RESUMO
Multidrug resistance (MDR) of human tumors has resulted in an immediate need to develop appropriate new drugs. This work outlines the development of 20 potent IQQ N-oxide derivatives in two isomeric families, both exhibiting nanomolar GI50 against human tumor cell lines. Preliminary NCI-60 tumor screening sees the C(6) isomers achieve a mean GI50 > 2 times lower than the corresponding C(7) isomers. MDR evaluation of nine selected compounds reveals that each presents lower GI50 concentrations in two MDR tumor cell lines. Four of the series display nanomolar GI50 values against MDR cells, having selectivity ratios up to 2.7 versus the sensitive (parental) cells. The most potent compound 25 inhibits the activity of drug efflux pumps in MDR cells, causes significant ROS accumulation, and potently inhibits cell proliferation, causing alterations in the cell cycle profile. Our findings are confirmed by 3D spheroid models, providing new candidates for studies against MDR cancers.
Assuntos
Antineoplásicos , Proliferação de Células , Resistência a Múltiplos Medicamentos , Resistencia a Medicamentos Antineoplásicos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Linhagem Celular Tumoral , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Proliferação de Células/efeitos dos fármacos , Relação Estrutura-Atividade , Espécies Reativas de Oxigênio/metabolismo , Isoquinolinas/farmacologia , Isoquinolinas/química , Isoquinolinas/síntese química , Ciclo Celular/efeitos dos fármacos , Descoberta de DrogasRESUMO
The evolution of bisindolyl maleimides and indolyl maleimide derivatives and their unique biological activities have stimulated great interest in medicinal chemistry programs. Bisindolylmaleimide (BIM)-type compounds arise from natural sources such as arcyriarubin and are biosynthetically related to indolocarbazoles. BIMs are commonly the immediate synthetic precursors of indolocarbazoles, lacking a central bond between the two aromatic units and making them more flexible and drug-like. Synthetic endeavours within this class of compounds are broad and have led to the development of both remarkably potent and selective protein kinase inhibitors. Clinical BIM examples include ruboxistaurin and enzastaurin, which are highly active inhibitors of protein kinase C-ß. While BIMs are widely recognised as protein kinase inhibitors, other modes of activity have been reported, including the inhibition of calcium signalling and antimicrobial activity. Critically, structural differences can be used to exploit new bioactivity and therefore it is imperative to discover new chemical entities to address new targets. BIMs can be highly functionalised or chemically manipulated, which provides the opportunity to generate new derivatives with unique biological profiles. This review will collate new synthetic approaches to BIM-type compounds and their associated bioactivities with a focus on clinical applications.
RESUMO
The 29th Annual GP2A (Group for the Promotion of Pharmaceutical chemistry in Academia) Conference was a virtual event this year due to the COVID-19 pandemic and spanned three days from Wednesday 25 to Friday 27 August 2021. The meeting brought together an international delegation of researchers with interests in medicinal chemistry and interfacing disciplines. Abstracts of keynote lectures given by the 10 invited speakers, along with those of the 8 young researcher talks and the 50 flash presentation posters, are included in this report. Like previous editions, the conference was a real success, with high-level scientific discussions on cutting-edge advances in the fields of pharmaceutical chemistry.
RESUMO
Pim kinases (proviral integration site for Moloney murine leukemia virus kinases) are overexpressed in various types of hematological malignancies and solid carcinomas, and promote cell proliferation and survival. Thus, Pim kinases are validated as targets for antitumor therapy. In this context, our combined efforts in natural product-inspired library generation and screening furnished very promising dibenzo[b,d]furan derivatives derived from cercosporamide. Among them, lead compound 44 was highlighted as a potent Pim-1/2 kinases inhibitor with an additional nanomolar IC50 value against CLK1 (cdc2-like kinases 1) and displayed a low micromolar anticancer potency towards the MV4-11 (AML) cell line, expressing high endogenous levels of Pim-1/2 kinases. The design, synthesis, structure-activity relationship, and docking studies are reported herein and supported by enzyme, cellular assays, and Galleria mellonella larvae testing for acute toxicity.
