Structure-activity relationships of a new class of aromatic bisphosphonates that inhibit tumor cell proliferation in vitro. - Archive ouverte HAL Accéder directement au contenu
Article Dans Une Revue Anticancer Research Année : 2005

Structure-activity relationships of a new class of aromatic bisphosphonates that inhibit tumor cell proliferation in vitro.

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Erwann Guenin
  • Fonction : Auteur
Dominique Ledoux
  • Fonction : Auteur
Olivier Oudar
  • Fonction : Auteur
Marc Lecouvey
  • Fonction : Auteur
Michel Kraemer
  • Fonction : Auteur

Résumé

We previously reported a simple and efficient one-pot procedure for synthesis of 1-hydroxymethylene-1,1-bisphosphonic acids (HMBP). According to this method, we synthesized a series of new aromatic HMBP and investigated structure-activity relationships by evaluating their anti-proliferative activity against A431 human tumor cell line. Our results showed that the introduction of an extra methylene group in a pyridyl-containing R2 side chain increased 100-fold the anti-proliferative activity of the HMBP. In contrast, this chemical modification did not modify the anti-proliferative activity of compounds substituted with a phenyl-containing R2 side chain. Para-substitution of the phenyl ring with various groups markedly influenced the HMBP activity, the order of potency (bromine > chlorine > fluorine = none) closely matching the atomic volume of the substituted group. Moreover, changes in the substitution position of the bromine group also affected the anti-proliferative activity, the more potent activity being obtained with para-substitution of the phenyl ring. In conclusion, this structure-activity study led us to identify the new aromatic HMBP [(4-Bromo-phenyl)-hydroxy-phosphono-methyl]-phosphonic acid as a potent in vitro anti-proliferative molecule against tumor cell lines (IC50 value of 9.5 x 10(-5) M). Interestingly, this compound can be further easily esterified on its phosphonic acid functions according to our chemical method and, thus, represents a potential candidate for the development of new esterified HMBP with enhanced pharmacokinetics.
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Dates et versions

hal-03945200 , version 1 (18-01-2023)

Identifiants

  • HAL Id : hal-03945200 , version 1
  • PUBMED : 15868957

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Erwann Guenin, Dominique Ledoux, Olivier Oudar, Marc Lecouvey, Michel Kraemer. Structure-activity relationships of a new class of aromatic bisphosphonates that inhibit tumor cell proliferation in vitro.. Anticancer Research, 2005, 25 (2A), pp.1139-45. ⟨hal-03945200⟩
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