Table 5.
Synthesis of KF Analogues following Scheme 2
| analogue | step | residue replaced | residue incorporated | |
|---|---|---|---|---|
| 25 | [Etg2]-KF | A5 | Fmoc-Thr-OH 2 | Fmoc-Etg-OH 2 |
| 26 | [d-Etg2]-KF | A5 | Fmoc-Thr-OH 2 | Fmoc-d-Etg-OH 2 |
| 27 | [(Z)-Dhf2]-KF | A5 | Fmoc-Thr-OH 2 | Fmoc-d/l-Phe-OH 2 |
| 28 | [dha2]-KF | A5 | Fmoc-Thr-OH 2 | Fmoc-Ser-OH |
| 29 | [d-Thr2]-KF | A5 | Fmoc-Thr-OH 2 | Fmoc-d-Thr-OH 2 |
| 30 | [d-allo-Thr2]-KF | A5 | Fmoc-Thr-OH 2 | Fmoc-d-allo-Thr-OH 2 |
| 31 | [Gly2]-KF | A5 | Fmoc-Thr-OH 2 | Fmoc-Gly-OH |
| 32 | [Aib2]-KF | A5 | Fmoc-Thr-OH 2 | Fmoc-Aib-OH |
| 33 | [Trp3]-KF | A5 | Fmoc-Phe-OH 3 | Fmoc-Trp-OH |
| 34 | [hCh3]-KF | A5 | Fmoc-Phe-OH 3 | Fmoc-hCh-OH |
| 35 | [Phe(3,4-Cl2)3,4(S)MeHex14]-KF | A5 | Fmoc-Phe-OH 3 | Fmoc-Phe(3,4-Cl2)-OH |
| 36 | [Phe(F5)3,4(S)MeHex14]-KF | A5 | Fmoc-Phe-OH 3 | Fmoc-Phe(F5)-OH |
| 37 | [Phe(4-I)3,4(S)MeHex14]-KF | A5 | Fmoc-Phe-OH 3 | Fmoc-Phe(4-I)-OH |
| 38 | [Phe(4-NO2)3,4(S)MeHex14]-KF | A5 | Fmoc-Phe-OH 3 | Fmoc-Phe(4-NO2)-OH |
| 39 | [Phe(4-F)3,4(S)MeHex14]-KF | A5 | Fmoc-Phe-OH 3 | Fmoc-Phe(4-F)-OH |
| 40 | [Tyr(Me)3,4(S)MeHex14]-KF | A5 | Fmoc-Phe-OH 3 | Fmoc-Tyr(Me)-OH |
| 41 | [Thi3,4(S)-MeHex14]-KF | A5 | Fmoc-Phe-OH 3 | Fmoc-Thi-OH |
| 42 | [Tic3,4(S)-MeHex14]-KF | A5 | Fmoc-Phe-OH 3 | Fmoc-Tic-OH |
| 43 | [Tyr3,4(S)-MeHex14]-KF | A5 | Fmoc-Phe-OH 3 | Fmoc-Tyr(t-Bu)-OH |
| 44 | [Oic3,4(S)-MeHex14]-KF | A5 | Fmoc-Phe-OH 3 | Fmoc-Oic-OH |
| 45 | [NMePhe3,4(S)MeHex14]-KF | A5 | Fmoc-Phe-OH 3 | Fmoc-NMe-Phe-OH |
| 46 | [Phe(2-Cl)3]-KF | A5 | Fmoc-Phe-OH 3 | Fmoc-Phe(2-Cl)-OH |
| 47 | [Phe(3-Cl)3]-KF | A5 | Fmoc-Phe-OH 3 | Fmoc-Phe(3-Cl)-OH |
| 48 | [Phe(4-Cl)3]-KF | A4 | 4(S)-MeHex 14 | 5-MeHex |
| A5 | Fmoc-Phe-OH 3 | Fmoc-Phe(4-Cl)-OH | ||
| 49 | [Phe(3,4-F2)3]-KF | A4 | 4(S)-MeHex 14 | 5-MeHex |
| A5 | Fmoc-Phe-OH 3 | Fmoc-Phe(3,4-F2)-OH | ||
| 50 | [NaI3]-KF | A4 | 4(S)-MeHex 14 | 5-MeHex |
| A5 | Fmoc-Phe-OH 3 | Fmoc-NaI-OH | ||
| 51 | [Bip3]-KF | A4 | 4(S)-MeHex 14 | 5-MeHex |
| A5 | Fmoc-Phe-OH 3 | Fmoc-Bip-OH | ||