Assuntos
Antineoplásicos/farmacologia , Benzofuranos/química , Benzofuranos/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-pim-1/antagonistas & inibidores , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Benzofuranos/síntese química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Modelos Moleculares , Estrutura Molecular , Mariposas , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Tirosina Quinases/metabolismo , Proteínas Proto-Oncogênicas c-pim-1/metabolismo , Células Tumorais CultivadasRESUMO
The pathogen Phytophthora infestans is responsible for worldwide catastrophic crop damage and discovery of new inhibitors of this organism is of paramount agricultural and industrial importance. Current strategies for crop treatment are inadequate with limitations of efficacy and market alternatives. Ellipticines have recently been reported to have fungicidal properties and have been assessed against P. infestans growth with promising results. We hereby report a probe of the ellipticine framework to investigate the alkyl subunit and screen a set ellipticines and derivatives to identify new lead compounds to act against P. infestans. A series of ellipticinium salt derivatives have been identified with exceptional growth inhibitory activity and apparent lack of toxicity towards a human cell-line surpassing the effect of known and marketed fungicides. This report identifies the potential of this natural product derivative as a novel fungicide.
RESUMO
The pathogen Phytophthora infestans is responsible for catastrophic crop damage on a global scale which totals billions of euros annually. The discovery of new inhibitors of this organism is of paramount agricultural importance and of critical relevance to food security. Current strategies for crop treatment are inadequate with the emergence of resistant strains and problematic toxicity. Natural products such as cinnamaldehyde have been reported to have fungicidal properties and are the seed for many new discovery research programmes. We report a probe of the cinnamaldehyde framework to investigate the aldehyde subunit and its role in a subset of aromatic aldehydes in order to identify new lead compounds to act against P. infestans. An ellipticine derivative which incorporates an aldehyde (9-formyl-6-methyl ellipticine, 34) has been identified with exceptional activity versus P. infestans with limited toxicity and potential for use as a fungicide.
RESUMO
The isoquinolinequinone (IQQ) pharmacophore is a privileged framework in known cytotoxic natural product families, caulibugulones and mansouramycins. Exploiting both families as a chemical starting point, we report on the structured development of an IQQ N-oxide anticancer framework which exhibits growth inhibition in the nM range across melanoma, ovarian and leukaemia cancer cell lines. A new lead compound (16, R6 = benzyl, R7 = H) exhibits nM GI50 values against 31/57 human tumour cell lines screened as part of the NCI60 panel and shows activity against doxorubicin resistant tumour cell lines. An electrochemical study highlights a correlation between electropositivity of the IQQ N-oxide framework and cytotoxicity. Adduct binding to sulfur based biological nucleophiles glutathione and cysteine was observed in vitro. This new framework possesses significant anticancer potential.
Assuntos
Antineoplásicos/farmacologia , Óxidos N-Cíclicos/farmacologia , Isoquinolinas/farmacologia , Quinonas/farmacologia , Antineoplásicos/síntese química , Benzilaminas/síntese química , Benzilaminas/farmacologia , Linhagem Celular Tumoral , Óxidos N-Cíclicos/síntese química , Relação Dose-Resposta a Droga , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Isoquinolinas/síntese química , Quinonas/síntese químicaRESUMO
Ellipticines have well documented anticancer activity, in particular with substitution at the 1-, 2-, 6- and 9-positions. However, due to limitations in synthesis and coherent screening methodology the full SAR profile of this anticancer class has not yet been achieved. In order to address this shortfall, we have set out to explore the anticancer activity of this potent natural product by substitution. We currently describe the synthesis of novel 11-substituted ellipticines with two specific derivatives showing potency and diverging cellular growth effects.
