- Inhibition of Connexin Hemichannels by New Amphiphilic Aminoglycosides without Antibiotic Activity
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Connexins hemichannels (HCs) from adjacent cells form gap junctional channels that mediate cell-to-cell communication. Abnormal opening of free undocked HCs can produce cell damage and participate in the mechanism of disorders such as cardiac infarct, stroke, deafness, skin diseases, and cataracts. Therefore, inhibitors of connexin HCs have great pharmacological potential. Antibiotic aminoglycosides (AGs) have been recently identified as connexin HC inhibitors, but their antibiotic effect is an issue for the treatment of disorders where infections do not play a role. Herein, we synthesized and tested several amphiphilic AGs without antibiotic effect for their inhibition against connexin HCs, using a newly developed cell-based bacterial growth complementation assay. Several leads with superior potency than the parent compound, kanamycin A, were identified. Unlike traditional AGs, these amphiphilic AGs are not bactericidal and are not toxic to mammalian cells, making them better than traditional AGs as HC inhibitors for clinical use and other applications.
- Alfindee, Madher N.,Subedi, Yagya P.,Fiori, Mariana C.,Krishnan, Srinivasan,Kjellgren, Abbey,Altenberg, Guillermo A.,Chang, Cheng-Wei T.
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- Synthesis of ring II/III fragment of Kanamycin: A new minimum structural motif for aminoglycoside recognition
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A novel protocol has been established to prepare the kanamycin ring II/III fragment, which has been validated as a minimum structural motif for the development of new aminoglycosides on the basis of its bactericidal activity even against resistant strains. Furthermore, its ability to act as a AAC-(6′) and APH-(3′) binder, and as a poor substrate for the ravenous ANT-(4′), makes it an excellent candidate for the design of inhibitors of these aminoglycoside modifying enzymes.
- Zárate, Sandra G.,Bastida, Agatha,Santana, Andrés G.,Revuelta, Julia
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- Effects of 5-O-Ribosylation of Aminoglycosides on Antimicrobial Activity and Selective Perturbation of Bacterial Translation
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We studied six pairs of aminoglycosides and their corresponding ribosylated derivatives synthesized by attaching a β-O-linked ribofuranose to the 5-OH of the deoxystreptamine ring of the parent pseudo-oligosaccharide antibiotic. Ribosylation of the 4,6-disubstituted 2-deoxystreptamine aminoglycoside kanamycin B led to improved selectivity for inhibition of prokaryotic relative to cytosolic eukaryotic in vitro translation. For the pseudodisaccharide aminoglycoside scaffolds neamine and nebramine, ribosylated derivatives were both more potent antimicrobials and more selective to inhibition of prokaryotic translation. On the basis of the results of this study, we suggest that modification of the 5-OH position of the streptamine ring of other natural or semisynthetic pseudodisaccharide aminoglycoside scaffolds containing an equatorial amine at the 2′ sugar position with a β-O-linked ribofuranose is a promising avenue for the development of novel aminoglycoside antibiotics with improved efficacy and reduced toxicity.
- Herzog, Ido M.,Louzoun Zada, Sivan,Fridman, Micha
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supporting information
p. 8008 - 8018
(2016/11/15)
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- Design, synthesis, and antibacterial activities of conformationally constrained kanamycin A derivatives
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A series of conformationally constrained kanamycin A derivatives with a 2′-hydroxyl group in ring I and a 5-hydroxyl group in ring II tethered by carbon chains were designed and synthesized. Pivotal 5,2′-hydroxyl groups were exposed, and the kanamycin A intermediate was synthesized from 5, 2′, 4″, 6″-di-O-benzylidene-protected tetraazidokanamycin A. Cyclic kanamycin A derivatives with intramolecular 8-, 9-, 10-, and 11-membered ethers were then prepared by cesium carbonate mediated Williamson ether synthesis or a ring-closing metathesis reaction. The kanamycin A derivatives were assayed against both susceptible and resistant bacterial strains. Although no derivative showed better antibacterial activities than kanamycin A, the antibacterial activities of these cyclic kanamycin A derivatives indeed varied with the length of the bridge. Moreover, different variations of activities were observed between the susceptible and resistant bacterial strains. More tightly constrained derivative 2 with a one-carbon bridge showed better activity than the others against susceptible strains, but it was much less effective for resistant bacterial strains than derivative 3 with a two-carbon bridge and derivative 6 with an unsaturated four-carbon bridge.
- Zhang, Wenxuan,Chen, Ying,Liang, Qingzhao,Li, Hui,Jin, Hongwei,Zhang, Liangren,Meng, Xiangbao,Li, Zhongjun
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p. 400 - 409
(2013/03/14)
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- Structure-based design of highly crowded ribostamycin/kanamycin hybrids as a new family of antibiotics
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Sugar sugar! The synthesis and evaluation of ribostamycin/kanamycin hybrids incorporating a highly crowded trisubstituted aminocyclitol unit that should provide maximum complementation with the RNA receptor are reported (see picture). Analysis shows that the existing conflicts between the different sugar rings can be significantly alleviated by a simple chemical modification, leading to an improvement in activity. (Figure Presented)
- Revuelta, Julia,Vacas, Tatiana,Corzana, Francisco,Gonzalez, Carlos,Bastida, Agatha,Asensio, Juan Luis
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supporting information; experimental part
p. 2986 - 2991
(2010/10/01)
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