Novel Synthesis of Cyclic Amide-Linked Analogs of Angiotensins II and III

Abstract

Cyclic amide-linked angiotension II (ANGII) analogues have been synthesized by novel strategies, in an attempt to test the ring clustering and the charge relay bioactive conformation recently suggested. These analogues were synthesized by connecting side chain amino and carboxyl groups at positions 1 and 8, 2 and 8, 3 and 8, and 3 and 5, N-terminal amino and C-terminal carboxyl groups at positions 1 and 8, 2 and 8, and 4 and 8, and side chain amino to C-terminal carboxyl group at positions 1 and 8. All these analogues were biologically inactive, except for cyclic [Sar1, Asp3, Lys5]ANGII (analogue 10) which had high contractile activity in the rat uterus assay (30% of ANGII) and [Lys1, Tyr(Me)4, Glu8]ANGII (analogue 7) which had weak antagonist activity (PA2 approximately 6). Precyclic linear peptides synthesized using 2-chlorotrityl chloride resin and N alpha-Fmoc-amino acids with suitable side chain protection were obtained in high yield and purity and were readily cyclized with benzotriazol-1-yloxytris(dimethylamino)-phosphonium hexafluorophosphate as coupling reagent. Molecular modeling suggests that the ring structure of the potent analogue can be accommodated in the charge relay conformation proposed for ANGII.

Design And Synthesis of a Novel Potent Myelin Basic Protein Epitope 87−99 Cyclic Analogue: Enhanced Stability and Biological Properties of Mimics Render Them a Potentially New Class of Immunomodulators

“…Related work in our laboratory has led to the design and synthesis of cyclic analogues for guinea pig MBP 72-85 , Thrombin receptor motif SFLLR, Angiotensins II and III, and GnRH (unpublished) which were able to maintain or suppress the biological function of the original peptide. 15,20,[23][24][25][26][27][28] We had previously demonstrated that injection of Lewis rats with linear or cyclic guinea pig MBP 72-85 peptides induced EAE. 19 15 In our in vivo rat studies, EAE was induced by the agonist guinea pig epitope MBP [72][73][74][75][76][77][78][79][80][81][82][83][84][85] and not by the human MBP 83-99 agonist peptide.…”

Biological activity of the novel cyclic angiotensin II analogue [Sar1,Lys3,Glu5]ANG II

“…In a series of ex vivo experiments using the rat uterus assay, we have shown that the cyclic ANG II analogue [Sar~,Asp3,LysS]ANG II has contractile activity (-30% of ANG II) [5]. In the present study, another similar cyclic ANG II analogue, namely [SarI,Lys3,GluS]ANG II, was found to have contractile activity in the rat uterus assay (-15% of ANG II) and to produce an immediate and sustained blood pressure elevation after iv administration in anesthetized rabbits.…”

“…Uterine horns from diethylstilbestrol-primed virgin Sprague-Dawley rats (150-250 g) were used in the experiment carried out as previously described [5]. Agonist activity was determined by matching the response with an equivalent response to ANG II (human).…”

“…Accordingly, we have recently developed novel strategies that allowed us to synthesize a series of cyclic amide-linked ANG II analogues [5]. Subsequent ex vivo experiments with the rat uterus assay revealed that the majority of these cyclic analogues were biologically inactive with the notable exception of the cyclic [Sart,Asp3,LysS]ANG II analogue, which had a potent contractile activity (~30% of that observed with ANG II).…”

“…Subsequent ex vivo experiments with the rat uterus assay revealed that the majority of these cyclic analogues were biologically inactive with the notable exception of the cyclic [Sart,Asp3,LysS]ANG II analogue, which had a potent contractile activity (~30% of that observed with ANG II). With the intention to further evaluate the ring-cluster conformation proposed for ANG II [5], we studied another cyclic ANG II analogue ([SarJ,Lys3,Glu 5] ANG II) ( Fig. 1) in both ex vivo experiments with the rat uterus assay and in vivo, after the intravenous (iv) administration in anesthetized rabbits, and we compared its biological activity with that of ANG II, the parent compound.…”