N-Methyl-N-D-fructosyl amphotericin B methyl ester (MF-AME), a novel antifungal agent of low toxicity: monomer/micelle control over selective toxicity.

Rational chemical modification of amphotericin B (AMB) led to the synthesis of sterically hindered AMB derivatives. The selected optimal compound, N-methyl-N-D-fructosyl amphotericin B methyl ester (MF-AME) retains the broad spectrum of antifungal activity of the parent antibiotic, and exhibits a two orders of magnitude lower toxicity in vivo and in vitro against mammalian cells. Comparative studies of MF-AME and AMB comprising the determination of the spectroscopic properties of monomeric and self-associated forms of the antibiotics, the investigation of the influence of self-association on toxicity to human red blood cells, and of the antibiotic-sterol interaction were performed. On the basis of the results obtained it can be assumed that the improvement of the selective toxicity of MF-AME could in part be a consequence of the diminished concentration of water soluble oligomers in aqueous medium, and the better ability to differentiate between cholesterol and ergosterol.

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Comparative in vitro studies on liposomal formulations of amphotericin B and its derivative, N-methyl-N-D-fructosyl amphotericin B methyl ester (MFAME).

Acta Biochimica Polonica ◽

10.18388/abp.2002_3822 ◽

2002 ◽

Vol 49 (1) ◽

pp. 67-75 ◽

Cited By ~ 1

Author(s):

Barbara Cybulska ◽

Karolina Kupczyk ◽

Joanna Szlinder-Richert ◽

Edward Borowski

Keyword(s):

Methyl Ester ◽

Amphotericin B ◽

Mammalian Cells ◽

Biological Properties ◽

Antagonistic Effect ◽

Molar Ratio ◽

Selective Toxicity ◽

Liposomal Formulations ◽

Amphotericin B Methyl Ester

N-Methyl-N-D-fructosyl amphotericin B methyl ester (MFAME) is a semisynthetic derivative of the antifungal antibiotic amphotericin B (AMB). In contrast to the parent antibiotic, the derivative is characterised by low toxicity to mammalian cells and good solubility in water of its salts. Comparative studies on biological properties of free MFAME, AMB and their liposomal formulations were performed. To obtain liposomal forms, the antibiotics were incorporated into small unilamellar vesicles composed of dimyristoyl phosphatidylcholine (DMPC) and DMPC:cholesterol or ergosterol, 8:2 molar ratio. The effectivity of the liposomal and free forms of AMB and MFAME were compared by determination of fungistatic and fungicidal activity against Candida albicans ATCC 10261, potassium release from erythrocytes, and haemolysis. The results obtained indicate that in contrast to AMB, incorporation of MFAME into liposomes did not further improve its selective toxicity. Studies on the antagonistic effect of ergosterol and cholesterol on the antifungal activity of the antibiotics indicated that sterol interference was definitely less pronounced in the case of MFAME than in the case of AMB.

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Comparative in vitro and in vivo evaluation of N-D-ornithyl amphotericin B methyl ester, amphotericin B methyl ester, and amphotericin B.

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.31.11.1756 ◽

1987 ◽

Vol 31 (11) ◽

pp. 1756-1760 ◽

Cited By ~ 11

Author(s):

R M Parmegiani ◽

D Loebenberg ◽

B Antonacci ◽

T Yarosh-Tomaine ◽

R Scupp ◽

...

Keyword(s):

Methyl Ester ◽

Amphotericin B ◽

In Vivo Evaluation ◽

Amphotericin B Methyl Ester

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Ketoconazole, amphotericin B, and amphotericin B methyl ester: comparative in vitro and in vivo toxicological effects on neutrophil function.

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.20.5.660 ◽

1981 ◽

Vol 20 (5) ◽

pp. 660-665 ◽

Cited By ~ 27

Author(s):

D J Marmer ◽

B T Fields ◽

G L France ◽

R W Steele

Keyword(s):

Methyl Ester ◽

Amphotericin B ◽

Neutrophil Function ◽

Toxicological Effects ◽

Amphotericin B Methyl Ester

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In vitro and in vivo comparisons of amphotericin B and N-D-ornithyl amphotericin B methyl ester.