RESUMO
Synthesis and biological evaluation of a series of novel indole derivatives as anticancer agents is described. A bisindolylmaleimide template has been derived as a versatile pharmacophore with which to pursue chemical diversification. Starting from maleimide, the introduction of an oxygen to the headgroup (hydroxymaleimide) was initially investigated and the bioactivity assessed by screening of kinase inhibitory activity, identifying substituent derived selectivity. Extension of the hydroxymaleimide template to incorporate substitution of the indole nitrogens was next completed and assessed again by kinase inhibition identifying unique selectivity patterns with respect to GSK-3 and CDK kinases. Subsequently, the anticancer activity of bisindolylmaleimides were assessed using the NCI-60 cell screen, disclosing the discovery of growth inhibitory profiles towards a number of cell lines, such as SNB-75 CNS cancer, A498 and UO-31 renal, MDA MB435 melanoma and a panel of leukemia cell lines. The potential for selective kinase inhibition by modulation of this template is evident and will inform future selective clinical candidates.
Assuntos
Antineoplásicos/farmacologia , Quinase 3 da Glicogênio Sintase/antagonistas & inibidores , Maleimidas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Maleimidas/síntese química , Maleimidas/química , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Relação Estrutura-AtividadeRESUMO
The synthesis and biological evaluation of a series of novel heterocyclic indole derivatives is described. The consolidation of the combretastatin and bisindolylmaleimide templates towards the inclusion of a novel heterocyclic ring proffered a versatile pharmacophore with which to pursue chemical diversification. Given literature precedent, maleimide was initially investigated in this role and the bioactivity assessed by measurement of NCI-60 cell panel growth. Subsequently, a range of 5-aminopyrazoles was designed and developed to explore the specific effect of heterocycle hydrogen bonding on cell growth. The unique electronic nature of the 5-aminopyrazole moiety allowed for regiospecific monosubstitution on different sites of the ring, such as thiourea substitution at the N(1) position for derivative 45 or trifluoroacetylation on the 5-amino position for 43. Further derivatisation led to the ultimate development of bicyclic pyrazolotriazinedione 41 and pyrimidine 42 systems. The antiproliferative activities of these 3,4-diaryl-5-aminopyrazoles were assessed using the NCI-60 cell screen, disclosing the discovery of distinct selectivity profiles towards a number of cell lines, such as SNB-75 CNS cancer, UO-31 and CAKI-1 renal cancer cells. A series of DNA topological assays discounted the interaction with topoisomerase II as a putative mechanism of action.
RESUMO
The most common phytosterols in the human diet are sitosterol and campesterol, which originate exclusively from plant derived food. These phytosterols are taken up by NPC1L1 transport from the intestine into the enterocytes together with cholesterol and other xenosterols. Phytosterols are selectively pumped back from the enterocytes into the intestinal lumen and on the liver site from hepatocytes into bile by heterodimeric ABCG5/G8 transporters. Like cholesterol, both phytosterols are prone to ring and side chain oxidation. It could be shown that oxyphytosterols, found in atherosclerotic tissue, are most likely of in situ oxidation (Schött et al.; Biochem. Biophys. Res. Commun. 2014 Apr 11;446(3):805-10). However, up to now, the entire mechanism of phytosterol oxidation is not clearly understood. Here, we provide further information about the oxidation of sitosterol and the transport of its oxidation products out of tissue. Our survey includes data of 104 severe aortic stenosis patients that underwent an elective aortic valve cusp replacement. We studied their phytosterol concentrations, as well as absolute and substrate corrected oxyphytosterol levels in plasma and valve cusp tissue. In addition, we also examined phytosterol and oxyphytosterol concentrations in plasma and tissues (from brain and liver) of 10 male ApoE knockout mice. The ratio of 7-oxygenated-sitosterol-to-sitosterol exceeds the ratio for 7-oxygenated-campesterol-to-campesterol in plasma and tissue of both humans and mice. This finding indicates that sitosterol is oxidized to a higher amount than campesterol and that a selective oxidative mechanism might exist which can differentiate between certain phytosterols. Secondly, the concentrations of oxyphytosterols found in plasma and tissue support the idea that oxysitosterols are preferably transported out of individual tissues. Selective oxidation of sitosterol and preferred transport of sitosterol oxidation products out of tissue seem to be a metabolic pathway of forced sitosterol clearance from tissue compartments.
