2. Academic Validation
  3. Antitumor potential of conjugable valinomycins bearing hydroxyl sites: in vitro studies

Antitumor potential of conjugable valinomycins bearing hydroxyl sites: in vitro studies

  • ACS Med Chem Lett. 2013 Oct 14;4(12):1189-92. doi: 10.1021/ml400300q.
Rosa M Iacobazzi 1,  Cosimo Annese 2,  Amalia Azzariti 3,  Lucia D'Accolti 2,  Massimo Franco 1,  Caterina Fusco 4,  Gianluigi La Piana 5,  Valentino Laquintana 1,  Nunzio Denora 1
Affiliations

Affiliations

  • 1 Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari "A. Moro" , via Orabona 4, 70125 Bari, Italy.
  • 2 Dipartimento di Chimica, Università degli Studi di Bari "A. Moro" , via Orabona 4, 70126 Bari, Italy ; CNR-Istituto di Chimica dei Composti Organometallici (ICCOM) , Bari Section, via Orabona 4, 70126 Bari, Italy.
  • 3 Istituto tumori IRCCS ″Giovanni Paolo II″ , viale Flacco 65, 70124 Bari, Italy.
  • 4 CNR-Istituto di Chimica dei Composti Organometallici (ICCOM) , Bari Section, via Orabona 4, 70126 Bari, Italy.
  • 5 Dipartimento di Bioscienze, Biotecnologie e Biofarmaceutica, Università degli Studi di Bari "A. Moro" via Orabona 4, 70126 Bari, Italy.
PMID: 24900628 DOI: 10.1021/ml400300q
Abstract

Following our pioneering studies on the direct and efficient introduction of derivatizable hydroxyl handles into the valinomycin (VLM, 1) structure, a K(+)-ionophore with potent antitumor activity, the ensuing conjugable analogues (HyVLMs 2, 3, and 4) have herein been compared to the parent macrocycle for their potential antiproliferative effects on a panel of Cancer cell lines, namely, human MCF-7, A2780, and HepG2, as well as rat C6 cells. On the basis of IC50 values, we find that hydroxyl analogues 3 and 4 are only moderately less active than 1, while analogue 2 experiences a heavily diminished activity. Cytofluorimetric analyses of MCF-7 cells treated with HyVLMs suggest that the latter depolarize mitochondria, thus retaining the typical VLM behavior. It is likely that C6 cells, for which the exceptionally potent cytotoxicity of VLM has never reported previously, follow the same fate, as evidenced by alteration of mitochondrial morphology upon incubation with each ionophore.

Keywords

Valinomycin; antitumor activity; cell cycle disturbances; cell death; hydroxylation; targeting.

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