A. Mucha, P. Kafarski, Łukasz Berlicki
Aug 5, 2011
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1
Influential Citations
454
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Journal
Journal of medicinal chemistry
Abstract
R-Aminophosphonic acids are broadly defined as analogues of amino acids in which the carboxylic group is replaced by a phosphonic acid or related group (usually phosphonous or phosphinic acids). This results in the presence of the characteristic N C P scaffold (Scheme 1). The biological activity and natural occurrence of these compounds (often called R-aminophosphonates) were discovered half a century ago. Since then, the chemistry and biology of this class of compounds have been developed into a distinct branch of phosphorus chemistry. It is generally acknowledged that R-aminophosphonates possess a broad capability of influencing physiologic and pathologic processes, with applications ranging from agrochemistry to medicine. In some cases, these compounds have been commercialized. A number of excellent reviews on various aspects of their activity in natural systems have been published. 12 The mode of action of aminophosphonates primarily involves the inhibition of enzymes of different class and origin. Despite its long history, this area of research remains intensively explored and frequently delivers new promising lead compounds in medicinal chemistry. The N C P molecular fragment and its chemistry offer many possibilities for structural modifications, which have resulted in broad biological relevance (Scheme 1). Often, R-aminophosphonic and phosphinic acids are considered simple analogues of their natural counterparts, carboxylic acids. Although carboxylic and phosphonic acid groups differ in shape (tetrahedral at phosphorus versus planar at carbon), acidity (with phosphonic acid being significantly more acidic), and steric bulk (the phosphorus atom has a much larger atomic radius than carbon), they frequently exhibit similar properties, with the phosphonic acid being recognized by enzymes or receptors as false substrates or inhibitors. However, the tetrahedral geometry of substituents around the phosphorus moiety causes it to resemble the high-energy transition state (TS) of ester and amide bond hydrolyses. The tetrahedral transition state is believed to be specifically stabilized in enzyme active sites, which has inspired numerous studies on their applications in regulating the activity of proteases. This approach has been most successful in the case of metalloproteases, which have an organophosphorus moiety in their active sites that facilitates the chelation of metal ions. This approach has resulted in the development of many potent inhibitors of various enzymes, such as the antihypertensive drug fosinopril, an angiotensin I converting enzyme (ACE) inhibitor. Recently, the N C P scaffold has been used to construct extended transition state analogues of amide bond synthesis or hydrolysis to find potent inhibitors of enzymes such as glutamine synthetase or urease. Reactive peptidyl phosphonate diaryl esters have been successfully used to covalently modify members of the serine hydrolase superfamily. This approach exploits their ability to phosphonylate the hydroxyl residue of the active-site serine of these enzymes. They act as competitive, irreversible inhibitors, which, after the formation of an initial enzyme substrate complex, bind to the active site via a transesterification reaction and thus block its catalytic function. The activity and selectivity of the interactions of inhibitors with target enzymes can be adjusted by structural optimization of the S1 residues and/or by the development of an extended peptide chain. Finally, aminomethylenebisphosphonic acids form a separate class of medicinally important compounds bearing the N C P skeleton. They are hydrolytically stable analogues of pyrophosphate characterized by a common P C P fragment in which a carbon phosphorus bond replaces an oxygen phosphorus bond. Their primary medical application is in combating osteoporosis. They exhibit very high affinity to bone tissue, being rapidly adsorbed at the bone surface, and they regulate the bone remodeling process. Because the action of bisphosphonates is limited to osseous tissue, they have also been used to deliver conjugated chemotherapeutic agents to bone. Likely because of their strong chelating properties, bisphosphonates also exhibit inhibitory properties toward a wide variety of metalloenzymes. In this Perspective, we present the key features of theN C P molecular fragment that govern the activity of the molecules that incorporate it. A general overview of known modes of action and target enzyme classes is briefly presented. Recent representative medicinal chemistry projects are described and discussed, including the achievements of our research group on leucine aminopeptidase and urease. Particular attention is given to the molecular aspects of the N C P mechanism of action and to the rational design of new compounds based on threedimensional structures. The potential future applications of this class of compounds are also discussed.