Based on the effectiveness of resveratrol and curcumin in carcinogenesis, (E)-3-(4-hydroxy-3-meth... more Based on the effectiveness of resveratrol and curcumin in carcinogenesis, (E)-3-(4-hydroxy-3-methoxyphenyl)-Nʹ-((E)-4-methoxybenzylidene) acrylohydrazide (PQM-162), curcumin–resveratrol hybrid derivative, was designed by molecular hybridization using a hydrazone functionality as a spacer moiety between pharmacophoric fragments inspired by the parent compounds. Objectives The present study aimed to evaluate the chemopreventive effects of the hybrid against pre-neoplastic lesions induced in the colon of rodents. Methods The doses were determined based on the reduction in DNA damage induced by doxorubicin [15 mg/kg body weight (b.w.)] in peripheral blood of Swiss mice. Doses of 8, 16, 32, and 64 mg/kg b.w. were antimutagenic. For the evaluation of pre-neoplastic lesions in the colon, Wistar rats were treated with PQM-162 at doses of 0.5, 1, and 2 mg/kg b.w. for 6 weeks using three approaches: simultaneous treatment, pre-treatment, and post-treatment. Pre-neoplastic lesions were induced...
Biochimica et Biophysica Acta (BBA) - General Subjects, 2021
BACKGROUND Garcinia brasiliensis is a species native to the Amazon forest. The white mucilaginous... more BACKGROUND Garcinia brasiliensis is a species native to the Amazon forest. The white mucilaginous pulp is used in folk medicine as a wound healing agent and for peptic ulcer, urinary, and tumor disease treatments. The activity of the proprotein convertases (PCs) Subtilisin/Kex is associated with the development of viral, bacterial and fungal infections, osteoporosis, hyperglycemia, atherosclerosis, cardiovascular, neurodegenerative and neoplastic diseases. METHODS Morelloflavone (BF1) and semisynthetic biflavonoid (BF2, 3 and 4) from Garcinia brasiliensis were tested as inhibitor of PCs Kex2, PC1/3 and Furin, and determined IC50, Ki, human proinflammatory cytokines secretion in Caco-2 cells, mechanism of inhibition, and performed molecular docking studies. RESULTS Biflavonoids were more effective in the inhibition of neuroendocrine PC1/3 than mammalian Furin and fungal Kex2. BF1 presented a mixed inhibition mechanism for Kex2 and PC1, and competitive inhibition for Furin. BF4 has no good interaction with Kex2 and Furin since carboxypropyl groups results in steric hindrance to ligand-protein interactions. Carboxypropyl groups of BF4 promote steric hindrance with Kex2 and Furin, but effective in the affinity of PC1/3. BF4 was more efficient at inhibiting PCl/3 (IC50 = 1.13 μM and Ki = 0,59 μM, simple linear competitive mechanism of inhibition) than Kex2, Furin. Also, our results strongly suggested that BF4 also inhibits the endogenous cellular PC1/3 activity in Caco-2 cells, since PC1/3 inhibition by BF4 causes a large increase in IL-8 and IL-1β secretion in Caco-2 cells. CONCLUSIONS BF4 is a potent and selective inhibitor of PC1/3. GENERAL SIGNIFICANCE BF4 is the best candidate for further clinical studies on inhibition of PC1/3.
We describe herein the therapeutic targets involved in Alzheimer’s disease as well as the availab... more We describe herein the therapeutic targets involved in Alzheimer’s disease as well as the available drugs and their synthetic routes. Bioactive compounds under development are also exploited to illustrate some recent research advances on the medicinal chemistry of Alzheimer’s disease, including structure-activity relationships for some targets. The importance of multi-target approaches, including some examples from our research projects, guides new perspectives in search of more effective drug candidates. This review comprises the period between 2001 and early 2020.
ABSTRACT Este artigo apresenta brevemente alguns exemplos da aplicação da modificação estrutural ... more ABSTRACT Este artigo apresenta brevemente alguns exemplos da aplicação da modificação estrutural sobre a (-)-cassina (1) e seu derivado LASSBio-767, além da hibridação molecular e simplificação molecular de compostos-protótipo como valioas estratégias em Química Medicinal na busca por novas entidades química bioativas e inovadoras.
A racemic crystalline form of terebic acid, C(7)H(10)O(4), which is an important industrial chemi... more A racemic crystalline form of terebic acid, C(7)H(10)O(4), which is an important industrial chemical compound, is reported for the first time. The crystal structure is stabilized by O-H···O and C-H···O hydrogen bonds which form racemic double layers parallel to (001).