Assuntos
Estenose da Valva Aórtica/sangue , Oxigênio/química , Sitosteroides/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Valva Aórtica/metabolismo , Valva Aórtica/patologia , Estenose da Valva Aórtica/patologia , Apolipoproteínas E/genética , Transporte Biológico , Encéfalo/metabolismo , Colesterol/metabolismo , Feminino , Cromatografia Gasosa-Espectrometria de Massas , Próteses Valvulares Cardíacas , Humanos , Fígado/metabolismo , Masculino , Camundongos , Camundongos Knockout , Pessoa de Meia-Idade , Oxirredução , Oxisteróis/metabolismo , Fitosteróis/sangue , Fitosteróis/metabolismoRESUMO
Structure-activity relationships for inhibition of erbB1, erbB2, and erbB4 were determined for a series of quinazoline- and pyrido[3,4-d]pyrimidine-based analogues of the irreversible pan-erbB inhibitor, canertinib. Cyclic amine bearing crotonamides were determined to provide rapid inhibition of cellular erbB1 autophosphorylation and good metabolic stability in liver microsome and hepatocyte assays. The influence of 4-anilino substitution on pan-erbB inhibitory potency was investigated. Several anilines were identified as providing potent, reversible pan-erbB inhibition. Optimum 4- and 6-substituents with known 7-substituents provided preferred irreversible inhibitors for pharmacodynamic testing in vivo. Quinazoline 54 and pyrido[3,4-d]pyrimidine 71 were identified as clearly superior to canertinib. Both compounds possess a piperidinyl crotonamide Michael acceptor and a 3-chloro-4-fluoroaniline, indicating these as optimized 6- and 4-substituents, respectively. Pharmacokinetic comparison of compounds 54 and 71 across three species selected compound 54 as the preferred candidate. Compound 54 (PF-00299804) has been assigned the nomenclature of dacomitinib and is currently under clinical evaluation.
Assuntos
Antineoplásicos/química , Receptores ErbB/antagonistas & inibidores , Morfolinas/química , Piridinas/química , Pirimidinas/química , Quinazolinas/química , Quinazolinonas/química , Administração Oral , Animais , Antineoplásicos/síntese química , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Cães , Xenoenxertos , Humanos , Injeções Intravenosas , Macaca fascicularis , Masculino , Camundongos Nus , Morfolinas/síntese química , Morfolinas/farmacocinética , Morfolinas/farmacologia , Transplante de Neoplasias , Fosforilação , Piridinas/síntese química , Piridinas/farmacocinética , Piridinas/farmacologia , Pirimidinas/síntese química , Pirimidinas/farmacocinética , Pirimidinas/farmacologia , Quinazolinas/síntese química , Quinazolinas/farmacocinética , Quinazolinas/farmacologia , Quinazolinonas/síntese química , Quinazolinonas/farmacocinética , Quinazolinonas/farmacologia , Ratos Sprague-Dawley , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Acute myeloid leukaemia (AML) is the most common type of leukaemia in adults and is associated with high relapse rates. Current treatment options have made significant progress but the 5 year survival for AML remains low and therefore, there is an urgent need to develop novel therapeutics. Ellipticines, a class of cancer chemotherapeutic agents, have had limited success clinically due to low solubility and toxic side effects. Isoellipticines, novel isomers of ellipticine, have been designed to overcome these limitations. One particular isoellipticine, 7-formyl-10-methylisoellipticine, has previously showed strong ability to inhibit the growth of leukaemia cell lines. In this study the anti-leukaemia effect of this compound was investigated in detail on an AML cell line, MV4-11. Over a period of 24 h 7-formyl-10-methyl isoellipticine at a concentration of 5 µM can kill up to 40 % of MV4-11 cells. Our research suggests that the cytotoxicity of 7-formyl-10-methylisoellipticine is partially mediated by an induction of mitochondrial reactive oxygen species (ROS). Furthermore, 7-formyl-10-methylisoellipticine demonstrated promising anti-tumour activity in an AML xenograft mouse model without causing toxicity, implying the potential of isoellipticines as novel chemotherapeutic agents in the treatment of leukaemia.
