Conjugation of Adenosine and Hexa-(d-arginine) Leads to a Nanomolar Bisubstrate-Analog Inhibitor of Basophilic Protein Kinases

• Published in: Journal of medicinal chemistry Vol. 49; no. 24; pp. 7150 - 7159
• Main Authors: Enkvist, Erki, Lavogina, Darja, Raidaru, Gerda, Vaasa, Angela, Viil, Indrek, Lust, Marje, Viht, Kaido, Uri, Asko
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 30.11.2006; Amer Chemical Soc
• Subjects: Adenosine - analogs & derivatives; Adenosine - chemical synthesis; Adenosine - chemistry; Arginine - analogs & derivatives; Arginine - chemical synthesis; Arginine - chemistry; Biological and medical sciences; Chemistry, Medicinal; Cyclic AMP-Dependent Protein Kinases - antagonists & inhibitors; Cyclic AMP-Dependent Protein Kinases - chemistry; Isoquinolines - chemical synthesis; Isoquinolines - chemistry; Life Sciences & Biomedicine; Medical sciences; Miscellaneous; Oligopeptides - chemical synthesis; Oligopeptides - chemistry; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Science & Technology; Stereoisomerism; Structure-Activity Relationship; Sulfonamides - chemical synthesis; Sulfonamides - pharmacology; CATALYTIC SUBUNIT; PHASE SYNTHESIS; SUBSTRATE-SPECIFICITY; IN-VITRO; DESIGN; PEPTIDES; LIGANDS; ATP; RESIDUES; STRATEGIES; Purine nucleoside; Spacer arm; Oligopeptides; Peptides; Enzyme; Nitrogen heterocycle; Transferases; Enzyme inhibitor; Oligomer; In vitro; Arginine polymer; Basophil; Aminoacid polymer; Signal transduction; Structure activity relation; Protein kinase; Bicyclic compound; Aromatic compound; Conjugated compound; Ribonucleoside; Chemical synthesis
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm0605942

Conjugates of oligoarginine peptides with adenine, adenosine, adenosine-5‘-carboxylic acid, and 5-isoquinolinesulfonic acid were synthesized and characterized as bisubstrate-analog inhibitors of cAMP-dependent protein kinase. Adenosine and adenine derivatives were connected to the N- or C-terminus of peptides containing four to six l- or d-arginine residues via a linker with a length that had been optimized in structure−activity studies. The orientation of the peptide chain strongly affected the activity of compounds incorporating d-arginines. The biligand inhibitor containing Hidaka's H9 isoquinolinesulfonamide connected to the l-peptide had 65 times higher potency than the corresponding adenosine-containing conjugate, while both types of the conjugate comprising d-peptides had similar low nanomolar activity. Two of the most active adenosine- and H9-peptide conjugates were tested in the panel of 52 different kinases. At 1 μM concentration, both compounds showed strong (more than 95%) inhibition of several basophilic AGC kinases, including pharmaceutically important kinases ROCK II and PKB/Akt.