturas determinadas por tecnicas de espectroscopia de RMN de 1 H e de 13 C, e no caso de ( 10 ) incluindo tecnicas bidimensionais (HSQC e HMBC).
Acetylcholinesterase (AChEis) inhibitors are used to treat neurodegenerative diseases like Alzhei... more Acetylcholinesterase (AChEis) inhibitors are used to treat neurodegenerative diseases like Alzheimer's disease (AD). L-hypaphorine (L-HYP) is a natural indole alkaloid that has been shown to have effects on the central nervous system (CNS). The goal of this research was to synthesize L-HYP and D-HYP and test their anticholinesterasic properties in rat brain regions. L-HYP suppressed acetylcholinesterase (AChE) activity only in the cerebellum, whereas D-HYP inhibited AChE activity in all CNS regions studied. No cytotoxic effect on normal human cells (HaCaT) was observed in the case of L-HYP and D-HYP although an increase in cell proliferation. Molecular modeling studies revealed that D-HYP and L-HYP have significant differences in their binding mode positions and interact stereospecifically with AChE's amino acid residues.
Herein we describe a simple method for the synthesis of Baylis-Hillman adducts and their acetates... more Herein we describe a simple method for the synthesis of Baylis-Hillman adducts and their acetates by utilizing inexpensively available cashew nut shell liquid (CNSL) natural resource. Furthermore, by using a molecular hybridization approach, a series of novel pyrimidine scaffolds (15a-15t) were synthesized by utilizing Baylis-Hillman acetate derivatives from cashew nut shell liquid (CNSL). All the newly synthesized compounds were screened for their in vitro antitumor activity. Baylis-Hillman compounds 5b and 5h showed promising anticancer activity against MCF-7. Among pyrimidine derivatives, compounds 15i, 15j and 15l showed promising activity against HEP-G2, whereas compounds 15j, 15k, 15l and 15m showed promising activity against MCF-7. In addition, compound 15m showed significant activity against K562 when compared with the standard. The structure-activity relationship (SAR) analysis suggests that the length of the carbon chain of phenyl ring played an important role in the poten...
Cytosporones, a class of octaketide resorcinolic lipids, have drawn the attention of researchers ... more Cytosporones, a class of octaketide resorcinolic lipids, have drawn the attention of researchers for exhibiting a number of notable biological properties. Herein, we describe routes to synthesize the bioactive synthetic resorcinolic lipids AMS35AA and AMS35BB with excellent overall yields using 3,5-dimethoxybenzoic acid as the starting material. The methods proved remarkably efficient to achieve the target compounds and comprise the synthesis of AMS35AA catalyzed by ascorbic acid (vitamin C).
Reaction of β-ketosulfones with different α-functionalized nitroalkenes affords diversely substit... more Reaction of β-ketosulfones with different α-functionalized nitroalkenes affords diversely substituted sulfonyl furans and dihydrofurans. β-Ketosulfones react with α-bromonitroalkenes and α-hydrazinonitroalkenes via cascade Michael addition-cyclization protocol to deliver nitrodihydrofurans and hydrazinodihydrofurans, respectively, bearing a key sulfonyl group, in excellent yields with broad substrate scope. Application of these products has been demonstrated by the synthesis of pyrroles and pyrazoles in good yields. Reaction of β-ketosulfones with nitroallylic acetates yield tetrasubstituted sulfonyl furans through a cascade SN2'-intramolecular Michael reaction followed by aromatization. Gram scale synthesis of a representative example of sulfonyl furan was carried out to demonstrate the synthetic efficiency of the methodology.
O liquido da casca da castanha do caju possui importantes propriedades biologicas e terapeuticas ... more O liquido da casca da castanha do caju possui importantes propriedades biologicas e terapeuticas e dentre elas cita-se a sua toxicidade as larvas do mosquito Aedes aegypti, que e o transmissor da dengue, uma importante questao de saude publica. Frente ao exposto o presente estudo avaliou os efeitos de um tensoativo do Liquido da Casca da Castanha do Caju (TaLCC) na mortalidade de larvas do mosquito A. aegypti, no desempenho reprodutivo, no desenvolvimento embriofetal e na estabilidade genetica em camundongos Swiss. Foram utilizadas 400 larvas de A. aegypti (terceiro estagio larval) submetidas ao TaLCC nas concentracao de 0,05mg/L, 0,5mg/L, 5mg/L. Tambem foram utilizados 20 camundongos femeas prenhes tratadas com o TaLCC nas doses de 5mg/kg e 50mg/kg de peso corporeo (p.c.), via oral (v.o.), no periodo gestacional, e mais 10 animais tratadas com agua potavel (veiculo do TaLCC) na proporcao de 0,1ml/10g (p.c., v.o.). Os resultados do ensaio larvicida demonstraram que a concentracao de...