Assuntos
Antineoplásicos/farmacologia , Elipticinas/farmacologia , Leucemia Mieloide Aguda/tratamento farmacológico , Espécies Reativas de Oxigênio/metabolismo , Animais , Linhagem Celular Tumoral , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Mitocôndrias/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Some chemotherapeutic drugs (prodrugs) require activation by an enzyme for efficacy. We and others have demonstrated the ability of probiotic bacteria to grow specifically within solid tumours following systemic administration, and we hypothesised that the natural enzymatic activity of these tumour-localised bacteria may be suitable for activation of certain such chemotherapeutic drugs. Several wild-type probiotic bacteria; Escherichia coli Nissle, Bifidobacterium breve, Lactococcus lactis and Lactobacillus species, were screened against a panel of popular prodrugs. All strains were capable of activating at least one prodrug. E. coli Nissle 1917 was selected for further studies because of its ability to activate numerous prodrugs and its resistance to prodrug toxicity. HPLC data confirmed biochemical transformation of prodrugs to their toxic counterparts. Further analysis demonstrated that different enzymes can complement prodrug activation, while simultaneous activation of multiple prodrugs (CB1954, 5-FC, AQ4N and Fludarabine phosphate) by E. coli was confirmed, resulting in significant efficacy improvement. Experiments in mice harbouring murine tumours validated in vitro findings, with significant reduction in tumour growth and increase in survival of mice treated with probiotic bacteria and a combination of prodrugs. These findings demonstrate the ability of probiotic bacteria, without the requirement for genetic modification, to enable high-level activation of multiple prodrugs specifically at the site of action.
Assuntos
Antineoplásicos/administração & dosagem , Proteínas de Bactérias/metabolismo , Neoplasias/tratamento farmacológico , Probióticos , Pró-Fármacos/administração & dosagem , Animais , Antraquinonas/administração & dosagem , Antraquinonas/uso terapêutico , Antineoplásicos/uso terapêutico , Aziridinas/administração & dosagem , Aziridinas/uso terapêutico , Bifidobacterium/enzimologia , Linhagem Celular Tumoral , Sistemas de Liberação de Medicamentos , Enzimas , Escherichia coli/enzimologia , Feminino , Lactobacillus/enzimologia , Lactococcus/enzimologia , Camundongos Endogâmicos BALB C , Neoplasias/patologia , Pró-Fármacos/uso terapêutico , Carga Tumoral/efeitos dos fármacos , Fosfato de Vidarabina/administração & dosagem , Fosfato de Vidarabina/análogos & derivados , Fosfato de Vidarabina/uso terapêuticoRESUMO
A systematic approach was developed to investigate the stability of gentamicin sulfate (GS) and GS/poly (lactic-co-glycolic acid) (PLGA) coatings on hydroxyapatite surfaces. The influence of environmental factors (light, humidity, oxidation and heat) upon degradation of the drug in the coatings was investigated using liquid chromatography with evaporative light scattering detection and mass spectrometry. GS coated rods were found to be stable across the range of environments assessed, with only an oxidizing atmosphere resulting in significant changes to the gentamicin composition. In contrast, rods coated with GS/PLGA were more sensitive to storage conditions with compositional changes being detected after storage at 60 °C, 75% relative humidity or exposure to light. The effect of γ-irradiation on the coated rods was also investigated and found to have no significant effect. Finally, liquid chromatography-mass spectrometry analysis revealed that known gentamines C1, C1a and C2 were the major degradants formed. Forced degradation of gentamicin coatings did not produce any unexpected degradants or impurities.