| 52 | [Phg3]-KF | A4 | 4(S)-MeHex 14 | 5-MeHex |
| A5 | Fmoc-Phe-OH 3 | Fmoc-Phg-OH | ||
| 53 | [Val4]-KF | B1 | Fmoc-DVal-OH 1 | Fmoc-Val-OH |
| 54 | [d-Dapa6]-KF | B2 | Fmoc-d-allo-Thr-OH 6 | Fmoc-d-Dapa |
| 55 | [D-Thr6]-KF | B2 | Fmoc-d-allo-Thr-OH 6 | Fmoc-d-Thr-OH |
| 56 | [d-Ser6]-KF | B2 | Fmoc-d-allo-Thr-OH 6 | Fmoc-d-Ser-OH |
| 71 | [Nε(Me)3-Lys8,4(S)-MeHex14]-KF | B3 | Fmoc-Orn(Boc)-OH 8 | Fmoc-Lys(Boc)-OH |
| B4 | 5-MeHex 14 | 4(S)-MeHex | ||
| – | additional step | DIPEA/MeI | ||
| 72 | [Lys8]-KF | B3 | Fmoc-Orn(Boc)-OH 8 | Fmoc-Lys(Boc)-OH |
| 73 | [Glu8]-KF | B3 | Fmoc-Orn(Boc)-OH 8 | Fmoc-Glu(t-Bu)-OH |
| B2 | Fmoc-d-allo-Ile-OH 7 | none | ||
| 75 | [Orn(NδTfa)8,4(S)MeHex14]-KF | B7 | 5-MeHex 14 | 4(S)-MeHex |
| – | additional step | TFA/DIPEA | ||
| 76 | [Orn(NδTfa)8,Thr(OTfa)12,4(S)MeHex14]-KF | B7 | 5-MeHex 14 | 4(S)-MeHex |
| – | additional step | TFA/DCM (1:1), 3 days | ||
| 77 | [Thr(OTfa)12,4(S)MeHex14]-KF | B7 | 5-MeHex 14 | 4(S)-MeHex |
| – | additional step | TFA/DCM (1:1), 3 days | ||
| 78 | [nod-allo-Ile7,noOrn8,noD-Pro9,noD-Val10,noVal11, noThr12,noD-Val13]-KF |
B2 | Fmoc-d-allo-Ile-OH 7 | none |
| B3 | Fmoc-Orn(Boc)-OH 8 | none | ||
| B3 | Fmoc-d-Pro-OH 9 | none | ||
| B3 | Fmoc-d-Val-OH 10 | none | ||
| B3 | Fmoc-Val-OH 11 | none | ||
| B3 | Fmoc-Thr(t-Bu)-OH 12 | none | ||
| B3 | Fmoc-d-Val-OH 13 | none | ||
| 79 | [noOrn8]-KF | B3 | Fmoc-Orn(Boc)-OH 8 | none |
| 80 | [noOrn8,nod-Pro9]-KF | B3 | Fmoc-Orn(Boc)-OH 8 | none |
| B3 | Fmoc-D-Pro-OH 9 | none | ||
| 81 | [noOrn8,nod-Pro9,nod-Val10]-KF | B3 | Fmoc-Orn(Boc)-OH 8 | none |
| B3 | Fmoc-d-Pro-OH 9 | none | ||
| B3 | Fmoc-d-Val-OH 10 | none | ||
| 82 | [noOrn ,nod-Pro9,nod-Val10,noVal11]-KF | B3 | Fmoc-Orn(Boc)-OH 8 | none |
| B3 | Fmoc-d-Pro-OH 9 | none | ||
| B3 | Fmoc-d-Val-OH 10 | none | ||
| B3 | Fmoc-Val-OH 11 | none | ||
| 83 | [noOrn8,nod-Pro9,nod-Val10,noVal11,noThr12]-KF | B3 | Fmoc-Orn(Boc)-OH 8 | none |
| B3 | Fmoc-d-Pro-OH 9 | none | ||
| B3 | Fmoc-d-Val-OH 10 | none | ||
| B3 | Fmoc-Val 11 | none | ||
| B3 | Fmoc-Thr(t-Bu)-OH 12 | none | ||
