title: Structure-activity relationships of a new class of aromatic bisphosphonates that inhibit tumor cell proliferation in vitro.
abstract: 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.
authors.affiliation: Laboratoire de Chimie Structurale Biomoléculaire (BioMoCeTi), CNRS UMR 7033, Université Paris 13, UFR SMBH, 74 rue Marcel Cachin, 93000 Bobigny, France.
authors.forename: Erwann
authors.initials: E
authors.lastname: Guenin
authors.forename: Dominique
authors.initials: D
authors.lastname: Ledoux
authors.forename: Olivier
authors.initials: O
authors.lastname: Oudar
authors.forename: Marc
authors.initials: M
authors.lastname: Lecouvey
authors.forename: Michel
authors.initials: M
authors.lastname: Kraemer
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004164:Diphosphonates / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D004354:Drug Screening Assays, Antitumor; D012968:Etidronic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D000068296:Risedronic Acid; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D004164:Diphosphonates; C029285:hydroxymethanediphosphonic acid; D000068296:Risedronic Acid; D012968:Etidronic Acid