Synthesis and structure/activity relationships of new guanidino derivatives of aminoglycoside antibiotics

  • Apeiron Biologics
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Of all known aminoglycoside antibiotics (AAs), only streptomycin and related compounds contain guanidino-groups in the streptamine part of the molecule. The authors were interested in guanidino derivatives of 2-deoxystreptamine-containing AAs. Guanylation of suitable, protected gentamicin C and kanamycin A derivatives, followed by deprotection, gave a series of highly active new compounds with N-guanyl substituents at N-1, N-3, N-2', N-6'. 2'-N-guanyl-gentamicin C 1 (86-451) was selected for further studies.

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... This less hindered aminomethyl function enables chemical distinction from the other amino functions with mildly activated acylating agents. N- benzyloxycarbonyloxy-5-norbornene-2,3-dicarboximide was hence used to selectively monoprotect paromomycin on position 6′′′ [40]. As previously described, for each of these intermediates, the other amino functions were next protected with the Teoc group. ...
Cationic lipid-based nonviral gene delivery is an attractive approach for therapeutic gene transfer. Basically, gene transfection can be achieved by using synthetic vectors that compact DNA, forming cationic lipoplexes which can interact with the cell plasma membrane by electrostatic interactions. Among the basic components of any cationic lipid, the type of cationic headgroup has been shown to have a major role in transfection efficiency. We have previously reported the DNA transfection potential of vectors characterized by a kanamycin A headgroup. The encouraging transfection results obtained with these compounds prompted us to evaluate the potential of cationic lipids bearing headgroups based on other aminoglycosides. Thus, we herein report the synthesis and gene transfection properties of novel cationic lipids consisting of cholesteryl or dioleyl moieties linked, via various spacers, to paromomycin or neomycin B headgroups. Our results confirm that these new aminoglycoside-based cationic lipids are efficient for gene transfection both in vitro and into the mouse airways in vivo. We also investigated physico-chemical properties of the DNA complexes formed by this particular type of synthetic vectors in order to better understand their structure-activity relationships.
This chapter discusses the new antibacterial agents, antimicrobial agents, and various aspects of antimicrobial chemotherapy. The orally active third generation cephalosporin FK 027 (FR 17027) continued to be extensively studied in vitro and in vivo. Oral administration of cefuroxime axetil, the 1-acetoxyethyl ester prodrug of cefuroxime, to human volunteers produced higher peak serum levels than an equivalent dose of ampicillin and urinary recovery of 35%. Novel oxacephem derivative (6315-S,7), exhibited broad, potent anti-bacterial spectrum with the exception of activity against Pseudornonas. The effect on antibacterial activity of α-substituents in the 2-(2-amino-4-thiazolyl)acetyl side chain of ceftizoxime had been of great interest to the researchers working on anti-bacteraial agents. Reviews and symposiums on this topic project penicillin as orally effective prodrug, delivering good blood levels of temocillin after oral administration to human volunteer. The chapter discusses the role of carbupenems, β-lactarnuse inhibitors, aminoglycosides, and other associated compounds and antibacterial agents. Interest remained high in the synthesis of nalidixic acid analogs. Rosoxacin derivative win 35,349 showed good activity in vitro and in vivo against strains of Staphylococcus aureus and epidennidus. Because of the improved potency and spectrum, most efforts were centered on 6-fluoro analogs of pipemidic acid. Pefloxacin (1589 RB, 39) penetrated inflammatory cerebrospinal fluid at effective anti-bacterial levels after oral or parenteral administration in patients with bacterial meningitis.
The reaction of 2, 3, 4-tri-O-acetyl-β-D-xylopyranosyl isothiocyanate 1 and 2-amino-4/6-substituted benzothiazoles 2a~2e gave xylopyranosylthioureas 3a~3e, which then reacted with alkyl/aryl amine in the presence of HgCl2 to afford a series of new guanidinoxylopyranosides (4a~4e, 5a~5e, 6a~6e and 7a~7e). The structures of the new compounds were established on the basis of elemental analyses, IR, 1H NMR and mass spectral data and all compounds took β-configuration. The biological activities of these compounds have been evaluated. Compounds 4c, 5b, 6b~6d and 7b showed anti-HIV-1 PR activity.
