RESUMO
A library of structurally related coumarins was generated through synthesis reactions and chemical modification reactions to obtain derivatives with antiproliferative activity both in vivo and in vitro. Out of a total of 35 structurally related coumarin derivatives, seven of them showed inhibitory activity in in vitro tests against Taq DNA polymerase with IC50 values lower than 250 µM. The derivatives 4-(chloromethyl)-5,7-dihydroxy-2H-chromen-2-one (2d) and 4-((acetylthio)methyl)-2-oxo-2H-chromen-7-yl acetate (3c) showed the most promising anti-polymerase activity with IC50 values of 20.7 ± 2.10 and 48.25 ± 1.20 µM, respectively. Assays with tumor cell lines (HEK 293 and HCT-116) were carried out, and the derivative 4-(chloromethyl)-7,8-dihydroxy-2H-chromen-2-one (2c) was the most promising, with an IC50 value of 8.47 µM and a selectivity index of 1.87. In addition, the derivatives were evaluated against Saccharomyces cerevisiae strains that report about common modes of actions, including DNA damage, that are expected for agents that cause replicative stress. The coumarin derivatives 7-(2-(oxiran-2-yl)ethoxy)-2H-chromen-2-one (5b) and 7-(3-(oxiran-2-yl)propoxy)-2H-chromen-2-one (5c) caused DNA damage in S. cerevisiae. The O-alkenylepoxy group stands out as that with the most important functionality within this family of 35 derivatives, presenting a very good profile as an antiproliferative scaffold. Finally, the in vitro antiretroviral capacity was tested through RT-PCR assays. Derivative 5c showed inhibitory activity below 150 µM with an IC50 value of 134.22 ± 2.37 µM, highlighting the O-butylepoxy group as the functionalization responsible for the activity.
RESUMO
The capacity of different naphthoquinones to inhibit and eradicate Yersinia enterocolitica biofilm was investigated and possible mechanisms of action were evaluated. Inhibition of biofilm formation and cell viability, quorum sensing (QS) inhibition and oxidative stress generation of 23 naphthoquinones were assayed against Yersinia enterocolitica. The best anti-biofilm agents at 100 µmol l-1 were compounds 3, 11 and 13, which showed biofilm inhibition higher than 75%. Compound 3 was the most effective against biofilm forming capacity of Y. enterocolitica WAP 314 with a minimum biofilm inhibitory concentration (MBIC) of 25 µmol l-1; while against Y. enterocolitica CLC001, the lowest MBIC was 6.1 µmol l-1 for compound 11. Acyl-homoserine lactones production was decreased with compound 13. We showed that the oxidative stress influence biofilm growth, by means of ROS and RNI increment. All treatments increased ROS and RNI values in the biofilm of both strains; while in planktonic cells, the increase was lesser. Additionally, Y. enterocolitica WAP 314 biofilm treated with compounds 11 and 13 showed above 80% of SOD consumption. In Y. enterocolitica CLC001 biofilm all compounds induced above 90% of SOD consumption. The SOD activity was higher in biofilm than in planktonic cells. In conclusion, this is the first study to demonstrate that naphthoquinones are able to inhibit biofilm formation of Y. enterocolitica without critical disturbing its planktonic growth. Naphthoquinones as anti-biofilm agents might potentially be useful in the treatment of biofilm-associated infections in the future.
Assuntos
Biofilmes/crescimento & desenvolvimento , Naftoquinonas/farmacologia , Yersinia enterocolitica/fisiologia , Acil-Butirolactonas/metabolismo , Biofilmes/efeitos dos fármacos , Regulação Bacteriana da Expressão Gênica/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Viabilidade Microbiana , Estrutura Molecular , Naftoquinonas/química , Estresse Oxidativo , Yersinia enterocolitica/efeitos dos fármacosRESUMO
A phytochemical study was performed on three native plant species from the central-western zone of Argentina: Buddleja cordobensis Grisebach, Baccharis salicina Torr. & A. Gray and Nepeta cataria L. We could obtain verbascoside (1) from B. cordobensis. From N. cataria, we could obtain 1, 5, 9-epi-deoxyloganic acid (2) L. Finally, we could isolate 2-ß-(L-rhamnopyranosyl)-3-angeloyloxy-15-acetyloxy-7,13(14)-E-dien-ent-labdane (3) and 2-ß-(L-rhamnopyranosyl)-3-α-angeloyloxy-15-hydroxy-7,13(14)-E-dien-ent-labdane (4) from B. salicina. Moreover, three derivatives from 1, and one semi-synthetic derivative from 2, were prepared. PCR reaction was used to analyse the activity against DNA polymerase and cell culture to determine cytotoxicity and antitumoral activity. Verbascoside (1) was strongly active in the nanomolar scale (IC50 = 356 nM) against DNA polymerization. Moreover, verbascoside was also strongly active in the nanomolar scale against human melanoma cell line (IC50 = 256 nM) and human colorectal cell line (IC50 = 320 nM). Furthermore, derivatives 6 and 7 were cytotoxic against both cancer cell lines.
