Calix[4]arene methylenebisphosphonic acids as calf intestine alkaline phosphatase inhibitors |
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Authors: | Vovk Andriy I Kalchenko Vitaly I Cherenok Sergey A Kukhar Valery P Muzychka Oxana V Lozynsky Myron O |
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Affiliation: | Institute of Bioorganic Chemistry and Petrochemistry, NAS of Ukraine, 02094, Kyiv-94, Ukraine. vovk@bpci.kiev.ua |
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Abstract: | Calix[4]arenes bearing one or two methylenebisphosphonic acid fragments were prepared via addition of diethylphosphite to the parent calix[4]arene aldehydes. The resulting compounds displayed stronger inhibition of calf intestine alkaline phosphatase than simple methylenebisphosphonic or 4-hydroxyphenyl methylenebisphosphonic acids. The action of these phosphorylated calix[4]arenes is concordant with partial mixed-type inhibition. The inhibition constants Ki and Ki' for the calix[4]arene bis(methylenebisphosphonic) acid in Tris-HCl buffer at pH 9 are 0.38 microM and 2.8 microM respectively. The replacement of the phosphoric acid moieties on the macrocycle with diethylphosphonates results in a sharp decrease of its inhibitory action. Preorganizing phosphonic acid fragments using a calixarene platform therefore provides a promising approach for the design of efficient alkaline phosphatase inhibitors. |
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