The guanidinium group plays a key role at many RNA-protein binding interfaces, including the complexes formed between transcriptional elongation factors with mRNA, tRNA synthetases with tRNAs, ribosomal proteins with rRNA, and viral regulatory proteins with their cognate RNA binding sites. 10 In contrast to ammonium groups, guanidinium groups are highly basic, planar, and exhibit directionality in their H-bonding interactions. We hypothesized that the RNA affinity and selectivity of aminoglycoside-based ligands can be increased by replacing the ammonium groups with guanidinium groups. In this report, we disclose a new family of RNA ligands, termed “guanidinoglycosides”, in which all of the ammonium groups of the natural aminoglycoside antibiotics have been converted into guanidinium groups (Figure 1). 11
An HPLC-PAD method using a gold working electrode and a triple-potential waveform was developed for the simultaneous determination of streptomycin and dihydrostreptomycin in veterinary drugs. Glucose was used as the internal standard, and the triple-potential waveform was optimized using a factorial and a central composite design. The optimum potentials were as follows: amperometric detection, E1=-0.15V; cleaning potential, E2=+0.85V; and reactivation of the electrode surface, E3=-0.65V. For the separation of the aminoglycosides and the internal standard of glucose, a CarboPac™ PA1 anion exchange column was used together with a mobile phase consisting of a 0.070molL(-1) sodium hydroxide solution in the isocratic elution mode with a flow rate of 0.8mLmin(-1). The method was validated and applied to the determination of streptomycin and dihydrostreptomycin in veterinary formulations (injection, suspension and ointment) without any previous sample pretreatment, except for the ointments, for which a liquid-liquid extraction was required before HPLC-PAD analysis. The method showed adequate selectivity, with an accuracy of 98-107% and a precision of less than 3.9%. Copyright © 2014 Elsevier B.V. All rights reserved.
In this study, guanidinylated chitosan hydrochloride (GCH) was synthesized and its structure was characterized by UV–vis and FTIR. The degree of substitution of guanidinylated chitosan was confirmed by elemental analysis. In vitro antiviral activity of guanidinium derivative on local infection and systemic infection of tobacco mosaic virus (TMV) inoculated were evaluated by semileaf method using different modes of GCH application and antiserum assay. Meanwhile, the morphological characteristic of virus treated by GCH was performed by transmission electron microscope. The results showed that GCH had better antiviral activity than chitosan. The average inhibitory rate of GCH on local infection was 84%, which was much higher than that of chitosan hydrochloride. It was shown that the guanidinylated chitosan was an efficient passivator, and its antiviral effect decreased after mechanical inoculation. The guanidinylated chitosan increased the resistance of plant against TMV and decreased the infection of the virus. The electron microscope photograph exhibited that GCH not only directly altered the configuration of TMV but also congregated and reduced the virus. © 2009 Wiley Periodicals, Inc. J Appl Polym Sci, 2009
Cationic lipids are currently actively investigated as an alternative approach to recombinant viruses for gene transfer studies and gene therapy applications. Basically, they rely on the formation of lipid/DNA aggregates via electrostatic interactions between their cationic headgroup and the negatively charged DNA. The development of new amphiphilic structures should allow to shed light on their still poorly understood structure/activity relationship and thereby help to design improved vectors. It appears that aminoglycosides, which are natural polyamines known to bind to nucleic acids, provide a favourable scaffold for the synthesis of a variety of cationic lipids because of their structural features and multifunctional nature. The synthesis and full characterization of a series of lipophilic derivatives of the aminoglycoside antibiotic kanamycin A, mainly kanamycin−cholesterol conjugates, are reported herein. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003)
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The new guanidinylation reagent N,N'-diBoc-N''-triflylguanidine was used to efficiently convert multiamine-containing glycosides including kanamycin A and B, tobramycin, paromomycin, and neomycin B to the corresponding fully guanidinylated analogues (guanidinoglycosides). This transformation occurs in the presence of H(2)O under mild conditions. Guanidinotobramycin and guanidinoneomycin B were found to inhibit the replication of the HIV virus with activities approximately 100 times greater than the parent aminoglycosides.
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