| 84 | [noOrn8,nod-Pro9,nod-Val10, noVal11,noThr12,nod-Val13]-KF |
B3 | Fmoc-Orn(Boc)-OH 8 | none |
| B3 | Fmoc-d-Pro-OH 9 | none | ||
| B3 | Fmoc-d-Val-OH 10 | none | ||
| B3 | Fmoc-Val-OH 11 | none | ||
| B3 | Fmoc-Thr(t-Bu)-OH 12 | none | ||
| B3 | Fmoc-d-Val-OH 13 | none | ||
| 85 | [noVal11,noThr12,noD-Val13]-KF | B3 | Fmoc-Val-OH 11 | none |
| B3 | Fmoc-Thr(t-Bu)-OH 12 | none | ||
| B3 | Fmoc-d-Val-OH 13 | none | ||
| 86 | [Pro9, 4(S)MeHex14]-KF | B3 | Fmoc-d-Pro-OH 9 | Fmoc-Pro-OH |
| 87 | [d-Pip9,4(S)MeHex14]-KF | B3 | Fmoc-d-Pro-OH 9 | Fmoc-d-Pip-OH |
| 88 | [d-Tic9,4(S)MeHex14]-KF | B3 | Fmoc-d-Pro-OH 9 | Fmoc-d-Tic-OH |
| 89 | [5(R)-Ph-Pro9,4(S)-MeHex14]-KF | B3 | Fmoc-d-Pro-OH 9 | Fmoc-5(R)-Ph-Pro-OH |
| 90 | [Val10,d-Val11]-KF | B3 | Fmoc-d-Val-OH 10 | Fmoc-Val-OH |
| B3 | Fmoc-Val-OH 11 | Fmoc-d-Val-OH | ||
| 91 | [hCh11]-KF | B3 | Fmoc-Val-OH 11 | Fmoc-hCh-OH |
| 92 | [hCh11,d-Cha13]-KF | B3 | Fmoc-Val-OH 11 | Fmoc-hCh-OH |
| B3 | Fmoc-d-Val-OH 13 | Fmoc-d-Cha-OH | ||
| 93 | [d-Cha13]-KF | B3 | Fmoc-d-Val-OH 13 | Fmoc-d-Cha-OH |
| 94 | [Gly11]-KF | B3 | Fmoc-Val-OH 11 | Fmoc-Gly-OH |
| 95 | [Phe11]-KF | B3 | Fmoc-Val-OH 11 | Fmoc-Phe-OH |
| 96 | [Ala11]-KF | B3 | Fmoc-Val-OH 11 | Fmoc-Ala-OH |
| 97 | [Leu11]-KF | B3 | Fmoc-Val-OH 11 | Fmoc-Leu-OH |
| 98 | [d-Val11]-KF | B3 | Fmoc-Val-OH 11 | Fmoc-d-Val-OH |
| 99 | [Pro11]-KF | B3 | Fmoc-Val-OH 11 | Fmoc-Pro-OH |
| 100 | [Gln11]-KF | B3 | Fmoc-Val-OH 11 | Fmoc-Gln-OH |
| 101 | [Orn11]-KF | B3 | Fmoc-Val-OH 11 | Fmoc-Orn(Boc)-OH |
| 102 | [Thr11]-KF | B3 | Fmoc-Val-OH 11 | Fmoc-Thr(t-Bu)-OH |
| 103 | [Glu11]-KF | B3 | Fmoc-Val-OH 11 | Fmoc-Glu(O-t-Bu)-OH |
| 106 | [Gly12]-KF | B3 | Fmoc-Thr(t-Bu)-OH 12 | Fmoc-Gly-OH |
| 107 | [Phe12]-KF | B3 | Fmoc-Thr(t-Bu)-OH 12 | Fmoc-Phe-OH |
| 108 | [Ala12]-KF | B3 | Fmoc-Thr(t-Bu)-OH 12 | Fmoc-Ala-OH |
| 109 | [Leu12]-KF | B3 | Fmoc-Thr(t-Bu)-OH 12 | Fmoc-Leu-OH |
| 110 | [d-Thr12]-KF | B3 | Fmoc-Thr(t-Bu)-OH 12 | Fmoc-d-Thr(t-Bu)-OH |
| 111 | [Pro12]-KF | B3 | Fmoc-Thr(t-Bu)-OH 12 | Fmoc-Pro-OH |
| 112 | [Gln12]-KF | B3 | Fmoc-Thr(t-Bu)-OH 12 | Fmoc-Gln-OH |