In the last few years research into Cannabis and its constituent phytocannabinoids has burgeoned,... more In the last few years research into Cannabis and its constituent phytocannabinoids has burgeoned, particularly in the potential application of novel cannabis phytochemicals for the treatment of diverse illnesses related to neurodegeneration and dementia, including Alzheimer’s (AD), Parkinson’s (PD) and Huntington’s disease (HD). To date, these neurological diseases have mostly relied on symptomatological management. However, with an aging population globally, the search for more efficient and disease-modifying treatments that could delay or mitigate disease progression is imperative. In this context, this review aims to present state of the art in the research with cannabinoids and novel cannabinoid-based drug candidates that have been emerged as novel promising alternatives for drug development and innovation in the therapeutics of a number of diseases, especially those related to CNS-disturbance and impairment.
Toxicology in vitro : an international journal published in association with BIBRA, Jan 31, 2017
Lung cancer is the most frequent type of cancer worldwide. In Brazil, only 14% of the patients di... more Lung cancer is the most frequent type of cancer worldwide. In Brazil, only 14% of the patients diagnosed with lung cancer survived 5years in the last decades. Although improvements in the therapeutic approach, it is relevant to identify new chemotherapeutic agents. In this framework, ruthenium metal compounds emerge as a promising alternative to platinum-based compounds once they displayed lower cytotoxicity and more selectivity for tumor cells. The present study aimed to evaluate the antitumor potential of innovative ruthenium(II) complex, [Ru(pipe)(dppb)(bipy)]PF6 (PIPE) on A549 cells, which is derived from non-small cell lung cancer. Results demonstrated that PIPE effectively reduced the viability and proliferation rate of A549 cells. When PIPE was used at 9μM there was increase in G0/G1 cell population with concomitant reduction in frequency of cells in S-phase, indicating cell cycle arrest in G1/S transition. Antiproliferative activity of PIPE was associated to its ability of r...
Nos ultimos anos, a Quimica Medicinal vem buscando novas alternativas e ferramentas capazes de tr... more Nos ultimos anos, a Quimica Medicinal vem buscando novas alternativas e ferramentas capazes de trazer maior agilidade, seguranca e um direcionamento mais eficiente no planejamento e prospeccao de candidatos a farmacos. Neste contexto, estrategias de descoberta de farmacos focando o desenvolvimento de ligantes que atuem sobre alvos especificos vem sendo rediscutidas, uma vez que tem aplicacao limitada em doencas multifatoriais, onde um conjunto de eventos bioquimicos e alvos proteicos estao envolvidos. Na ultima decada surge uma nova abordagem no planejamento de ligantes baseada na polifarmacologia, visando a descoberta de entidades quimicas capazes de atuar em multiplos alvos simultaneamente. Desde 2005, a literatura vem relatando uma serie de trabalhos que utilizam essa estrategia inovadora para o planejamento de farmacos contra a Doenca de Alzheimer (DA). A DA e uma doenca neurodegenerativa, caracterizada por uma serie de eventos interconectados envolvendo a deposicao intra e extracelular de fragmentos proteicos, a instalacao de um complexo processo neuro-inflamatorio, disfuncao mitocondrial, apoptose e morte neuronal. Como consequencia da evolucao da doenca, o paciente passa por deficits de memoria e colinergico, passando a incapacidade motora, funcional e morte. Nesta breve revisao, tivemos o objetivo de apresentar os mais recentes avancos (2013-2014) da Quimica Medicinal no planejamento e descoberta de novos candidatos a prototipos de farmacos multialvo potencialmente uteis ao tratamento da DA. Este trabalho e um complemento a outro artigo de revisao, recentemente publicado por nosso grupo, que cobre o periodo anterior de 2005-2012. Na maioria dos trabalhos discutidos aqui, a rivastigmina, tacrina, donepezil e galantamina tem sido utilizados como modelos de inibidores de acetilcolinesterase para o planejamento de novos hibridos moleculares com perfil de acao multiplo. Em outros casos, produtos naturais como a curcumina, resveratrol, berberina e quercetina tem sido eleitos por suas caracteristicas neuroprotetoras, antiapoptotica, anti-inflamatoria e antioxidante para o desenho de novas entidades quimicas com propriedades inovadoras e com potencial terapeutico para o tratamento mais eficiente da DA. DOI: 10.5935/1984-6835.20150027
Based on the effectiveness of resveratrol and curcumin in carcinogenesis, (E)-3-(4-hydroxy-3-meth... more Based on the effectiveness of resveratrol and curcumin in carcinogenesis, (E)-3-(4-hydroxy-3-methoxyphenyl)-Nʹ-((E)-4-methoxybenzylidene) acrylohydrazide (PQM-162), curcumin–resveratrol hybrid derivative, was designed by molecular hybridization using a hydrazone functionality as a spacer moiety between pharmacophoric fragments inspired by the parent compounds. Objectives The present study aimed to evaluate the chemopreventive effects of the hybrid against pre-neoplastic lesions induced in the colon of rodents. Methods The doses were determined based on the reduction in DNA damage induced by doxorubicin [15 mg/kg body weight (b.w.)] in peripheral blood of Swiss mice. Doses of 8, 16, 32, and 64 mg/kg b.w. were antimutagenic. For the evaluation of pre-neoplastic lesions in the colon, Wistar rats were treated with PQM-162 at doses of 0.5, 1, and 2 mg/kg b.w. for 6 weeks using three approaches: simultaneous treatment, pre-treatment, and post-treatment. Pre-neoplastic lesions were induced...
