Antiproliferative activity of ester derivatives of monensin A at the C-1 and C-26 positions.

Monensin A (MON) is a polyether ionophore antibiotic, which shows a wide spectrum of biological activity, including anticancer activity. A series of structurally diverse monensin esters including its C-1 esters (1-9), C-26-O-acetylated derivatives (10-15), and lactone (16) was synthesized and for the first time evaluated for their antiproliferative activity against four human cancer cell lines with different drug-sensitivity level. All of the MON derivatives exhibited in vitro antiproliferative activity against cancer cells at micromolar concentrations. The majority of the compounds was able to overcome the drug resistance of LoVo/DX and MES-SA/DX5 cell lines. The most active compounds proved to be MON C-26-O-acetylated derivatives (10-15) which exhibited very good resistance index and high selectivity index.

Brazilian red pepper fruit essential oil (Schinus terebinthifolius) may replace monensin in high concentrate diets for feedlot lambs / Óleo essencial dos frutos de aroeira (Schinus terebinthifolius) pode substituir a monensina em dietas com elevado teor de concentrado para cordeiros confinados

Essential oil (EO) from Brazilian red pepper fruit contains compounds with antimicrobial activity, and could be possible substitutes for the antibiotics commonly used in ruminant nutrition. The objectives of the present study were to evaluate the effects of the Brazilian red pepper fruit EO (Schinus terebinthifolius) as a substitute for monensin on performance, carcass characteristics and meat of lambs fed high concentrate diets. Forty-eight lambs were used, 24 males (20 ½ Dorper × ½ Santa Inês and 4 Santa Inês) and 24 females (24 ½ Dorper × ½ Santa Inês), with 21.54 ± 0.88 kg of initial body weight (BW) and 78 ± 2.4 days of age, in a randomized complete block design. The experiment lasted 56 days, divided into 2 periods of 28 days each. The treatments were defined by the inclusion in diets of 8 ppm of monensin (MON), and the doses 0.14% (14EO), 0.28% (28EO) and 0.42% (42EO) of red pepper fruit EO. The additives were included in a base diet with a 10:90 of forage to concentrate ratio. At the end of 56 days, 32 animals were slaughtered for the measurement of carcass parameters and meat composition. There was no interaction among treatments and periods for average daily gain (P = 0.08), DM intake (P = 0.36), feed efficiency (P = 0.24) and oocyst of Eimeria ssp. in feces (P = 0.46). The treatments did not affect (P > 0.05) the average daily gain (ADG), dry matter intake (DMI) and feed efficiency. Lambs fed diets containing monensin had less (P < 0.01) oocyst/g compared with the diet 14EO. There was no effect of diets on carcass characteristics. The treatments with higher doses of the Brazilian red pepper fruit EO had reduced mineral content of meat compared to monensin. The red pepper fruit EO demonstrated the potential to replace monensin in feedlot lambs fed high concentrate diets, maintaining performance and carcass characteristics. However, the monensin has greater capacity to control coccidiosis in feedlot lambs.

Os óleos essenciais (OE) dos frutos de aroeira possuem compostos com atividade antimicrobiana, sendo possíveis substitutos aos antibióticos comumente utilizados na nutrição de ruminantes. Os objetivos do presente estudo foram avaliar os efeitos da inclusão do óleo essencial de aroeira fruta (Schinus terebinthifolius) como substituto da monensina sobre o desempenho, características de carcaça e da carne de cordeiros alimentados com dietas contendo elevado teor de concentrado. Foram utilizados 48 cordeiros, 24 machos (20 ½ Dorper × ½ Santa Inês e 4 Santa Inês) e 24 fêmeas (24 ½ Dorper × ½ Santa Inês), com peso inicial de 21,54 ± 0,88 kg e 78 ± 2,4 dias de idade, em delineamento de blocos completos casualizados. O experimento teve duração de 56 dias, divididos em 2 períodos de 28 dias cada. Os tratamentos foram definidos pela inclusão na dieta de 8 ppm de monensina sódica (MON) e as doses de 0,14% (14EO), 0,28% (28EO) e 0,42% (42EO) de óleo essencial dos frutos da aroeira. As dietas experimentais foram compostas por 10% de volumoso e 90% de concentrado. Ao final dos 56 dias, 32 animais foram abatidos para a mensuração dos parâmetros de carcaça e análise química da carne. Não houve interação entre tratamento e período para o ganho médio diário (P = 0,08), consumo de MS (P = 0,36), eficiência alimentar (P = 0,24) e contagem de oocistos de Eimeria ssp. (P = 0,46). Não houve efeito (P > 0,05) dos tratamentos no ganho de peso médio diário (GMD), consumo de matéria seca (CMS) e eficiência alimentar (EA). Cordeiros alimentados com dietas contendo monensina tiveram menor (P < 0,01) contagem de oocistos/g de fezes comparado com a dieta 14OE. Não houve efeito das dietas sobre as características de carcaça. A inclusão de 0,28 e 0,42% de OE de aroeira fruto reduziram a concentração de matéria mineral da carne dos cordeiros comparados ao tratamento MON. O OE dos frutos da aroeira demonstrou capacidade de substituir a monensina, apresentando resultados similares com relação ao desempenho e características de carcaça. Entretanto, a monensina apresentou maior capacidade no controle de coccidiose

Anti-proliferative activity of Monensin and its tertiary amide derivatives.

