Abstract
Amino-1,1-bisphosphonates have become increasingly important in different fields of chemistry, medicine and agriculture. The combination of the unique physical, chemical and biological properties of methylenebisphosphonate and aminophosphonate fragments opens wide possibilities for the design of biologically active compounds including therapeutic agents to treat bone disorders related to calcium metabolism, immunomodulators, anti-infectives and plant growth regulators. The scope of this review is to summarize the existing strategies for the preparation of diversely functionalized 1-amino-1,1-bisphosphonates and to illustrate their utility as synthetic building blocks.
Highlights
Aminophosphonic acids are amino carboxylic acid mimetics in which the carboxylic group is substituted by phosphonic acid residue P(O)(OH)2.1 On the other hand, geminal aminobisphosphonates, which are characterized by a P-C(N)-P backbone, besides that they are structural analogs of α-aminophosphonic acids, may be considered as carbon analogs of endogenous pyrophosphate (PPi) which is a regulator of calcium metabolism in living systems
Bisphosphonate 6 is a potent inhibitor of the methylerithritolphosphate (MEP) pathway enzyme deoxyxylulose-5-phosphate reductoisomerase which is used in the protozoan parasite Plasmodium falciparum, a causative agent of malaria.[11,25]
Similar amidation reaction was applied for the synthesis of estradiol-bisphosphonate conjugates (E2-BPs) 88-93 in which the linkers were sensitive to esterases, proteases, and acidic conditions on bones to act as bone-seeking E2 prodrugs
Summary
Aminophosphonic acids are amino carboxylic acid mimetics in which the carboxylic group is substituted by phosphonic acid residue P(O)(OH)2.1 On the other hand, geminal aminobisphosphonates, which are characterized by a P-C(N)-P backbone, besides that they are structural analogs of α-aminophosphonic acids, may be considered as carbon analogs of endogenous pyrophosphate (PPi) which is a regulator of calcium metabolism in living systems. A close position of the nitrogen atom with respect of the bisphosphonate backbone results in an increase of the acidity of the phosphonate groups, allowing an efficient chelating of metal ions already at low pH values.[40,41] In addition, the role of PO3H2 and R1R2N groups attached to a prochiral carbon probably consists in that they provide specific orientation of the molecule on the surface of a biological object via hydrogen bond formation Pharmacophores, such as substituents A and R2, R3, may impart some physiologic activity to the molecule.
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