The Nomenclature of 1-aminoalkylphosphonic Acids and Derivatives: Evolution of the Code System

The approach for the unification of published proposals for the nomenclature and abbreviations of ami-noalkylphosphonic acids and their derivatives is presented. Their modification was made on the basis of the IUPAC–IUB rules concerning the nomenclature and code system of proteinogenic amino acids. Our present proposal formulates the supplementary code and nomenclature system allowing unambiguous description of phosphonic analogs of proteinogenic amino acids, their analogs, homologs, metabolites, and derivatives including phosphonopeptides.


INTRODUCTION
Aminophosphonic acids (AA P ) as structural analogs of protein amino acids (AA C ) are extremely important antimetabolites which compete with their carboxylic counterparts for the active sites of enzymes and other cell receptors (Kafarski & Mastalerz, 1984;Kukhar & Hudson, 2000;Kafarski & Lejczak, 2001).
The first attempt for codification of aminophosphonic acids and their N-aminoacyl derivatives, namely P-terminal phosphonopeptides, was made as early as 1978 [L-Ala(P); L-Ala-L-Ala(P) (Allen et al., 1978)].This attempt, based on the structural analogy of amino acids (2-aminoalkanoic acids; AA (C) ) and amino-phosphonic acids (1-aminoalkylphosphonic acids; AA P ), adapted the IUPAC rules for the nomenclature and code system of proteinogenic amino acids.The code, proposed by Allen et al. (1978), allows for the differentiation between an amino acid and aminophosphonic acid, both alone and also as constituents of phosphonopeptides, e.g.Ala vs. Ala(P) (Table 2).
As a consequence of this fact, the substitution of long formal IUPAC names of 1-aminoalkylphosphonic acids, by short trivial names, derived from the amino acids nomenclature, was proposed.This approach expressed the structural analogy of aminophosphonic acids AA P to their carboxylic analogs AA (C) , and was achieved by the addition of the "phosphono" prefix to the trivial names of amino acids (e.g., the phosphonic analog of alanine was named phosphono-alanine).
Modification of these proposals according to the IU-PAC-IUB rules (IUPAC-IUB, 1984) allowed for the formulation of the supplementary code and nomenclature system for phosphonic analogs of proteinogenic amino acids, and their analogs, homologs, metabolites, and derivatives, including phosphonopeptides.The guiding principles for this code and nomenclature system proposal are delineated in Tables 5-14.

Acyclic Aminophosphonic Acids
The fully systematic forms for acyclic aminophosphonic acids are derived from corresponding alkylphosphonic acids in which carbon linked to phosphorus atom is numbered as C1 or Cα (Table 5).A heteroatom has the same number as the carbon atom to which it is attached, e.g.N-1 is on C-1, N-5 is on C-5, etc.

Phosphonic Analog of Proline
The carbon atoms in prolines, both in carboxylic as well as phosphonic, are numbered as in pyrrolidine, the nitrogen atom being numbered N-1, and proceeding towards the carboxyl or the phosphonic group (Table 6).

Aromatic Aminophosphonic Acids
The carbon atoms in aromatic rings of the phosphonic analogs of phenylalanine, tyrosine and/or tryptophan can be numbered as in systematic nomenclature, with 1' (or 3' for tryptophan), designating the carbon atom bearing the aliphatic chain.The carbon atoms of this chain can be designated with C1 or Cα (for the carbon atom attached to the amino and phosphonic groups) and C2 or Cβ for the adjacent atom (the atom attached to the ring system) (Table 7).

Use of the Prefix 'Homo' and 'Nor'
An α-amino acid that is similar to one of the common ones, but that contains one more methylene group in the carbon chain, may be named by adding prefix 'homo' to the name of that common amino acid.'Homo' in the sense of a higher homologue is commonly used for homoserine and homocysteine.
The prefix 'nor' in the names 'norvaline' and 'norleucine' presents amino acidic isomers with not branched (normal) carbon chain.Both of these prefixes can be easily adapted for the nomenclature of aminophosphonates (Table 8 and 9).

Configuration at the α-Carbon Atom
This is usually described using the Fischer-Rosanoff convention (D-and L-) or Cahn-Ingold-Prelog (R-and S-) convention, in which L-α-amino acids, both the carboxyl (IUPAC CNOC, 1976) as well as the phosphonic forms (Dhavan & Redmore, 1987), are represented by the structures illustrated in Table 10.
These illustrate that L-amino acids and L-aminophosphonic acids, due to the order of preference: Table 1.Names and abbreviations of some phosphorus-containing compounds of biochemical importance according to IUPAC-IUB rules (IUPAC-IUB, 1978) 1-Aminoalkylphosphonic acid nomenclature exhibit different RS configurations.Thus, the L-configuration of amino acids (AA (C) ), nearly always corresponds to S (with the exception of L-cysteine), whereas the L-configuration of aminophosphonic acids (AA P ), always correspond to R.
The nomenclature "allo" and "threo" and also cis and trans have been applied in a similar way for the diastereoisomers of amino acids (threonines or prolines) and aminophosphonic acids (phosphonic analogs of threonine) (Bongini et al., 1996).

SYMBOLISM -GENERAL CONSIDERATIONS ON THE THREE-LETTER SYMBOLS
The trivial name for aminophosphonic acids can be derived from common names of their carboxylic analogs (e.g., aminomethylphosphonic acid vs. glycine), modified Table 2. Applied names and abbreviations for phosphonic analogs of proteinogenic amino acids and their metabolites and/or homologs with phospho or related prefix (phosphono or phospha) by the addition of the prefix "phosphono" (aminomethylphosphonic acid → phosphonoglycine).
Subsequently, the three-letter symbols of aminophosphonic acids (e.g., aminomethylphosphonic acid → phosphonoglycine) can be formed by the modification of their carboxylic analog symbols (e.g., Gly for glycine) by the addition to their right side the capital letter symbolizing the phosphono group in the superscript (Gly vs. Gly P ).
The comparison of nomenclature and symbolism for representative examples of amino acids and their phosphonic analogs is presented in Table 11.
Suggested nomenclature and symbolism for phosphonic analogs of the set of proteinogenic α-amino acids are listed in Table 12.

CONCLUSIONS
We believe that the implementation of the nomenclature and abbreviations proposed here will remove the ambiguity and will simplify the description of phosponate analogs of amino acids and their derivatives, including phosphonopeptides.Acceptance of these rules will facilitate unambiguous communication of research involving these classes of compounds.

a
The trivial name refers to the l or d or dl-amino acid.b Use of the one-letter symbols should be restricted to the comparison of long sequences (3-20 residues).c The systematic names and formulas given refer to hypothetical forms in which amino groups are not protonated and phosphonic groups are not dissociated.1-Aminoalkylphosphonic acid nomenclature

Table 4 . Applied codes for representative phosphoramidate and phosphonamidate enzyme inhibitors Table 5. Atom numbering in acyclic amino phosphonic acids
1-Aminoalkylphosphonic acid nomenclature