Abstract

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 1-10nM and in 20 or 125mM 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 degrees 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.

Autore Pugliese

• Fusco Caterina

Tutti gli autori

• Annese C.; Abbrescia D. I.; Catucci L.; D'Accolti L.; Denora N.; Fanizza I.; Fusco C.; La Piana G.

Titolo volume/Rivista

Journal of peptide science

Anno di pubblicazione

2013

ISSN

1075-2617

ISBN

Non Disponibile

Numero di citazioni Wos

Nessuna citazione

Ultimo Aggiornamento Citazioni

Non Disponibile

Numero di citazioni Scopus

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Ultimo Aggiornamento Citazioni

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Settori ERC

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Codici ASJC

Non Disponibile