Calix[4]arene methylenebisphosphonic acids as calf intestine alkaline phosphatase inhibitors

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.

Functionalization reactions of calixarenes

“…88 In order to study phosphorylation which occurs in biochemical processes, the phosphatase inhibitory properties of compounds 28 and 29 have been investigated. 89 In these experiments it was found that the introduction of methylenebisphosphonic acid 28 onto calix [4]arene 30 to form compounds such as 33 and 34, results in the efficient inhibition of alkaline phosphatase whereas this inhibition of 28 itself is only very low. For these phosphatase inhibitory studies, calixarenes 33 and 34 containing one and two units of 28, respectively, were synthesized via the reactions of calixarene aldehydes 31 and 32.…”

Calix[4]arene α-hydroxymethylphosphonic acids as potential inhibitors of protein tyrosine phosphatases

“…Recent studies have identified PTPs as targets for new bioactive phosphonate compounds [27,28]. It has been shown also that preorganizing phosphonic or methylenebisphosphonic acids into calix [4]arene derivatives provides a promising approach to design effective inhibitors of alkaline phosphatase [29][30][31], Yersinia protein tyrosine phosphatase [32], and PTP1B [33].…”

The development of bisphosphonates for therapeutic uses, and bisphosphonate structure-activity consideration

“…[88][89][90][91] Thus, condensation of aldehydes with diethyl phosphonate, followed by sulfonylation of the α-OH with methanesulfonyl chloride and subsequent substitution by another molecule of diethyl phosphonate provides the corresponding bisphosphonates 112 (Scheme 41) in a one-pot procedure. 89 In another report, addition of tetraethyl methylene-bis-phosphonate 15b to 3-tert-butyl-4-hydroxy-1-naphthaldehyde 113a afforded 2-[3-tert-butyl-4-hydroxynaphthyl]ethenylidene-1,1-bisphosphonate, 114a. 90 In similar instance, 3-methoxy-4-hydroxy-1-naphthaldehyde 113b gave the corresponding bisphosphonate 114b (Scheme 42).…”