RESUMO
In this study, the potential effects of bacteria on the efficacy of frequently used chemotherapies was examined. Bacteria and cancer cell lines were examined in vitro and in vivo for changes in the efficacy of cancer cell killing mediated by chemotherapeutic agents. Of 30 drugs examined in vitro, the efficacy of 10 was found to be significantly inhibited by certain bacteria, while the same bacteria improved the efficacy of six others. HPLC and mass spectrometry analyses of sample drugs (gemcitabine, fludarabine, cladribine, CB1954) demonstrated modification of drug chemical structure. The chemoresistance or increased cytotoxicity observed in vitro with sample drugs (gemcitabine and CB1954) was replicated in in vivo murine subcutaneous tumour models. These findings suggest that bacterial presence in the body due to systemic or local infection may influence tumour responses or off-target toxicity during chemotherapy.
Assuntos
Antineoplásicos/farmacocinética , Aziridinas/farmacocinética , Cladribina/farmacocinética , Neoplasias do Colo/tratamento farmacológico , Desoxicitidina/análogos & derivados , Vidarabina/análogos & derivados , Animais , Antineoplásicos/farmacologia , Aziridinas/farmacologia , Biotransformação , Cladribina/farmacologia , Neoplasias do Colo/metabolismo , Neoplasias do Colo/microbiologia , Neoplasias do Colo/patologia , Desoxicitidina/farmacocinética , Desoxicitidina/farmacologia , Escherichia coli/crescimento & desenvolvimento , Feminino , Injeções Intralesionais , Injeções Subcutâneas , Listeria/crescimento & desenvolvimento , Camundongos , Transplante de Neoplasias , Pele/efeitos dos fármacos , Pele/microbiologia , Pele/patologia , Resultado do Tratamento , Vidarabina/farmacocinética , Vidarabina/farmacologia , GencitabinaRESUMO
In this study, we compare the distribution of intraperitoneally injected sitosterol, 7ß-hydroxysitosterol or vehicle only (control) for 28days in male ApoE-/- mice. Furthermore we examine its impact on surrogate markers of cholesterol biosynthesis and sterol absorption rate in plasma, brain and liver tissues from these animals. Injection of sitosterol revealed a 32.1% (P=0.013) lower plasma total cholesterol compared with control. Cholesterol corrected plasma and absolute brain and liver levels of sitosterol are 4.1-, 1.7-, and 7.2-fold (P<0.001 for all) higher, respectively. This is in accordance with a reduced plasma campesterol to cholesterol ratio (-16.2%; P=0.018) together with a 24.1% (P=0.047) lower concentration of hepatic lathosterol. After injection of 7ß-hydroxysitosterol the concentrations of 7ß-hydroxysitosterol in plasma, brain and liver are 21.0-, 65.8- and 42.7-fold (P<0.001 for all) higher, respectively, compared with control. Injection of 7ß-hydroxysitosterol revealed significantly lower plasma cholesterol corrected cholestanol and campesterol (-44.2%; P=0.001 and -24.5; P=0.004) as well as lower absolute liver cholestanol levels (-31.9%; P<0.001) compared with control. Intraperitoneally injected sitosterol and 7ß-hydroxysitosterol differently influence cholesterol metabolism in plasma and liver. We conclude that the polar 7ß-hydroxysitosterol compound can pass the blood brain barrier with higher efficacy than its substrate, sitosterol. Though present in higher amounts in the brain, both, sitosterol and 7ß-hydroxysitosterol do not influence cholesterol metabolism in the brain as proven by our surrogate markers.
Assuntos
Apolipoproteínas E/deficiência , Barreira Hematoencefálica/metabolismo , Sitosteroides/sangue , Animais , Apolipoproteínas E/metabolismo , Transporte Biológico , Colesterol/biossíntese , Éteres/química , Injeções Intraperitoneais , Fígado/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Especificidade por SubstratoRESUMO
Phytosterols and their oxidation products have become increasingly investigated in recent years with respect to their roles in diet and nutrition. We present a comprehensive review of recent literature on Phytosterol Oxidation Products (POP) identifying critical areas for future investigation. It is evident that POP are formed on food storage/preparation; are absorbed and found in human serum; do not directly affect cholesterol absorption; have evidence of atherogenicity and inflammation; have distinct levels of cytotoxicity; are implicated with high levels of oxidative stress, glutathione depletion, mitochondrial dysfunction and elevated caspase activity.
