1. Analgesic dipeptides. VI.: Synthesis and structure-activity relationships of N-terminal modified analogues of the analgesic compounds H-Xaa-Trp(Nps)-OMe (Xaa=Lys, Orn, Arg)
M T García-López, R González-Muñiz, J R Harto, M T Molinero, J del Río Arch Pharm (Weinheim). 1989 Mar;322(3):145-52. doi: 10.1002/ardp.19893220306.
In order to determine the influence of the N-terminal amino group of the dipeptide derivatives H-Xaa-Trp(Nps)-OMe[Xaa = Lys (2a), Orn (2b), Arg (2c)] on their antinociceptive effects, the syntheses of their corresponding deaminated, acetylated and dimethylated analogues have been achieved. Deamino and dimethyl analogues of 2a,b,6a,b, and 18a,b were prepared by coupling the corresponding N omega-Z- and N omega-Z-N alpha-Me2 amino acids with H-Trp-OMe, using the DCC/HOSu method, followed by sulfenylation of the resulting compounds and removal of the Z groups. Guanidylation of 6b and 18b provided the arginine analogues 6c and 18c, respectively. Ac-Xaa-Trp(Nps)-OMe [Xaa = Lys (11a), Orn (11b) were synthesized by acetylation of H-Xaa(Z)-Trp(Nps)-OMe with acetic anhydride, in the presence of 4-dimethylaminopyridine, and subsequent removal of the Z groups. Coupling of Ac-Arg-OH.HC1 with H-Trp-OMe, using the DCC/HOSu procedure, followed by sulfenylation of the resulting 8:3 diastereomeric mixture of L,L and L,D dipeptides afforded Ac-ambo-Arg-Trp(Nps)-OMe 11c+11d. The antinociceptive effects of 6a-c, 11a-d, and 18 a-c were evaluated after i.c.v. administration in mice. The N alpha-acetyl dipeptides 11 were found to exhibit a naloxone-reversible antinociceptive effects comparable with those of 2, while N-deaminated and N,N-dimethylated analogues were inactive.
2. Analgesic dipeptide derivatives. 3. Synthesis and structure-activity relationships of o-nitrophenyl-modified analogues of the analgesic compound H-Lys-Trp(NPS)-OMe
M T Garcia-López, R González-Muñiz, M T Molinero, J R Naranjo, J Del Rio J Med Chem. 1987 Sep;30(9):1658-63. doi: 10.1021/jm00392a023.
A series of analogues of the analgesic dipeptide derivative H-Lys-Trp(NPS)-OMe has been designed to determine the influence of the (2-nitrophenyl)sulfenyl (NPS) moiety on the activity. The syntheses and antinociceptive effects of these analogues of general formula H-Lys-Trp(R)-OMe [R = phenylsulfenyl (PS) (9); R = (2-carbomethyoxyphenyl)sulfenyl (CmPS) (10); R = (4-nitrophenyl)sulfenyl (pNPS) (11); R = (2,4-dinitrophenyl)sulfenyl (DNPS) (12); R = [2-(acetylamino)-2-carbomethoxyethyl]sulfenyl (AacCmES) (13); R = [2-(acetylamino)phenyl]sulfenyl (AacPS) (17); R = tert-butylsulfenyl (t-BuS) (23); R = (2-carbomethoxyethyl)sulfenyl (CmES) (24)] are described. Reaction of Z-Lys(Z)-Trp-OMe (3) with PS-, CmPS-, pNPS-, DNPS-, and AacCmES-Cl afforded the corresponding 2-(sulfenyl)tryptophan derivatives, which on treatment with boron-tris(trifluoroacetate)/trifluoroacetic acid or trimethylsilyl iodide in acetonitrile (Me3SiI/CH3CN) provided 9-13, respectively. Sulfenylation of 3 with NPS-Cl gave Z-Lys(Z)-Trp(NPS)-OMe, which, on catalytic hydrogenation of the nitro group using 10% Pd/C followed by acetylation of the resulting amino function and removal of the protecting Z groups, gave 17. Condensation of 2-(tert-butylsulfenyl)- and 2-[(2-carbomethoxyethyl)sulfenyl]tryptophan methyl ester, obtained by reaction of methyl 3a-hydroxy-1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]indole-2-carboxyla te with the corresponding thiol, with Z-Lys(Z)-OSu afforded Z-Lys(Z)-Trp(t-BuS)-OMe and Z-Lys(Z)-Trp(CmES)-OMe, which on treatment with Me3SiI/CH3CN provided 23 and 24, respectively. Intracerebroventricular administration of 10 elicited a naloxone-reversible antinociceptive effect in mice similar to that of H-Lys-Trp(NPS)-OMe. No analgesia was however found with the phenylsulfenyl or acyclic sulfenyl substituted dipeptides 9, 11, and 17 or 13, 23, and 24. The Trp(DNPS)-containing analogue was neurotoxic. Structure-activity studies indicate that the role of the NPS and CmPS moieties could be related to the adoption of a preferential active conformation.
3. Total Synthesis of Alloviroidin
Carol M Taylor, Samuel K Kutty, Benson J Edagwa Org Lett. 2019 Apr 5;21(7):2281-2284. doi: 10.1021/acs.orglett.9b00567. Epub 2019 Mar 12.
Alloviroidin is a cyclic heptapeptide, produced by several species of Amanita mushrooms, that demonstrates high affinity for F-actin as is characteristic of virotoxins and phallotoxins. Alloviroidin was synthesized via a [3 + 4] fragment condensation of Fmoc-d-Thr(OTBS)-d-Ser(OTBS)-(2 S,3 R,4 R)-DHPro(OTBS)2-OH and H-Ala-Trp(2-SO2Me)-(2 S,4 S)-DHLeu(5-OTBS)-Val-OMe to form bond A. The linear heptapeptide favored a turn conformation, facilitating cyclization between Val1 and d-Thr2 (position B). Global deprotection and HPLC purification afforded alloviroidin with NMR spectra in excellent agreement with the natural product.