Assuntos
Buddleja , Glicosídeos , Glucosídeos/farmacologia , Glicosídeos/farmacologia , Humanos , FenóisRESUMO
BACKGROUND: The discovery of new chemotherapeutic agents still remains a continuous goal to achieve. DNA polymerases and topoisomerases act in nucleic acids metabolism modulating different processes like replication, mitosis, damage repair, DNA topology and transcription. It has been widely documented that Polymerases serve as molecular targets for antiviral and antitumoral chemotherapy. Furthermore, telomerase is a ribonucleoprotein with exacerbated activity in most of the tumor cell lines, becoming as an emergent target in Cancer treatment. METHODS: We undertook an exhaustive search of bibliographic databases for peer-reviewed research literature related to the last decade. The characteristics of screened bibliography describe structure activity relationships and show the principal moieties involved. This work tries to summarize the investigation about natural and semi-synthetic products with natural origin with the faculty to inhibit key enzymes that play a crucial role in DNA metabolism. RESULTS: Eighty-five data references were included in this review, showing natural products widely distributed throughout the plant kingdom and their bioactive properties such as tumor growing inhibitory effects, and anti-AIDS activity. CONCLUSION: The findings of this review confirm the importance to find new drugs and biologically active natural products, and their potential medicinally useful benefits.
Assuntos
Antivirais/farmacologia , Produtos Biológicos/farmacologia , Neoplasias/tratamento farmacológico , Inibidores da Síntese de Ácido Nucleico/farmacologia , Inibidores da Topoisomerase/farmacologia , Viroses/tratamento farmacológico , Antivirais/química , Antivirais/uso terapêutico , Produtos Biológicos/química , Produtos Biológicos/uso terapêutico , DNA/metabolismo , DNA Topoisomerases/química , DNA Topoisomerases/metabolismo , DNA Polimerase Dirigida por DNA/química , DNA Polimerase Dirigida por DNA/metabolismo , Humanos , Terapia de Alvo Molecular/métodos , Neoplasias/genética , Inibidores da Síntese de Ácido Nucleico/química , Inibidores da Síntese de Ácido Nucleico/uso terapêutico , Relação Estrutura-Atividade , Inibidores da Topoisomerase/química , Inibidores da Topoisomerase/uso terapêutico , Viroses/genética , Viroses/virologiaRESUMO
Several natural and synthetic coumarins were assayed against different cancer cell lines. Four of them have shown cytotoxicity against a panel of three human solid tumor cell lines (HeLa, T-47D, and WiDr) and a clearly activity/hydrophobicity relationship. Compound 13 proved to be the most active product in all cell lines tested, with values of 8.0 (±0.38) µM against HeLa cells and also able to inhibit Taq DNA polymerase. This dual activity of 13 makes it a candidate to be considered as a "lead" compound in the search for novel antitumor drugs.