Cytosporones, a class of octaketide resorcinolic lipids, have drawn the attention of researchers ... more Cytosporones, a class of octaketide resorcinolic lipids, have drawn the attention of researchers for exhibiting a number of notable biological properties. Herein, we describe routes to synthesize the bioactive synthetic resorcinolic lipids AMS35AA and AMS35BB with excellent overall yields using 3,5-dimethoxybenzoic acid as the starting material. The methods proved remarkably effi cient to achieve the target compounds and comprise the synthesis of AMS35AA catalyzed by ascorbic acid (vitamin C).
Recent studies showed that resorcinolic lipid 3-Heptyl-3,4,6-trimethoxy-3H-isobenzofuran-1-one (A... more Recent studies showed that resorcinolic lipid 3-Heptyl-3,4,6-trimethoxy-3H-isobenzofuran-1-one (AMS 35AA) may be an important chemotherapy adjuvant, that is not genotoxic nor mutagenic. It is noteworthy that, when AMS35AA is associated with cyclophosphamide, it increases the mutagenic damage, splenic phagocytosis, neutropenia, and induces apoptosis in liver and kidneys. Taken this into account, the present study performed an accurate morphometric investigation of the consequences of the association between AMS35AA and cyclophosphamide on the hepatocytes morphology of Swiss mice. Our results provide strong evidence that the AMS35AA is not toxic and does not induce cellular hyperplasia or hypertrophy in the hepatocytes, which could lead the development of malignant neoplasia. Then, our data support the view that the resorcinolic lipid derivative is not toxic to the hepatocyte, which therefore could have therapeutic applications. Palavras-chave: lipídio resarcinólico; citosporonas, hep...
Colon cancer incidence rates are increasing annually, a scenario aggravated by genetic and epigen... more Colon cancer incidence rates are increasing annually, a scenario aggravated by genetic and epigenetic alterations that promote drug resistance. Recent studies showed that novel synthetic selenium compounds are more efficient and less toxic than conventional drugs, demonstrating biocompatibility and pro-oxidant effects on tumor cells. This study aimed to investigate the cytotoxic effect of MRK-107, an imidazo [1,2- a]pyridine derivative, in 2D and 3D cell culture models of colon cancer (Caco-2 and HT-29). Sulforhodamine B results revealed a GI50 of 2.4 µM for Caco-2, 1.1 µM for HT-29, and 22.19 µM for NIH/3T3 in 2D cultures after 48 h of treatment. Cell recovery, migration, clonogenic, and Ki-67 results corroborated that MRK-107 inhibits cell proliferation and prevents cell regeneration and metastatic transition by selectively reducing migratory and clonogenic capacity; non-tumor cells (NIH/3T3) re-established proliferation in less than 18 h. The oxidative stress markers DCFH-DA and ...
3-heptylidene-4,6-dimethoxy-3H-isobenzofuran-1-one (Phthalide 1) is the precursor of three resorc... more 3-heptylidene-4,6-dimethoxy-3H-isobenzofuran-1-one (Phthalide 1) is the precursor of three resorcinol lipids that have been described as potential chemotherapeutic agents and capable of potentiating the effects of cyclophosphamide. In this study, we evaluated the genotoxic potential, cell-killing potential, and interactions with cyclophosphamide and cisplatin of phthalide 1. Twelve groups were created from 120 mice: Negative Control, cyclophosphamide (100 mg/kg), cisplatin (6 mg/kg), Phthalide 1 (5, 10 and 20 mg/kg), and associations of 1 with cyclophosphamide and 1 with cisplatin. The results demonstrate that 1 increases (p < 0.05) the frequency of chromosomal damage, liver and kidney cell death, and splenic phagocytosis. The association of 1 with cyclophosphamide and cisplatin demonstrated a chemopreventive effect and, therefore, a reduction (p < 0.05) in the frequency of chromosomal damage. However, cell death and splenic phagocytosis did not suffer significant variations. ...
