| New derivatives of kanamycin B obtained by combined modifications in positions 1 and 6". Synthesis, microbiological properties, and in vitro and computer-aided toxicological evaluation. | |
| | |
MedLine Citation:
|
PMID: 2016726 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
|
Substitution of the C-1 atom in the 2-deoxystreptamine moiety of gentamicin C2, a broad-spectrum aminoglycoside antibiotic, by an axial hydroxymethyl group has been reported to confer protection against most clinically important bacterial enzymes inactivating aminoglycosides, while simultaneously reducing the nephrotoxic potential of this drug. We report here on a similar modification of kanamycin B. Microbiological evaluation, however, revealed no useful protection, as established by the almost complete lack of activity of 1-C-(hydroxymethyl)kanamycin B against an array of organisms producing defined types of aminoglycoside-inactivating enzymes and against which 1-C-(hydroxymethyl)gentamicin C2 and amikacin (1-N-[(S)-2-hydroxy-4-aminobutyryl]kanamycin A) are active. Moreover, toxicological evaluation, based on the in vitro measurement of the drug inhibitory potential toward lysosomal phospholipases, a predictive test of the intrinsic nephrotoxic potential of aminoglycosides, showed not decreased but rather increased toxicity. Comparative conformational analysis of the interactions of the drug with a phosphatidylinositol monolayer explained the lack of protective effect, since no significant change of the mode of insertion of the derivative in this monolayer was detected compared to that of kanamycin B. Combination of a 1-C-(hydroxymethyl) substituent with a 6"-chloro, 6"-acetamido substituent resulted in a partial improvement of the toxicological behavior with no loss of activity for the 6"-chloro and the 6"-azido derivatives, but not to the extent of obtaining better derivatives than kanamycin B itself. We, therefore, suggest that the advantages of an axial hydroxymethyl substituent at C-1 are probably restricted to the gentamicin family and do not extend to kanamycins. It might be concluded that the structural differences between gentamicins and kanamycins play an important, still undescribed role both in their effective recognition by aminoglycoside-inactivating enzymes, which are responsible for most of the clinically important cases of resistance to aminoglycosides, and also in the interactions with phospholipids, which in turn cause nephrotoxicity. |
| | |
Authors:
|
A Van Schepdael; R Busson; H J Vanderhaeghe; P J Claes; L Verbist; M P Mingeot-Leclercq; R Brasseur; P M Tulkens |
Related Documents
:
|
8820476 - Possible role of the intestinal p-450 enzyme system in a cyclosporine-clarithromycin in... 2584546 - Medications of elderly institutionalized incontinent females. 3271186 - Amiodarone drug interactions: potential beneficial and adverse effects. 10435726 - Modification of the pharmacokinetics of high-dose cyclophosphamide and cisplatin by ant... 19689246 - The menstrual cycle and drug metabolism. 9583066 - Connective tissue disorders and pregnancy. recommendations for prescribing. |
Publication Detail:
|
Type: Comparative Study; Journal Article; Research Support, Non-U.S. Gov't |
Journal Detail:
|
Title: Journal of medicinal chemistry Volume: 34 ISSN: 0022-2623 ISO Abbreviation: J. Med. Chem. Publication Date: 1991 Apr |
Date Detail:
|
Created Date: 1991-05-21 Completed Date: 1991-05-21 Revised Date: 2006-11-15 |
Medline Journal Info:
|
Nlm Unique ID: 9716531 Medline TA: J Med Chem Country: UNITED STATES |
Other Details:
|
Languages: eng Pagination: 1483-92 Citation Subset: IM |
Affiliation:
|
Laboratorium voor Farmaceutische Chemie, Rega Institut, Katholieke Universiteit Leuven, Belgium. |
Export Citation:
|
APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
|
Gram-Positive Bacteria
/
drug effects Indicators and Reagents Kanamycin / analogs & derivatives*, chemical synthesis*, chemistry, pharmacology, toxicity Microbial Sensitivity Tests Models, Molecular Molecular Conformation Molecular Structure Structure-Activity Relationship |
| Chemical | |
Reg. No./Substance:
|
0/Indicators and Reagents; 4696-76-8/bekanamycin; 59-01-8/Kanamycin |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
Previous Document: New derivatives of kanamycin B obtained by modifications and substitutions in position 6''. 2. In vi...
Next Document: Freeze-fracture cytochemistry: a simplified guide and update on developments.