| 113 | [Orn12]-KF | B3 | Fmoc-Thr(t-Bu)-OH 12 | Fmoc-Orn(Boc)-OH |
| 114 | [Glu12]-KF | B3 | Fmoc-Thr(t-Bu)-OH 12 | Fmoc-Glu(O-t-Bu)-OH |
| 115 | [Val12]-KF | B3 | Fmoc-Thr(t-Bu)-OH 12 | Fmoc-Val-OH |
| 116 | [Gly13]-KF | B3 | Fmoc-d-Val-OH 13 | Fmoc-Gly-OH |
| 117 | [d-Phe13]-KF | B3 | Fmoc-d-Val-OH 13 | Fmoc-d-Phe-OH |
| 118 | [d-Ala13]-KF | B3 | Fmoc-d-Val-OH 13 | Fmoc-d-Ala-OH |
| 119 | [d-Leu13]-KF | B3 | Fmoc-d-Val-OH 13 | Fmoc-d-Leu-OH |
| 120 | [Val13]-KF | B3 | Fmoc-d-Val-OH 13 | Fmoc-Val-OH |
| 121 | [d-Pro13]-KF | B3 | Fmoc-d-Val-OH 13 | Fmoc-d-Pro-OH |
| 122 | [d-Thr13]-KF | B3 | Fmoc-d-Val-OH 13 | Fmoc-d-Thr(t-Bu)-OH |
| 123 | [d-Glu13]-KF | B3 | Fmoc-d-Val-OH 13 | Fmoc-d-Glu(O-t-Bu)-OH |
| 124 | [d-Gln13]-KF | B3 | Fmoc-d-Val-OH 13 | Fmoc-d-Gln-OH |
| 125 | [Orn13]-KF | B3 | Fmoc-d-Val-OH 13 | Fmoc-d-Orn(Boc)-OH |
| 126 | [no5-MeHex14]-KF | B4 | 5-MeHex 14 | none |
| 127 | [Ac14]-KF | B4 | 5-MeHex 14 | AcOH |
| 128 | [Tfa14]-KF |
B4 | 5-MeHex 14 | TFA |
| 129 | [But14]-KF | B4 | 5-MeHex 14 | But-OH |
| 130 | [3-MeBut14]-KF | B4 | 5-MeHex 14 | 3-MeBut-OH |
| 131 | [3,3-dMeBut14]-KF | B4 | 5-MeHex 14 | 3,3-dMeBut-OH |
| 132 | [4-MePen14]-KF | B4 | 5-MeHex 14 | 4-MePen-OH |
| 133 | [(c/t)MecHex14]-KF | B4 | 5-MeHex 14 | (c/t)-MecHex-OH |
| 134 | [4(R)-MeHex14]-KF | B4 | 5-MeHex 14 | 4(R)-MeHex-OH |
| 135 | [Hep14]-KF | B4 | 5-MeHex 14 | Hep-OH |
| 136 | [6,6-dFHep14]-KF | B4 | 5-MeHex 14 | 6,6-dFHep-OH |
| 137 | [Pfh14]-KF | B4 | 5-MeHex 14 | Pfh-OH |
| 138 | [Oct14]-KF | B4 | 5-MeHex 14 | Oct-OH |
| 139 | [Und14]-KF | B4 | 5-MeHex 14 | Und-OH |
| 140 | [Palm14]-KF | B4 | 5-MeHex 14 | Palm-OH |
| 141 | [Icos14]-KF | B4 | 5-MeHex 14 | Icos-OH |
| 142 | [2,4-hexadie14]-KF | B4 | 5-MeHex 14 | 2,4-hexadie-OH |
| 143 | [Bza14]-KF | B4 | 5-MeHex 14 | Bza-OH |
| 144 | [p-MeBza14]-KF | B4 | 5-MeHex 14 | p-MeBza-OH |
| 145 | [p-TflBza14]-KF | B4 | 5-MeHex 14 | p-TflBza-OH |
| 146 | [Pipe14]-KF | B4 | 5-MeHex 14 | Pipe-OH |
| 147 | [3,5-dFPhAc14]-KF | B4 | 5-MeHex 14 | 3,5-dFPhAc-OH |
| 148 | [p-TflPhAc14]-KF | B4 | 5-MeHex 14 | p-TflPhAc-OH |