Biochimica et Biophysica Acta (BBA) - General Subjects, 2021
BACKGROUND Garcinia brasiliensis is a species native to the Amazon forest. The white mucilaginous... more BACKGROUND Garcinia brasiliensis is a species native to the Amazon forest. The white mucilaginous pulp is used in folk medicine as a wound healing agent and for peptic ulcer, urinary, and tumor disease treatments. The activity of the proprotein convertases (PCs) Subtilisin/Kex is associated with the development of viral, bacterial and fungal infections, osteoporosis, hyperglycemia, atherosclerosis, cardiovascular, neurodegenerative and neoplastic diseases. METHODS Morelloflavone (BF1) and semisynthetic biflavonoid (BF2, 3 and 4) from Garcinia brasiliensis were tested as inhibitor of PCs Kex2, PC1/3 and Furin, and determined IC50, Ki, human proinflammatory cytokines secretion in Caco-2 cells, mechanism of inhibition, and performed molecular docking studies. RESULTS Biflavonoids were more effective in the inhibition of neuroendocrine PC1/3 than mammalian Furin and fungal Kex2. BF1 presented a mixed inhibition mechanism for Kex2 and PC1, and competitive inhibition for Furin. BF4 has no good interaction with Kex2 and Furin since carboxypropyl groups results in steric hindrance to ligand-protein interactions. Carboxypropyl groups of BF4 promote steric hindrance with Kex2 and Furin, but effective in the affinity of PC1/3. BF4 was more efficient at inhibiting PCl/3 (IC50 = 1.13 μM and Ki = 0,59 μM, simple linear competitive mechanism of inhibition) than Kex2, Furin. Also, our results strongly suggested that BF4 also inhibits the endogenous cellular PC1/3 activity in Caco-2 cells, since PC1/3 inhibition by BF4 causes a large increase in IL-8 and IL-1β secretion in Caco-2 cells. CONCLUSIONS BF4 is a potent and selective inhibitor of PC1/3. GENERAL SIGNIFICANCE BF4 is the best candidate for further clinical studies on inhibition of PC1/3.
We describe herein the therapeutic targets involved in Alzheimer’s disease as well as the availab... more We describe herein the therapeutic targets involved in Alzheimer’s disease as well as the available drugs and their synthetic routes. Bioactive compounds under development are also exploited to illustrate some recent research advances on the medicinal chemistry of Alzheimer’s disease, including structure-activity relationships for some targets. The importance of multi-target approaches, including some examples from our research projects, guides new perspectives in search of more effective drug candidates. This review comprises the period between 2001 and early 2020.
ABSTRACT Este artigo apresenta brevemente alguns exemplos da aplicação da modificação estrutural ... more ABSTRACT Este artigo apresenta brevemente alguns exemplos da aplicação da modificação estrutural sobre a (-)-cassina (1) e seu derivado LASSBio-767, além da hibridação molecular e simplificação molecular de compostos-protótipo como valioas estratégias em Química Medicinal na busca por novas entidades química bioativas e inovadoras.
A racemic crystalline form of terebic acid, C(7)H(10)O(4), which is an important industrial chemi... more A racemic crystalline form of terebic acid, C(7)H(10)O(4), which is an important industrial chemical compound, is reported for the first time. The crystal structure is stabilized by O-H···O and C-H···O hydrogen bonds which form racemic double layers parallel to (001).