O aumento da incidencia de câncer e os altos custos de tratamento estimulam a busca por novo comp... more O aumento da incidencia de câncer e os altos custos de tratamento estimulam a busca por novo compostos para uso na prevencao, tratamento bem como em tratamentos coadjuvantes. Diante do exposto, o presente estudo avaliou o acido (Z) -4-((4-il-1,5-dimetil-3-oxo-2-fenil-2,3-di-hidro-1H-pirazol) amino)-4-oxobut-2-enoico (IR- 001) quanto a integridade genetica, atividade imunomodulatoria e inducao apoptose bem como seus efeitos em associacao com os quimioterapicos comerciais doxorrubicina, cisplatina e ciclofosfamida. Esse composto foi planejado e sintetizado com base em dois radicais, um deles, a 4-aminoantipirina que e descrito como efetivo antioxidante e antinflamatorio e o outro 1,4-dioxo-2butenil que e um efetivo agente citotoxico. Os resultados indicaram que o IR-001 e um efetivo quimioprotetor por nao ser mutagenico e apresentar boa capacidade antigenotoxica (ate 94,15%), antimutagenica (ate 92,49%), imunomodulatoria (aumenta a fagocitose esplenica e a frequencia de linfocitos) e ...
A study of [3 + 2] cycloaddition reactions of a bicyclic nitrone with various cyclopentenes has c... more A study of [3 + 2] cycloaddition reactions of a bicyclic nitrone with various cyclopentenes has clarified the diastereomeric preferences as a function of the olefinic structure. It has also identified an important stereochemical difference between nitrones and the analogous azomethine ylides in [3 + 2] cycloaddition reactions.
Orbital: The Electronic Journal of Chemistry, 2020
Neste trabalho, foi planejada a sintese de lipideos resorcinolicos analogos as citosporonas utili... more Neste trabalho, foi planejada a sintese de lipideos resorcinolicos analogos as citosporonas utilizando metodos classicos de sintese orgânica. O objetivo principal foi a preparacao dos compostos: acido 2,4-dihidroxi-6-octil-benzoico ( 6 ) e 2,4-diidroxi-6-(8-oxooctil)-benzoico ( 7 ). Foram estudadas rotas de sintese visando a producao desses compostos, foi possivel obtencao de tres intermediarios avancados, com sucesso: 2,4 dimetoxi-6-octil-benzoato de etila ( 8 ), 2-hidroxi-4-metoxi-6-octil-benzoato de etila ( 9 ) e acido 2-hidroxi-4-metoxi-6-octil-benzoico ( 10 ), os quais tiveram suas estruturas determinadas por tecnicas de espectroscopia de RMN de 1 H e de 13 C, e no caso de ( 10 ) incluindo tecnicas bidimensionais (HSQC e HMBC).
Acetylcholinesterase (AChEis) inhibitors are used to treat neurodegenerative diseases like Alzhei... more Acetylcholinesterase (AChEis) inhibitors are used to treat neurodegenerative diseases like Alzheimer's disease (AD). L-hypaphorine (L-HYP) is a natural indole alkaloid that has been shown to have effects on the central nervous system (CNS). The goal of this research was to synthesize L-HYP and D-HYP and test their anticholinesterasic properties in rat brain regions. L-HYP suppressed acetylcholinesterase (AChE) activity only in the cerebellum, whereas D-HYP inhibited AChE activity in all CNS regions studied. No cytotoxic effect on normal human cells (HaCaT) was observed in the case of L-HYP and D-HYP although an increase in cell proliferation. Molecular modeling studies revealed that D-HYP and L-HYP have significant differences in their binding mode positions and interact stereospecifically with AChE's amino acid residues.
Herein we describe a simple method for the synthesis of Baylis-Hillman adducts and their acetates... more Herein we describe a simple method for the synthesis of Baylis-Hillman adducts and their acetates by utilizing inexpensively available cashew nut shell liquid (CNSL) natural resource. Furthermore, by using a molecular hybridization approach, a series of novel pyrimidine scaffolds (15a-15t) were synthesized by utilizing Baylis-Hillman acetate derivatives from cashew nut shell liquid (CNSL). All the newly synthesized compounds were screened for their in vitro antitumor activity. Baylis-Hillman compounds 5b and 5h showed promising anticancer activity against MCF-7. Among pyrimidine derivatives, compounds 15i, 15j and 15l showed promising activity against HEP-G2, whereas compounds 15j, 15k, 15l and 15m showed promising activity against MCF-7. In addition, compound 15m showed significant activity against K562 when compared with the standard. The structure-activity relationship (SAR) analysis suggests that the length of the carbon chain of phenyl ring played an important role in the poten...
