title: Applying the prodrug strategy to α-phosphonocarboxylate inhibitors of Rab GGTase--synthesis and stability studies.
abstract: Fourteen novel prodrug-like analogs of two highly ionic phosphonocarboxylate inhibitors of Rab geranylgeranyl transferase were synthesized and preliminary assessment of their chemical and enzymatic stability was evaluated in buffers (pH 6.5 and 7.4) and rat intestinal homogenate (pH 6.5). Both acidic groups in phosphonocarboxylates were subject to modification. Phosphonic acid was protected either as bis(acyloxyalkyl) ester or phosphonodiamidate derived from amino acids. The carboxylic acid group was either left unchanged or was studied as ethyl ester. The compounds exhibited favorable stability in physiologically relevant pH (t1/2 above 18 h), while in intestinal homogenate they showed a large variety of half-lives (from 5 minutes to over 150 hours). LC MS studies have shown that the main product of decomposition under studied conditions resulted from cleavage of one of the ester (for acyloxyalkyl analogs) or amide (for phosphonodiamidate) bonds with phosphorus.
authors.affiliation: Institute of Organic Chemistry, Lodz University of Technology, Żeromskiego 116, 90-924 Łódź, Poland. katarzyna.blazewska@p.lodz.pl.
authors.forename: Łukasz
authors.initials: Ł
authors.lastname: Joachimiak
authors.forename: Łukasz
authors.initials: Ł
authors.lastname: Janczewski
authors.forename: Jarosław
authors.initials: J
authors.lastname: Ciekot
authors.forename: Janusz
authors.initials: J
authors.lastname: Boratyński
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Błażewska
mesh_terms: D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors*; D000818:Animals; D002264:Carboxylic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D004355:Drug Stability; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D007413:Intestinal Mucosa / Q000378:metabolism; D063065:Organophosphonates / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D051381:Rats
chemical_list: D002264:Carboxylic Acids; D004791:Enzyme Inhibitors; D063065:Organophosphonates; D011355:Prodrugs; D019883:Alkyl and Aryl Transferases; C075607:Rab geranylgeranyltransferase