New tertiary amide derivatives of polyether ionophore Monensin A (MON) were synthesised and their anti-proliferative activity against cancer cell lines was studied. Very high activity (IC50=0.09 µM) and selectivity (SI=232) of MON against human biphenotypic myelomonocytic leukemia cell line (MV4-11) was demonstrated. The MON derivatives obtained exhibit interesting anti-proliferative activity, high selectivity index and also are able to break the drug-resistance of cancer cell line.

Crotonyl-coenzyme A reductase provides methylmalonyl-CoA precursors for monensin biosynthesis by Streptomyces cinnamonensis in an oil-based extended fermentation.

It is demonstrated that crotonyl-CoA reductase (CCR) plays a significant role in providing methylmalonyl-CoA for monensin biosynthesis in oil-based 10-day fermentations of Streptomyces cinnamonensis. Under these conditions S. cinnamonensis L1, a derivative of a high-titre producing industrial strain C730.1 in which ccr has been insertionally inactivated, produces only 15 % of the monensin yield. Labelling of the coenzyme A pools using [3H]-beta-alanine and analysis of intracellular acyl-CoAs in the L1 and C730.1 strains demonstrated that loss of ccr led to lower levels of the monensin precursor methymalonyl-CoA, relative to coenzyme A. Expression of a heterologous ccr gene from Streptomyces collinus fully restored monensin production to the L1 mutant. Using C730.1 and an oil-based extended fermentation an exceptionally efficient and comparably intact incorporation of ethyl [3,4-13C2]acetoacetate into both the ethylmalonyl-CoA- and methylmalonyl-CoA-derived positions of monensin was observed. No labelling of the malonyl-CoA-derived positions was observed. The opposite result was observed when the incorporation study was carried out with the L1 strain, demonstrating that ccr insertional inactivation has led to a reversal of carbon flux from an acetoacetyl-CoA intermediate. These results dramatically contrast similar analyses of the L1 mutant in glucose-soybean medium which indicate a role in providing ethylmalonyl-CoA but not methylmalonyl-CoA, thus causing a change in the ratio of monensin A and monensin B analogues, but not the overall monensin titre. These results demonstrate that the relative contributions of different pathways and enzymes to providing polyketide precursors are thus dependent upon the fermentation conditions. Furthermore, the generally accepted pathways for providing methylmalonyl-CoA for polyketide production may not be significant for the S. cinnamonensis high-titre monensin producer in oil-based extended fermentations. An alternative pathway, leading from the fatty acid catabolite acetyl-CoA, via the CCR-catalysed reaction is proposed.

Effects of laidlomycin propionate and monensin on the in vitro mixed ruminal microorganism fermentation.

The objective of this study was to compare the effects of laidlomycin propionate and monensin on the in vitro fermentation of ground corn, Trypticase, or alfalfa hay by mixed ruminal microorganisms. Ruminal fluid was collected from two steers fed 9.27 kg DM of a high-concentrate (62.2% ground corn and 17.4% cottonseed hulls) diet per day and composited. In the first study, no ionophore was included in the diet; the diet in the second study contained 11.1 g of laidlomycin propionate per ton of feed. The animals were allowed an adjustment period of 14 d for each dietary treatment before samples were collected. When ruminal fluid from unadapted animals was used, both monensin and laidlomycin propionate decreased (P<.05) CH4 concentration and the acetate:propionate ratio with ground corn and alfalfa hay. Monensin reduced (P<.05) in vitro dry matter disappearance of alfalfa and increased (P<.05) final pH in the ground corn and alfalfa hay fermentations. Both laidlomycin propionate and monensin decreased (P<.05) concentrations of acetate, propionate, isobutyrate, isovalerate, CH4, and NH3 in Trypticase fermentations. When ruminal fluid from adapted animals was used, both ionophores still reduced the concentrations of most fermentation products. However, there was generally less inhibition compared with fermentations inoculated with unadapted mixed ruminal microorganisms. In the presence of 5 mM maltose, mixed ruminal bacteria produced high concentrations (10 to 11 mM) of lactate, and addition of both ionophores to these fermentations was effective in reducing (P<.05) lactate production. In conclusion, laidlomycin propionate alters the mixed ruminal microorganism fermentation in a manner similar to monensin, but, at the concentrations used in this study, monensin seemed to be a more potent inhibitor.

Effect of carboxylic ionophores on measles virus hemagglutinin protein.

We have studied the effect of two carboxylic ionophores, monensin and laidlomycin, on the replication of measles virus in KB cells. The yield of infectious virus was markedly depressed at the concentrations of the ionophores which had no effect on overall viral protein synthesis. The ionophores selectively blocked the migration of hemagglutinin (H) glycoprotein from Golgi apparatus to the cell surface. As a result, H glycoprotein is prevented from being converted from incompletely glycosylated form to the mature form. The inhibitory effect on the transport and glycosylation of H was reversed, although gradually, upon the removal of the ionophores.