“…667 Another limitation arises from the synthetic difficulties encountered in the systematic modification of cyclosporins. [680][681][682] An interesting derivatization of cyclosporin by selective N-alkylation at N5 has provided several compounds with promising anti-HIV-1 activity 683 (Chart 15).…”
Section: G From Ppiase Inhibitors To Novel Therapeuticsmentioning
confidence: 99%
“…Crystallographic data as well as structure−activity relationship studies have allowed the delineation of the cyclophilin- and calcineurin-binding moieties. , Series of modified CsA derivatives 177 and 178 , (Chart ) have shown interesting anti-HIV-1 activities, but the therapeutic use of cyclosporin derivatives is marred by numerous side-effects such as liver and kidney toxicity, induction of apoptosis, and stimulation of growth of existing cancers . Another limitation arises from the synthetic difficulties encountered in the systematic modification of cyclosporins. − An interesting derivatization of cyclosporin by selective N-alkylation at N5 has provided several compounds with promising anti-HIV-1 activity (Chart ). 15 Cyclosporin A (CsA) 75 and Two Non-Immunosuppressive Analogues 177 and 178 that Inhibit Cyclophilin hCyp-18 a a Immunosuppressive effect of compounds 177 and 178 is below 0.1% relative to that of CsA.…”
Section: G From Ppiase Inhibitors To Novel Therapeuticsmentioning
“…667 Another limitation arises from the synthetic difficulties encountered in the systematic modification of cyclosporins. [680][681][682] An interesting derivatization of cyclosporin by selective N-alkylation at N5 has provided several compounds with promising anti-HIV-1 activity 683 (Chart 15).…”
Section: G From Ppiase Inhibitors To Novel Therapeuticsmentioning
confidence: 99%
“…Crystallographic data as well as structure−activity relationship studies have allowed the delineation of the cyclophilin- and calcineurin-binding moieties. , Series of modified CsA derivatives 177 and 178 , (Chart ) have shown interesting anti-HIV-1 activities, but the therapeutic use of cyclosporin derivatives is marred by numerous side-effects such as liver and kidney toxicity, induction of apoptosis, and stimulation of growth of existing cancers . Another limitation arises from the synthetic difficulties encountered in the systematic modification of cyclosporins. − An interesting derivatization of cyclosporin by selective N-alkylation at N5 has provided several compounds with promising anti-HIV-1 activity (Chart ). 15 Cyclosporin A (CsA) 75 and Two Non-Immunosuppressive Analogues 177 and 178 that Inhibit Cyclophilin hCyp-18 a a Immunosuppressive effect of compounds 177 and 178 is below 0.1% relative to that of CsA.…”
Section: G From Ppiase Inhibitors To Novel Therapeuticsmentioning
“…15 Cyclosporin derivatives devoid of immunosuppressive activity are interesting inhibitors since CsA is a selective high-affinity ligand of hCyp-18. 20,[23][24][25][26][27] However, synthesis of series of cyclic undecapetides is generally timeconsuming 28,29 and conceptually difficult because the global conformation of the molecule is strongly influenced by side-chain modifications. 30 Moreover, cyclosporin-based treatments cause chronic renal and hepatic toxicities, 31 facilitate apoptosis, 32 and induce cancer progression.…”
Cyclophilin A (hCyp-18), a ubiquitous cytoplasmic peptidyl-prolyl cis/trans isomerase (PPIase), orchestrates HIV-1 core packaging. hCyp-18, incorporated into the virion, enables core uncoating and RNA release and consequently plays a critical role in the viral replication process. hCyp-18 specifically interacts with a single exposed loop of the Gag polyprotein capsid domain via a network of nine hydrogen bonds which mainly implicates a 7-mer fragment of the loop. As previously reported, the corresponding linear heptapeptide Ac-Val-His-Ala-Gly-Pro-Ile-Ala-NH(2) (2) binds to hCyp-18 with a low affinity (IC(50) = 850 +/- 220 microM) but a potentially useful selectivity for hCyp-18 relative to hFKBP-12, another abundant PPIase. On the basis of X-ray structures of Gag fragments:hCyp-18 complexes, we generated a series of modified peptides in order to probe the determinants of the interaction and hence to select a peptidic ligand displaying a higher affinity than the capsid domain of Gag. We synthesized a series of heptapeptides to test the energetic contribution of amino acids besides the Gly-Pro moiety. In particular the importance of the histidine residue for the interaction was underscored. We also investigated the influence of N- and C-terminal modifications. Hexapeptides containing either deaminovaline (Dav) in place of the N-terminal valine or substitution of the C-terminal alanine amide with a benzylamide group displayed increased affinities. Combination of both modifications gave the most potent competitor Dav-His-Ala-Gly-Pro-Ile-NHBn (28) which has a higher affinity for hCyp-18 (K(d) = 3 +/- 0.5 microM) than the entire capsid protein (K(d) = 16 +/- 4 microM) and a very low affinity for hFKBP-12. Some of our results strongly suggest that the title compound is not a substrate of hCyp-18 and interacts preferentially in the trans conformation.
“…More traditional solution phase approaches have relied on the derivatization of the more readily accessible handle 1 (amino acid residue 1 based on Cyclosporin A nomenclature as depicted in Figure below), easily derivatized via either the hydroxyl or the olefin moieties . Seebach in his seminal paper on the development of chemistry on the Cyclosporin A core exemplified the strong conformational bias of the macrocyclic structure and took advantage of this feature to selectively alkylate the sarcosine amino acid residue 3 . More recently, in collaboration with Beller, we demonstrated the direct functionalization of the macrocyclic polypeptide core via the selective reduction of the Abu fragment of the macrocyclic peptide .…”
A practical
and robust process for the derivatization of Cyclosporin
A was demonstrated. The processes rely on the opening of Cyclosporin
A and removal of amino acid fragments via Edman degradation, with
the isolation of crystalline tetrafluoroboric salts of the corresponding
acyclic polypeptides.
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