Calix[4]arene methylenebisphosphonic acids as calf intestine alkaline phosphatase inhibitors.
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.
Vovk
Andriy I
AI
Institute of Bioorganic Chemistry and Petrochemistry, NAS of Ukraine, 02094, Kyiv-94, Ukraine. vovk@bpci.kiev.ua
Kalchenko
Vitaly I
VI
Cherenok
Sergey A
SA
Kukhar
Valery P
VP
Muzychka
Oxana V
OV
Lozynsky
Myron O
MO
D000469:Alkaline Phosphatase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D047250:Calixarenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002417:Cattle; D007422:Intestines / Q000201:enzymology*; D063065:Organophosphonates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
D063065:Organophosphonates; D047250:Calixarenes; D000469:Alkaline Phosphatase