Assuntos
Aterosclerose/metabolismo , Inflamação/metabolismo , Mitocôndrias/metabolismo , Fitosteróis/metabolismo , Caspases/metabolismo , Colesterol/metabolismo , Alimentos , Glutationa/metabolismo , Humanos , Oxirredução , Estresse Oxidativo , Fitosteróis/sangue , Fitosteróis/farmacocinéticaRESUMO
Drugs that inhibit DNA topoisomerase I and DNA topoisomerase II have been widely used in cancer chemotherapy. We report herein the results of a focused medicinal chemistry effort around novel ellipticinium salts which target topoisomerase I and II enzymes with improved solubility. The salts were prepared by reaction of ellipticine with the required alkyl halide and evaluated for DNA intercalation, topoisomerase inhibition and growth inhibition against 12 cancer cell lines. Results from the topoisomerase I relaxation assay indicated that all novel ellipticine derivatives behaved as intercalating agents. At a concentration of 100 µM, specific topoisomerase I inhibition was not observed. Two of the derivatives under investigation were found to fully inhibit the DNA decatenation reaction at a concentration of 100 µM, indicative of topoisomerase II inhibition. N-Alkylation of ellipticine was found to enhance the observed growth inhibition across all cell lines and induce growth inhibition comparable to that of Irinotecan (CPT-11; GI(50) 1-18 µM) and in some cell lines better than Etoposide (VP-16; GI(50) = 0.04-5.2 µM). 6-Methylellipticine was the most potent growth inhibitory compound assessed (GI(50) = 0.47-0.9 µM). N-Alkylation of 6-methylellipticine was found to reduce this response with GI(50) values in the range of 1.3-28 µM.
Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , DNA Topoisomerases Tipo II/metabolismo , DNA Topoisomerases Tipo I/metabolismo , Elipticinas/farmacologia , Inibidores da Topoisomerase I/farmacologia , Inibidores da Topoisomerase II/farmacologia , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Elipticinas/síntese química , Elipticinas/química , Células HT29 , Humanos , Células MCF-7 , Estrutura Molecular , Relação Estrutura-Atividade , Inibidores da Topoisomerase I/síntese química , Inibidores da Topoisomerase I/química , Inibidores da Topoisomerase II/síntese química , Inibidores da Topoisomerase II/químicaRESUMO
The cytotoxic effects of the oxidised derivatives of the phytosterols, stigmasterol and ß-sitosterol, have previously been shown to be similar but less potent than those of the equivalent cholesterol oxides in the U937 cell line. The objective of the present study was to compare the cytotoxic effects of the oxidised derivatives of synthetic mixtures of campesterol and dihydrobrassicasterol in both the U937 and HepG2 cell lines. The parent compounds consisted of a campesterol: dihydrobrassicasterol mix at a ratio of 2:1 (2CMP:1DHB) and a dihydrobrassicasterol:campesterol mix at a ratio of 3:1 (3DHB:1CMP). The 2CMP:1DBH oxides were more cytotoxic in the U937 cells than the 3DBH:1CMP oxides but the difference in cytotoxicity was less marked in the HepG2 cells. The order of toxicity of the individual oxidation products was found to be similar to that previously observed for cholesterol, ß-sitosterol and stigmasterol oxidation products in the U937 cell line. There was an increase in apoptotic nuclei in U937 cells incubated with the 7-keto and 7ß-OH derivatives of both 2CMP:1DHB and 3DHB:1CMP and also in the presence of 3DHB:1CMP-3ß,5α,6ß-triol and 2CMP:1DHB-5ß,6ß-epoxide. An additional oxidation product synthesised from 2CMP:1DHB, 5,6,22,23-diepoxycampestane, was cytotoxic but did not induce apoptosis. These results signify the importance of campesterol oxides in the overall paradigm of phytosterol oxide cytotoxicity.