Novel synthesis of various orthogonally protected Cα-methyllysine analogues and biological evaluation of a vapreotide analogue containing (S)-α-methyllysine.
Prochiral malonic diesters containing a quaternary carbon center have been successfully transformed into a diverse set of (t)Boc-Fmoc-α(2,2)-methyllysine-OH analogues through chiral malonic half-ester intermediates obtained via enzymatic (Pig Liver Esterase, PLE) hydrolysis. The variety of chiral half-ester intermediates, which vary from 1 to 6 methylene units in the side chain, are achieved in moderate to high optical purity and in good yields. The PLE hydrolysis of malonic diesters with various side chain lengths appears to obey the Jones's PLE model according to the stereochemical configurations of the resulting chiral half-esters. The established synthetic strategy allows the construction of both enantiomers of α(2,2)-methyllysine analogues, and a (S)-β(2,2)-methyllysine analogue from a common synthon by straightforward manipulation of protecting groups. Two different straightforward and cost effective synthetic strategies are described for the synthesis of α(2,2)-methyllysine analogues. The described strategies should find significant usefulness in preparing novel peptide libraries with unnatural lysine analogues. A Vapreotide analogue incorporating (S)-α(2,2)-methyllysine was prepared. However, the Vapreotide analogue with (S)-α-methyl-α-lysine is found to lose its specific binding to somatostatin receptor subtype 2 (SSTR2).
University of Southern Mississippi, Hattiesburg, MS 39406, USA.
Souvik
S
Banerjee
Walker J
WJ
Wiggins
Jessie L
JL
Geoghegan
Catherine T
CT
Anthony
Eugene A
EA
Woltering
Douglas S
DS
Masterson
D000818:Animals; D006868:Hydrolysis; D008099:Liver / Q000201:enzymology; D008239:Lysine / Q000031:analogs & derivatives* / Q000737:chemistry; D008314:Malonates / Q000737:chemistry; D015394:Molecular Structure; D011485:Protein Binding / Q000187:drug effects; D013004:Somatostatin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D013552:Swine
D008314:Malonates; C051458:vapreotide; D013004:Somatostatin; C049907:2-methyllysine; D008239:Lysine