Assuntos
Antineoplásicos Fitogênicos/farmacologia , Cumarínicos/farmacologia , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Células HeLa , Humanos , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
Human Immunodeficiency Virus (HIV) is the viral agent of Acquired Immunodeficiency Syndrome (AIDS), and at present, there is no effective vaccine against HIV. Reverse Transcriptase (RT) is an essential enzyme for retroviral replication, such as HIV as well as for other RNA infectious viruses like Human T lymphocyte virus. Polymerases act in DNA metabolism, modulating different processes like mitosis, damage repair, transcription and replication. It has been widely documented that DNA Polymerases and Reverse Transcriptases serve as molecular targets for antiviral and antitumoral chemotherapy. Coumarins are oxygen heterocycles that are widely distributed throughout the plant kingdom. Natural coumarins have attraction due to their bioactive properties such as tumor promotion inhibitory effects, and anti-HIV activity. Coumarins and derivates exhibit potent inhibitory effects on HIV-1 replication in lymphocytes and compounds isolated from Calophyllum inophyllum or DCK derivates showed inhibitory activity against human RT. Furthermore, natural isocoumarins isolated from cultures of fungi or hydroxycoumarins were able to inhibit human DNA polymerase. In view of their importance as drugs and biologically active natural products, and their medicinally useful properties, extensive studies have been carried out on the synthesis of coumarin compounds in recent years. Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs), a class of antiretroviral chemotherapeutic agents, act by binding to an allosteric pocket showing, generally, low toxicity. This work tries to summarize the investigation about natural and synthetic coumarins with the ability to inhibit key enzymes that play a crucial role in DNA metabolism and their possible application as antiretroviral and antitumoral agents.
Assuntos
Cumarínicos/farmacologia , DNA Polimerase Dirigida por DNA/metabolismo , Infecções por HIV , Neoplasias , Inibidores da Síntese de Ácido Nucleico/farmacologia , Inibidores da Transcriptase Reversa/farmacologia , Antineoplásicos/farmacologia , Antivirais/farmacologia , Simulação por Computador , Descoberta de Drogas/métodos , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/metabolismoRESUMO
DNA polymerases are enzymes that play a crucial role in DNA metabolism such as replication, repair, transcription, recombination, and chromosome segregation during mitosis. Herein we report the isolation of a new iridoid (6-epi-catalpol, 2) and per-O-acetyl-verbascoside (11) from aerial part of Buddleja cordobensis Grisebach (Buddlejaceae). From compound 2, we have obtained eight compounds by chemical transformation. This group of compounds at a concentration of 500µM was assayed against Taq DNA polymerase. Compound 11 (per-O-acetyl-verbascoside) was the most active with an IC50 of 1.21±0.18µM; compounds 9, 2 and 8 were strong inhibitors with IC50 values of 5.57±0.70, 21.62±0.22 and 78.13±0.93µM, respectively. Compounds 11 and 9 could be a leader structures to development new anticancer chemotherapy medicines and a useful tool to investigate DNA polymerase activity.
Assuntos
Inibidores Enzimáticos/farmacologia , Glucosídeos/farmacologia , Fenóis/farmacologia , Taq Polimerase/antagonistas & inibidores , Concentração Inibidora 50RESUMO
Synthetic coumarins were prepared in high yields using ionic liquids as an environmental friendly alternative. 3,4-Dimethyl-7-hydroxycoumarin (3ab) and 3-isopropyl-4-methyl-5,7-dihydroxycoumarin (3bc) showed interesting activity against Taq DNA polymerase with IC50 values of 115.7 microM and 82.2 microM, respectively. Also, 4-methyl-7-hydroxycoumarin (3aa) and 4-methyl-5,7-dihydroxycoumarin (3ba) exhibited inhibitory activity against MMLV-RT with IC50 values of 23.5 microM and 18.3 microM, respectively. These inhibitors could have importance as antiretroviral chemotherapeutic agents and also for the development of antitumor drugs.
Assuntos
Cumarínicos/síntese química , Inibidores Enzimáticos/síntese química , Extratos Vegetais/síntese química , Cumarínicos/química , Cumarínicos/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Estrutura Molecular , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Taq Polimerase/antagonistas & inibidoresRESUMO
Coumarin derivatives were prepared using natural products isolated from plants belonging in the Pterocaulon genus (Asteraceae) and commercial drugs. Some molecules have displayed interesting activity against myeloid murine leukemia virus-reverse transcriptase (MMLV-RT) (compounds 20 and 28 produced inhibition with IC50 values of 38.62 and 50.98 µM, respectively) and Taq DNA polymerase (analogues 13 and 14 produced inhibition with IC50 values of 48.08 and 57.88 µM, respectively). Such inhibitors may have importance as antiretroviral chemotherapeutic agents and also in the development of anticancer drugs.
