Structure-activity relationships of a new class of aromatic bisphosphonates that inhibit tumor cell proliferation in vitro
Guenin, E.; Ledoux, D.; Oudar, O.; Lecouvey, M.; Kraemer, M.
Anticancer Research 25(2a): 1139-1145
2005
ISSN/ISBN: 0250-7005 PMID: 15868957 Document Number: 594264
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 A437 human tumor cell line. Our results showed that the introduction of an extra methylene group in a pyridyl-containing R-2 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 R-2 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) phosphoric 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.