Long-acting angiotensin II inhibitors containing hexafluorovaline in position 8

Abstract

An improved synthesis of hexafluorovaline (Hfv) derivatives, i.e., DL-Hfv-OBzl and Boc-DL-Hfv, is described. Incorporation of hexafluorovaline into angiotensin resulted in [Sar1,Hfv8]AII and [Sar1,D-Hfv8]AII. At the nanogram/milliliter dose range, the L congener was 20-100 times more active as either angiotensin agonist or angiotensin antagonist than its D diastereomer on isolated tissue preparations. At the microgram dose range, both [Sar1,Hfv8]AII and [Sar1,D-Hfv8]AII were significantly more effective than [Sar1,Leu8]AII as angiotensin II inhibitors, producing prolonged blockade of the pressor response toward angiotensin II for over 1 h.

Gelatinase-mediated migration and invasion of cancer cells

“…Additionally, the fluorine-substituted amino acids are more hydrophobic than the normal amino acids (Yoder and Kumar, 2002). As a result, proteins with fluoroamino acids often show an increase in thermal stability ) and/or increased resistance to proteases and improved bioavailability (Hsieh et al, 1987). For these reasons, fluorine substitutions are also used in chemical compounds as a final push to increase their activity as exemplified by the MMP-2/α V β 3 integrin interaction-inhibiting molecule .…”

“…A limiting factor is that only some amino acid analogues are incorporated thus constraining the diversity of the libraries that may be constructed. However, even a single amino acid analogue may significantly change the properties of the polypeptides (Hsieh et al, 1987;. To further improve the system, the phage infectivity of the auxotrophic hosts should also be increased.…”

Enantioselective synthesis of (2R, 3S)‐ and (2S, 3R)‐4,4,4‐trifluoro‐N‐Fmoc‐O‐tert‐butyl‐threonine and their racemization‐free incorporation into oligopeptides via solid‐phase synthesis

“…The residue was purified by column chromatography on silica gel (hexanes : ethyl acetate = 30 : 1) to give a colorless oil (57.2 g, 80%). (2R, 3S)-Benzoic acid 4,4,4-trifluoro-2, 3-dihydroxy-butyl ester, 5a-To a stirred mixture of tert-butyl alcohol (400 mL) and water (400 mL) were added (DHQD) 2 PHAL (1.3 g, 1.67 mmol), K 3 Fe(CN) 6 (81.5 g, 247 mmol), K 2 CO 3 (34.2 g, 247 mmol), and OsO 4 (6.5 mL of 0.1 M aqueous solution, 0.65 mmol) at room temperature. After the solid was dissolved, the solution was cooled to 0 °C.…”

“…Like threonine, tfT has two chiral centers and hence four stereoisomers: (2S, 3R), (2R, 3S), (2S, 3S) and (2R, 3R). Previous work by Goodman and coworkers has demonstrated clearly that the stereochemistry of Thr 6 and Thr 8 has critical impact on the bioactivity of octreotide. 22 Hence, to achieve desired pharmaceutical benefits, it is absolutely essential that tfT is incorporated into octreotide as pure enantiomers in a racemization-free manner.…”

“…The introduction of fluorinated amino acids into peptides and proteins often has significant impact on their physicochemical and biological properties, such as increased stability, 1 decreased helical propensity, 2 preferential association in solution 3 and in lipids, 4 enhanced membrane binding, 5 prolonged in vivo half-life 6 and promotion of chemotaxis. 7 Furthermore, incorporation of fluorinated amino acids makes it possible to investigate the conformation and metabolism of host peptides or proteins by 19 F NMR.…”