| 149 | [p-TflCinn14]-KF | B4 | 5-MeHex 14 | p-TflCinn-OH |
| 150 | [4-dMeaBut14]-KF | B4 | 5-MeHex 14 | 4-dMeaBut-OH |
| 151 | [4-GuBut14]-KF | B4 | 5-MeHex 14 | 4-GuBut-OH |
| 152 | [6-Ohep14]-KF | B4 | 5-MeHex 14 | 6-Ohep-OH |
| 153 | [4-Ac-OBut14]-KF | B4 | 5-MeHex 14 | 4-Ac-OBut |
| 154 | [4-OHBut14]-KF | B4 | 5-MeHex 14 | 4-OHBut-OH |
| 155 | [4-(4-AcOBut)OBut14]-KF | B4 | 5-MeHex 14 | 4-(4-Ac-OBut)OBut-OH |
| 156 | [d-allo-IleiBut14]-KF | B4 | 5-MeHex 14 | Fmoc-d-allo-Ile-OH |
| additional step | iBut-OH | |||
| 157 | [Lit14]-KF | B4 | 5-MeHex 14 | Lit-OH |
| 158 | [Lit(OTfa)14]-KF | B4 | 5-MeHex 14 | Lit-OH |
| B7 | – | trifluoroacetylion | ||
| 159 | [d-Val1,d-Phe3,Val4,allo-Ile5,allo-Thr6,allo-Ile7, d-Orn8,Pro9,Val10,d-Val11,d-Thr12,Val13]-KF |
A1 | Fmoc-d-Val-OH 4 | Fmoc-Val-OH |
| A2 | Fmoc-d-allo-Ile-OH 5 | Fmoc-allo-Ile-OH | ||
| A2 | Fmoc-d-allo-Thr-OH 6 | Fmoc-allo-Thr-OH | ||
| A2 | Fmoc-d-allo-Ile-OH 7 | Fmoc-allo-Ile-OH | ||
| A3 | Fmoc-Orn(Boc)-OH 8 | Fmoc-d-Orn(Boc)-OH | ||
| A3 | Fmoc-d-Pro-OH 9 | Fmoc-Pro-OH | ||
| A3 | Fmoc-d-Val-OH 10 | Fmoc-Val-OH | ||
| A4 | Fmoc-Val-OH 11 | Fmoc-d-Val-OH | ||
| A4 | Fmoc-Thr(t-Bu)-OH 12 | Fmoc-d-Thr(t-Bu)-OH | ||
| A4 | Fmoc-d-Val-OH 13 | Fmoc-Val-OH | ||
| 160 | [d-Cha4,d-Cha4,d-Cha7]-KF | B1 | Fmoc-d-Val-OH 4 | Fmoc-d-Cha-OH |
| B2 | Fmoc-d-allo-Ile-OH 5 | Fmoc-d-Cha-OH | ||
| B2 | Fmoc-d-allo-Ile-OH 7 | Fmoc-d-Cha-OH | ||
| 161 | [d-Val5,d-Va7]-KF | B2 | Fmoc-d-allo-Ile-OH 5 | Fmoc-d-Val-OH |
| B2 | Fmoc-d-allo-Ile-OH 7 | Fmoc-d-Val-OH | ||
| 162 | [Phe(3,4-Cl2)3,pCF3 Cinn14]-KF | 4 | 5-MeHex 14 | p-CF3 Cinn-OH |
| 5 | Fmoc-hCh-OH 3 | Fmoc-Phe(3,4-Cl2)-OH | ||
| 163 | [noVal11,noThr12,nod-Val13,Mst14]-KF | B3 | Fmoc-Val-OH 11 | none |
| B3 | Fmoc-Thr(t-Bu)-OH 12 | none | ||
| B3 | Fmoc-d-Val-OH 13 | none | ||
| B4 | 5-MeHex 14 | Mst-OH | ||
| 164 | [Thr(OTfa)12,Lit(OTfa)14]-KF | A4 | 5-MeHex 14 | LiOH |
| A7 | additional step | TFA/DCM (1:1) | ||
| 165 | [no5-MeHex14,N-(Hep)2-d-Val13]-KF | A4 | additional step | heptanaldehyde/NaBH3CN/DMF and AcOH (9:1) |