Diamondoid Amino Acid‐Based Peptide Kinase A Inhibitor Analogues

Abstract

The incorporation of diamondoid amino acids (DAAs) into peptide‐like drugs is a general strategy to improve lipophilicity, membrane permeability, and metabolic stability of peptidomimetic pharmaceuticals. We designed and synthesized five novel peptidic DAA‐containing kinase inhibitors of protein kinase A using a sophisticated molecular dynamics protocol and solid‐phase peptide synthesis. By means of a thermophoresis binding assay, NMR, and crystal structure analysis, we determined the influence of the DAAs on the secondary structure and binding affinity in comparison to the native protein kinase inhibitor, which is purely composed of proteinogenic amino acids. Affinity and binding pose are largely conserved. One variant showed 6.5‐fold potency improvement, most likely related to its increased side chain lipophilicity. A second variant exhibited slightly decreased affinity presumably due to loss of hydrogen‐bond contacts to surrounding water molecules of the first solvation shell.

Annulated carbamates are precursors for the ring contraction of the adamantane framework

“…The iminium salt intermediate Int1-OTf is reduced in the next step using LiAlH 4 to form the product 5 ( Fig. 4 ) or it can be trapped by other nucleophiles such as a nitrile using the Strecker reaction with TMSCN to form compound 15, precursor for non-biogenic α-amino acids 20 as demonstrated on the synthesis of compound 16 ( Scheme 2 ).…”

Towards a qualitative understanding of the carbonyl reactivity of α-substituted ethyl 5-oxohomoadamantyl-4-carboxylates

“…Found: C,70.04;H,8.62;N,4.76. Ethyl 2,4,5,6,7,8,9,8:6,pyrrole-3a(3H)-carboxylate (14). A mixture of ethyl 4-(cyanomethyl)-5-oxotricyclo [4.3.1.1 3,8 ]undecane-4-carboxylate (2h, 11 4.0 g, 14.50 mmol), ethanol (50 ml), 25% NH 3 solution in water (10 mL) and freshly prepared [10.0 g of Ni-Al alloy (weight ratio of 50 : 50) was slowly added to an aqueous solution of NaOH (6.0 M, 50 mL) under stirring over ice water at a controlled temperature between 10-20 °C over 1 h].…”

“…,73.53;H,8.87;N,5.36. Found: C,73.57;H,8.84;N;3,3a,4,5,6,7,8,9,8:6,10dimethanocyclonona[b]pyrrol-1-ium chloride (15). Ethyl 2, 4,5,6,7,8,9,10-octahydro-4,8:6,10-dimethanocyclone[b]pyrrole-3а(3Н)-carboxylate (14, 0.20 g, 0.77 mmol) was dissolved in 35% HCl (3 ml), and then the solution was concentrated; the residue was recrystallized from benzene.…”

“…calcd for C 16 H 24 O 3 (264.37): C,72.69;H,9.15. Found: C,72.76;H,8 ]undecan-4-one (4). A solution of ethyl 4-hydroxy-5-oxotricyclo[4.3.1.1 3,8 ]undecane-4-carboxylate (2d, 10 1.00 g, 6.58 mmol) in ethanol (10 ml) and 50% NaOH (1 ml) was stirred for 6 h at 25 °C; the solvent was removed on a rotary evaporator; 50% H 2 SO 4 (5 ml) was added to the residue and left for 2 h at 25 °C with stirring; the precipitate was filtered off and recrystallized from ethyl acetate.…”

“…This could affect the level of biological activity and the affinity to biological targets, like receptors or ion channels. 4 There are several reports on the biological activity of homoadamantane derivatives 5 a , b ,6 (Fig. 1b) including amines which are analogues of the corresponding adamantyl NMDA antagonist e.g.…”