In the last few years research into Cannabis and its constituent phytocannabinoids has burgeoned,... more In the last few years research into Cannabis and its constituent phytocannabinoids has burgeoned, particularly in the potential application of novel cannabis phytochemicals for the treatment of diverse illnesses related to neurodegeneration and dementia, including Alzheimer’s (AD), Parkinson’s (PD) and Huntington’s disease (HD). To date, these neurological diseases have mostly relied on symptomatological management. However, with an aging population globally, the search for more efficient and disease-modifying treatments that could delay or mitigate disease progression is imperative. In this context, this review aims to present state of the art in the research with cannabinoids and novel cannabinoid-based drug candidates that have been emerged as novel promising alternatives for drug development and innovation in the therapeutics of a number of diseases, especially those related to CNS-disturbance and impairment.
Toxicology in vitro : an international journal published in association with BIBRA, Jan 31, 2017
Lung cancer is the most frequent type of cancer worldwide. In Brazil, only 14% of the patients di... more Lung cancer is the most frequent type of cancer worldwide. In Brazil, only 14% of the patients diagnosed with lung cancer survived 5years in the last decades. Although improvements in the therapeutic approach, it is relevant to identify new chemotherapeutic agents. In this framework, ruthenium metal compounds emerge as a promising alternative to platinum-based compounds once they displayed lower cytotoxicity and more selectivity for tumor cells. The present study aimed to evaluate the antitumor potential of innovative ruthenium(II) complex, [Ru(pipe)(dppb)(bipy)]PF6 (PIPE) on A549 cells, which is derived from non-small cell lung cancer. Results demonstrated that PIPE effectively reduced the viability and proliferation rate of A549 cells. When PIPE was used at 9μM there was increase in G0/G1 cell population with concomitant reduction in frequency of cells in S-phase, indicating cell cycle arrest in G1/S transition. Antiproliferative activity of PIPE was associated to its ability of r...
Nos ultimos anos, a Quimica Medicinal vem buscando novas alternativas e ferramentas capazes de tr... more Nos ultimos anos, a Quimica Medicinal vem buscando novas alternativas e ferramentas capazes de trazer maior agilidade, seguranca e um direcionamento mais eficiente no planejamento e prospeccao de candidatos a farmacos. Neste contexto, estrategias de descoberta de farmacos focando o desenvolvimento de ligantes que atuem sobre alvos especificos vem sendo rediscutidas, uma vez que tem aplicacao limitada em doencas multifatoriais, onde um conjunto de eventos bioquimicos e alvos proteicos estao envolvidos. Na ultima decada surge uma nova abordagem no planejamento de ligantes baseada na polifarmacologia, visando a descoberta de entidades quimicas capazes de atuar em multiplos alvos simultaneamente. Desde 2005, a literatura vem relatando uma serie de trabalhos que utilizam essa estrategia inovadora para o planejamento de farmacos contra a Doenca de Alzheimer (DA). A DA e uma doenca neurodegenerativa, caracterizada por uma serie de eventos interconectados envolvendo a deposicao intra e extracelular de fragmentos proteicos, a instalacao de um complexo processo neuro-inflamatorio, disfuncao mitocondrial, apoptose e morte neuronal. Como consequencia da evolucao da doenca, o paciente passa por deficits de memoria e colinergico, passando a incapacidade motora, funcional e morte. Nesta breve revisao, tivemos o objetivo de apresentar os mais recentes avancos (2013-2014) da Quimica Medicinal no planejamento e descoberta de novos candidatos a prototipos de farmacos multialvo potencialmente uteis ao tratamento da DA. Este trabalho e um complemento a outro artigo de revisao, recentemente publicado por nosso grupo, que cobre o periodo anterior de 2005-2012. Na maioria dos trabalhos discutidos aqui, a rivastigmina, tacrina, donepezil e galantamina tem sido utilizados como modelos de inibidores de acetilcolinesterase para o planejamento de novos hibridos moleculares com perfil de acao multiplo. Em outros casos, produtos naturais como a curcumina, resveratrol, berberina e quercetina tem sido eleitos por suas caracteristicas neuroprotetoras, antiapoptotica, anti-inflamatoria e antioxidante para o desenho de novas entidades quimicas com propriedades inovadoras e com potencial terapeutico para o tratamento mais eficiente da DA. DOI: 10.5935/1984-6835.20150027
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Papers by Claudio Viegas Jr.