Assuntos
Cumarínicos/química , Cumarínicos/farmacologia , Inibidores da Transcriptase Reversa/química , Inibidores da Transcriptase Reversa/farmacologia , Taq Polimerase/antagonistas & inibidores , Animais , Asteraceae/química , Linhagem Celular Tumoral , Ativação Enzimática/efeitos dos fármacos , Concentração Inibidora 50 , Camundongos , Modelos Biológicos , Estrutura Molecular , Vírus da Leucemia Murina de Moloney/enzimologia , Preparações de Plantas/química , Inibidores da Transcriptase Reversa/síntese químicaRESUMO
Some members of a series of cinnamic acid derivatives possess promising inhibitory activities in cellular assays against fungi of the Aspergillus genus. In order to search for a possible molecular target of such compounds, their role as Taq polymerase I inhibitors was studied. Four of the compounds studied displayed IC50 values within the range of those considered active as DNA polymerase inhibitors when searching for new cytotoxic molecules. The results obtained in our molecular modeling study appear to show that the inhibitory activity depends on the presence of a stabilizing interaction between the phenylpropanoid derivatives and the residues Asp610, Thr664, Phe667, Tyr671, and Asp785 located in the active site of Taq polymerase I. Also, it is possible to assert that the polymerization of DNA would be the molecular target of cinnamic acid derivatives with antifungal activity, which correlates with the inhibition of Taq polymerase I and the quantitative descriptor for the lipophilia (ClogP).
Assuntos
Antifúngicos , Aspergillus/efeitos dos fármacos , Aspergillus/enzimologia , Cinamatos/farmacologia , Inibidores Enzimáticos/farmacologia , Taq Polimerase/antagonistas & inibidores , Cinamatos/química , Inibidores Enzimáticos/química , Testes de Sensibilidade Microbiana , Modelos MolecularesRESUMO
Two iridoid scaffolds were synthesized enantioselectively using as key step an l-proline-catalyzed alpha-formyl oxidation. The in vitro antiproliferative activities were evaluated against a representative panel of human solid tumor cell lines. Both iridoids induced considerably growth inhibition in the range 0.38-1.86muM. Cell cycle studies for these compounds showed the induction of cell cycle arrest at the G(1) phase. This result was consistent with a decrease in the expression of cyclin D1. Damaged cells underwent apoptosis as indicated by specific Annexin V staining.
Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Proliferação de Células/efeitos dos fármacos , Glucosídeos/química , Glucosídeos/farmacologia , Iridoides/química , Iridoides/farmacologia , Anexina A5/metabolismo , Antineoplásicos/síntese química , Western Blotting , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Inibidores Enzimáticos/metabolismo , Glucosídeos/síntese química , Humanos , Glucosídeos Iridoides , Iridoides/síntese química , Modelos Moleculares , Conformação Molecular , Relação Estrutura-AtividadeRESUMO
The naturally occurring iridoid catalpol (1) is a Taq DNA polymerase inhibitor. However, its poor lipophilicity might account for the lack of biological activity against human solid tumor cell lines. The traditional prodrug approach by means of peracetylation of the free hydroxyl groups led to a compound, which showed a marginal growth inhibition against the most sensitive cell line A2780 (ovarian cancer). However, the formation of analogs bearing one to three silyl ether groups led to antiproliferative compounds against a panel of six human solid tumor cell lines, with GI50 values in the range 1.8-4.8 microM. Cell cycle studies revealed arrest in G0/G1 phase that is consistent with DNA polymerase inhibition.
Assuntos
Antineoplásicos/síntese química , Compostos de Amônio Quaternário/química , Compostos de Amônio Quaternário/farmacologia , Taq Polimerase/antagonistas & inibidores , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Pró-Fármacos/química , Silanos/química , Silanos/uso terapêutico , Relação Estrutura-AtividadeRESUMO
Growth inhibitory activities and nutritional indices of catalpol (1), 8-O-acetylharpagide (2), and harpagide (3) were determinated in larvae and adults of Tribolium castaneum, respectively. Compound 1 produced a series of allelochemical effects probably related with the DNA synthesis. This iridoid possessed the highest inhibitory activity against DNA polymerase. Molecular orbital calculations suggest that a pi-pi charge transfer recognition model could explain the action of iridioids toward nucleic acid synthesis.