Cytosporones, a class of octaketide resorcinolic lipids, have drawn the attention of researchers ... more Cytosporones, a class of octaketide resorcinolic lipids, have drawn the attention of researchers for exhibiting a number of notable biological properties. Herein, we describe routes to synthesize the bioactive synthetic resorcinolic lipids AMS35AA and AMS35BB with excellent overall yields using 3,5-dimethoxybenzoic acid as the starting material. The methods proved remarkably efficient to achieve the target compounds and comprise the synthesis of AMS35AA catalyzed by ascorbic acid (vitamin C).
Reaction of β-ketosulfones with different α-functionalized nitroalkenes affords diversely substit... more Reaction of β-ketosulfones with different α-functionalized nitroalkenes affords diversely substituted sulfonyl furans and dihydrofurans. β-Ketosulfones react with α-bromonitroalkenes and α-hydrazinonitroalkenes via cascade Michael addition-cyclization protocol to deliver nitrodihydrofurans and hydrazinodihydrofurans, respectively, bearing a key sulfonyl group, in excellent yields with broad substrate scope. Application of these products has been demonstrated by the synthesis of pyrroles and pyrazoles in good yields. Reaction of β-ketosulfones with nitroallylic acetates yield tetrasubstituted sulfonyl furans through a cascade SN2'-intramolecular Michael reaction followed by aromatization. Gram scale synthesis of a representative example of sulfonyl furan was carried out to demonstrate the synthetic efficiency of the methodology.
O liquido da casca da castanha do caju possui importantes propriedades biologicas e terapeuticas ... more O liquido da casca da castanha do caju possui importantes propriedades biologicas e terapeuticas e dentre elas cita-se a sua toxicidade as larvas do mosquito Aedes aegypti, que e o transmissor da dengue, uma importante questao de saude publica. Frente ao exposto o presente estudo avaliou os efeitos de um tensoativo do Liquido da Casca da Castanha do Caju (TaLCC) na mortalidade de larvas do mosquito A. aegypti, no desempenho reprodutivo, no desenvolvimento embriofetal e na estabilidade genetica em camundongos Swiss. Foram utilizadas 400 larvas de A. aegypti (terceiro estagio larval) submetidas ao TaLCC nas concentracao de 0,05mg/L, 0,5mg/L, 5mg/L. Tambem foram utilizados 20 camundongos femeas prenhes tratadas com o TaLCC nas doses de 5mg/kg e 50mg/kg de peso corporeo (p.c.), via oral (v.o.), no periodo gestacional, e mais 10 animais tratadas com agua potavel (veiculo do TaLCC) na proporcao de 0,1ml/10g (p.c., v.o.). Os resultados do ensaio larvicida demonstraram que a concentracao de...
Cytosporones, a class of octaketide resorcinolic lipids, have drawn the attention of researchers ... more Cytosporones, a class of octaketide resorcinolic lipids, have drawn the attention of researchers for exhibiting a number of notable biological properties. Herein, we describe routes to synthesize the bioactive synthetic resorcinolic lipids AMS35AA and AMS35BB with excellent overall yields using 3,5-dimethoxybenzoic acid as the starting material. The methods proved remarkably effi cient to achieve the target compounds and comprise the synthesis of AMS35AA catalyzed by ascorbic acid (vitamin C).
Recent studies showed that resorcinolic lipid 3-Heptyl-3,4,6-trimethoxy-3H-isobenzofuran-1-one (A... more Recent studies showed that resorcinolic lipid 3-Heptyl-3,4,6-trimethoxy-3H-isobenzofuran-1-one (AMS 35AA) may be an important chemotherapy adjuvant, that is not genotoxic nor mutagenic. It is noteworthy that, when AMS35AA is associated with cyclophosphamide, it increases the mutagenic damage, splenic phagocytosis, neutropenia, and induces apoptosis in liver and kidneys. Taken this into account, the present study performed an accurate morphometric investigation of the consequences of the association between AMS35AA and cyclophosphamide on the hepatocytes morphology of Swiss mice. Our results provide strong evidence that the AMS35AA is not toxic and does not induce cellular hyperplasia or hypertrophy in the hepatocytes, which could lead the development of malignant neoplasia. Then, our data support the view that the resorcinolic lipid derivative is not toxic to the hepatocyte, which therefore could have therapeutic applications. Palavras-chave: lipídio resarcinólico; citosporonas, hep...
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