Vinyl Sulfide Cyclized Analogues of Angiotensin II with High Affinity and Full Agonist Activity at the AT₁Receptor

Abstract

Vinyl sulfide cyclized analogues of the octapeptide angiotensin II that are structurally related to the cyclic disulfide agonist c[Hcy(3,5)]Ang II have been prepared. The synthesis relies on the reaction of the mercapto group of a cysteine residue in position 3 with the formyl group of allysine incorporated in position 5 of angiotensin II. A mixture of the cis and the trans isomers was formed, and these were separated and isolated by RP-HPLC. Thus, the three-atom CH(2)[bond]S[bond]S element of the AT(1) receptor agonist c[Hcy(3,5)]Ang II has been displaced by a bioisosteric three-atom S[bond]CH[double bond]CH element. A comparative conformational analysis of the 13-membered ring systems of c[Hcy(3,5)]Ang II and the 13-membered cyclic vinyl sulfides with cis and trans configuration, respectively, suggested that all three systems adopted very similar low-energy conformations. This similarity was also reflected in the bioactivity. Both of the compounds that contained the ring systems encompassing the cis or trans vinyl sulfide elements between positions 3 and 5 exhibited K(i) values less than 2 nM and exerted full agonism at the AT(1) receptor. In contrast, vinyl sulfide cyclization involving the amino acid residues 5 and 7 rendered inactive compounds. The cyclic vinyl sulfides that have agonist activity were both shown to possess low-energy conformers compatible with the previously proposed 3D model for the bioactive conformation of Ang II.

Synthesis of Disubstituted Dithioethers: tert-Butoxide Promoted Elimination/Ring Opening of 1,3-Dithianes Followed by Palladium-Catalyzed C–S Bond Formation

“…Workup of the reaction resulted in a brown oil (0.2095 g, 72%). 1 (4-Cyanophenyl)(3-(styrylthio)propyl)sulfane (14). The title compound was prepared using the general procedure with 4-bromobenzonitrile (0.182 g, 1.0 mmol).…”

Microwave accelerated efficient synthesis of N-fluorenylmethoxycarbonyl/t-butoxycarbonyl/benzyloxycarbonyl-5-oxazolidinones

“…4 Recently, Johannesson et al employed oxazolidinones as the key intermediates for the synthesis of angiotensin II analogues with full agonistic activity at the ATreceptor. 5,6 The synthesis of 5-oxazolidinones is generally carried out by refluxing the mixture of N-protected amino acid, paraformaldehyde, and p-toluene sulfonic acid in toluene or benzene for several hours, until the solution becomes homogeneous with azeotropic removal of water using a Dean Stark apparatus, which is cumbersome and time consuming. In recent years, the utility of microwave irradiated organic synthesis has been explored due to its simplicity and to achieve rapid chemical modifications with cleaner products and high yield.…”

Stereoselective chlorothiolation of artemisinin-derived C-10 oxa terminal alkynes

“…Many natural products and synthetic compounds containing the vinyl sulfide moiety exhibit promising biological properties, such as anticancer, antimalarial, antimicrobial, and antifungal activities [17][18][19][20][21]. In continuation of our interest in the synthesis of artemisinin derivatives as antimalarial and anticancer agents, we decided to introduce the vinyl sulfide moiety in the artemisnin framework to enhance its anticancer activity profile.…”