Document Detail


Site-dependent biological activity of valinomycin analogs bearing derivatizable hydroxyl sites.
MedLine Citation:
PMID:  24129979     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
Valinomycin (VLM, 1) is a K(+) ionophore cyclodepsipeptide capable of depolarizing mitochondria and inducing apoptosis to several mammalian cell types, including a number of tumor cell lines. With the aim of creating VLM-based ligand-targeted anticancer drugs that may selectively convey VLM to pathological cells, we have previously introduced derivatizable hydroxyl handles into the VLM structure, allowing to access a three-entity library of monohydroxyl VLMs (HyVLMs) bearing the OH group at the isopropyl side chain of a d-Hyi, d-Val, or l-Val residue (analogs 2-4, respectively). Herein, the levels of bioactivity retained by the conjugable HyVLMs have been assessed on the basis of their ability to alter the functionality of isolated rat-liver mitochondria. Experiments run with HyVLMs in the range 1-10 nM and in 20 or 125 mM KCl medium show that the hydroxyl group reduces the potency of HyVLMs relative to VLM to an extent that depends upon the molecular site involved in the hydroxylation. On the other hand, estimation of the stability constants of complexes (in methanol at 25 °C) of each analog with Na(+) , K(+) , and Cs(+) reveals that HyVLMs nicely retain the VLM binding features, except for a moderate increase in the stability of Na(+) complexes. These findings, along with pertinent structural considerations, suggest that the incorporation of OH into the VLM structure might actually have altered its K(+) transporting ability across mitochondrial membranes. Besides facing new aspects of VLM structure-activity relationship, these studies set the basis for the rational design of ligand-HyVLMs conjugates through derivatization of hanging OH group. Copyright © 2013 European Peptide Society and John Wiley & Sons, Ltd.
Authors:
Cosimo Annese; Daniela I Abbrescia; Lucia Catucci; Lucia D'Accolti; Nunzio Denora; Immacolata Fanizza; Caterina Fusco; Gianluigi La Piana
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2013-10-15
Journal Detail:
Title:  Journal of peptide science : an official publication of the European Peptide Society     Volume:  -     ISSN:  1099-1387     ISO Abbreviation:  J. Pept. Sci.     Publication Date:  2013 Oct 
Date Detail:
Created Date:  2013-10-16     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9506309     Medline TA:  J Pept Sci     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Copyright Information:
Copyright © 2013 European Peptide Society and John Wiley & Sons, Ltd.
Affiliation:
Dipartimento di Chimica, Università degli Studi di Bari A. Moro, via Orabona 4, 70126, Bari, Italy; CNR-Istituto dei Composti Organometallici (ICCOM), Bari section, via Orabona 4, 70126, Bari, Italy.
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