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.27.3.302 ◽

1985 ◽

Vol 27 (3) ◽

pp. 302-305 ◽

Cited By ~ 11

Author(s):

G S Kobayashi ◽

J R Little ◽

G Medoff

Keyword(s):

Methyl Ester ◽

Amphotericin B ◽

Amphotericin B Methyl Ester

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In vitro antiherpetic activity of water-soluble amphotericin B methyl ester

Archives of Virology ◽

10.1007/bf01317438 ◽

1975 ◽

Vol 48 (4) ◽

pp. 391-394 ◽

Cited By ~ 16

Author(s):

N. M. Stevens ◽

C. G. Engle ◽

P. B. Fisher ◽

W. Mechlinski ◽

C. P. Schaffner

Keyword(s):

Methyl Ester ◽

Amphotericin B ◽

Water Soluble ◽

Antiherpetic Activity ◽

Amphotericin B Methyl Ester

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Activity of Indenoisoquinolines against African Trypanosomes

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00650-07 ◽

2008 ◽

Vol 53 (1) ◽

pp. 123-128 ◽

Cited By ~ 11

Author(s):

Rahul P. Bakshi ◽

Dongpei Sang ◽

Andrew Morrell ◽

Mark Cushman ◽

Theresa A. Shapiro

Keyword(s):

Anticancer Agents ◽

Mammalian Cells ◽

Sleeping Sickness ◽

Water Soluble ◽

African Trypanosomes ◽

In Vivo Experiments ◽

Topoisomerase Ib ◽

Topoisomerase Poisons

ABSTRACT African trypanosomiasis (sleeping sickness), caused by protozoan Trypanosoma brucei species, is a debilitating disease that is lethal if untreated. Available drugs are antiquated, toxic, and compromised by emerging resistance. The indenoisoquinolines are a class of noncamptothecin topoisomerase IB poisons that are under development as anticancer agents. We tested a variety of indenoisoquinolines for their ability to kill T. brucei. Indenoisoquinolines proved trypanocidal at submicromolar concentrations in vitro. Structure-activity analysis yielded motifs that enhanced potency, including alkylamino substitutions on N-6, methoxy groups on C-2 and C-3, and a methylenedioxy bridge between C-8 and C-9. Detailed analysis of eight water-soluble indenoisoquinolines demonstrated that in trypanosomes the compounds inhibited DNA synthesis and acted as topoisomerase poisons. Testing these compounds on L1210 mouse leukemia cells revealed that all eight were more effective against trypanosomes than against mammalian cells. In preliminary in vivo experiments one compound delayed parasitemia and extended survival in mice subjected to a lethal trypanosome challenge. The indenoisoquinolines provide a promising lead for the development of drugs against sleeping sickness.

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Anti-Herpes Simplex Virus (HSV) Effect of Amphotericin B Methyl Ester in Vivo

Parasites, Fungi, and Viruses ◽

10.1007/978-1-4684-3129-2_49 ◽

1976 ◽

pp. 339-346 ◽

Cited By ~ 2

Author(s):

H. Shiota ◽

B. R. Jones ◽

C. P. Schaffner

Keyword(s):

Herpes Simplex Virus ◽

Herpes Simplex ◽

Methyl Ester ◽

Amphotericin B ◽

Amphotericin B Methyl Ester ◽

Simplex Virus

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The activity of superoxide-dismutase in animal cell culture CHO-K1 after treatment with fullerenol and mytomicine C

Hemijska industrija ◽

10.2298/hemind0903143b ◽

2009 ◽

Vol 63 (3) ◽

pp. 143-149 ◽

Cited By ~ 1

Author(s):

Visnja Bogdanovic ◽

Marija Slavic ◽

Jasminka Mrdjanovic ◽

Slavica Solajic ◽

Aleksandar Djordjevic

Keyword(s):

Superoxide Dismutase ◽

Mammalian Cells ◽

Animal Cell ◽

Water Soluble ◽

Cytotoxic Agents ◽

Antioxidant Defenses ◽

Free Radical Scavengers ◽

Sod Activity

Eukaryotic cell survives in predominantly reduced conditions. Homeostasis of cellular redox system is an imperative of cell surviving and its normal metabolism. ROS are well recognized for playing a dual role as both deleterious and beneficial species, since they can be either harmful or beneficial to living systems. These species are mutagenic compounds known to lead to DNA damage, favor cell transformation, and contribute to the development of a variety of malignant diseases. All the effects of oxidants are influenced by the cellular antioxidant defenses. This multilayer system consists of low molecular weight components and several antioxidant enzymes. Superoxide dismutases (SODs) are the only enzymes dismuting superoxide radicals. Mitomycin C, a cross-linking agent, demonstrated genotoxicity in all in vitro and in vivo test systems in mammalian cells and animals. Water-soluble fullerenes are well known as cytotoxic agents for many cell lines in vitro. At the other side, fullerenols are good free radical scavengers and antioxidants both in vitro and in vivo. This paper investigates the effects of fullerenol on survival and fullerenol/ /mytomicine (MMC) treatment on superoxide-dismutase (SOD) activity in CHO-K1 cells. Samples were treated 3 and 24 h with fullerenol (C60(OH)24) at concentration range 0.01-0.5 mg/mL and survival was monitored with dye exclusion test (DET). The activity of total SOD was estimated in samples treated with chosen concentrations of fullerenol and MMC (0.5 and 0.1 mg/mL) after 3 and 24 h of cell incubation. Increasing of C60(OH)24 concentration leads to decreasing of percent of surviving cells 3 and 24 h after incubation. The activity of total SOD enhanced with higher concentration of fullerenol, while decreased in the highest concentration at both experimental points. In samples treated with MMC, as well as in samples treated with fullerenol (0.0625 mg/mL) + MMC was noticed boost in total SOD activity in comparison with controls. Treatment with fullerenol decreased SOD activity in rest of samples treated with MMC. Decreased activity of superoxide-dismutase in almost all samples treated with fullerenol and MMC might be contributed to antioxidative properties of fullerenol. Increased enzyme level at concentration of 0.0625 mg/mL may be due to its prooxidative activity.

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Zinc(II)-Dipicolylamine Coordination Complexes as Targeting and Chemotherapeutic Agents for Leishmania major

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00410-16 ◽

2016 ◽

Vol 60 (5) ◽

pp. 2932-2940 ◽

Cited By ~ 14

Author(s):

Douglas R. Rice ◽

Paola Vacchina ◽

Brianna Norris-Mullins ◽

Miguel A. Morales ◽

Bradley D. Smith

Keyword(s):

Cutaneous Leishmaniasis ◽

Mammalian Cells ◽

Leishmania Major ◽

Parasite Burden ◽

Coordination Complexes ◽

Chemotherapeutic Agents ◽

Selective Toxicity ◽

Content Type

ABSTRACTCutaneous leishmaniasis is a neglected tropical disease that causes painful lesions and severe disfigurement. Modern treatment relies on a few chemotherapeutics with serious limitations, and there is a need for more effective alternatives. This study describes the selective targeting of zinc(II)-dipicolylamine (ZnDPA) coordination complexes towardLeishmania major, one of the species responsible for cutaneous leishmaniasis. Fluorescence microscopy ofL. majorpromastigotes treated with a fluorescently labeled ZnDPA probe indicated rapid accumulation of the probe within the axenic promastigote cytosol. The antileishmanial activities of eight ZnDPA complexes were measured using anin vitroassay. All tested complexes exhibited selective toxicity againstL. majoraxenic promastigotes, with 50% effective concentration values in the range of 12.7 to 0.3 μM. Similar toxicity was observed against intracellular amastigotes, but there was almost no effect on the viability of mammalian cells, including mouse peritoneal macrophages.In vivotreatment efficacy studies used fluorescence imaging to noninvasively monitor changes in the red fluorescence produced by an infection of mCherry-L. majorin a mouse model. A ZnDPA treatment regimen reduced the parasite burden nearly as well as the reference care agent, potassium antimony(III) tartrate, and with less necrosis in the local host tissue. The results demonstrate that ZnDPA coordination complexes are a promising new class of antileishmanial agents with potential for clinical translation.

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