Chapter 20. Therapeutic Approaches to Rheumatoid Arthritis and Other Autoimmune Diseases

Analogs of the Marine Immunosuppressant Microcolin A: Preparation and Biological Activity

“…The reaction mixture was allowed to stand at room temperature under nitrogen for 6 h and then placed into a freezer overnight. The solvent was removed under reduced pressure to give 2.6 mg of 95% (by NMR) pure 3: HRLSIMS (MH+) caled, for C-uHesOioNs 790.497, found 790.497, 0 mmu; NMR (500 MHz, CDCI3) <5 7.24 (dd, 1H, J = 5.8, 2.1, H-3), 6.97 (d, 1H, J = 8.4, N ), 6.06 (dd, 1H, J = 6.3, 1.6, H-2), 5.51 (dd, 1H, J = 9.0,4.7, aHyp), 5.29 (dd, 1H, J = 10.5, 4.7, aMeLeu), 5.25 (dd, 1H, J = 6.8, 2.6, /SThr), 4.96 (d, 1H, = 11.0, aMeVal), 4.94 (dd, 1H, J = 8.9, 2.6, aThr), 4.75 (qt, 1H, 6.8, 1.6, H-4), 4.23 (dd, 1H, J = 11.6, 6.3, yHyp), 3.72 (dd, 1H, J = 11.0, 7.3, ÓHyp), 3.70 (dd, 1H, J = 11.0, 4.2, ÓHyp), 3.10 (s, 3H, NMeVal), 2.96 (s, 3H, NMeLeu), 2.84 (m, 1H, H-36), 2.83 (m, 1H, /SHyp), 2.26 (m, 1H, /SNMeVal), 2.02 (s, 3H, 10-OAc), 2.01 (s, 3H, 25-OAc), 1.98 (m, 1H, /SHyp), 1.87 (ddd, 1H, J = 13.4, 9.0, 4.7, H-37), 1.73 (ddd, 1H, J = 14.6, 10.0, 4.6, /SNMeLeu), 1.54 (m, 1H, H-30), 1.48 (d, 3H, J = 6.8, H-6), 1.42 (m, 1H, H-31), 1.27 (bm, 2H, H-38), 1.25 (bm, 4H, H-39, H-40), 1.23 (bm, 2H, H-41), 1.16 (d, 3H, J = 6.8, yThr), 1.14 (d, 3H, J = 6.8, H-44), 1.10 (m, 1H, H-37), 1.07 (m, 1H, H-39), 1.02 (d, 3H, J = 6.8, ÓNMeLeu), 0.95 (d, 3H, J = 6.8, yNMeVal), 0.88 (t, 3H, J = 6.8, H-42), 0.87 (d, 3H, J = 6.8, H-32), 0.84 (d, 3H, J = 6.8, H-43, 0.81 (d, 3H, J = 6.8, yNMeVal); 13C NMR (90 MHz, CDCls) ó 177.87 (s), 171.38 (s), 170.45 (s), 170.26 (s), 169.89 (s), 169.74 (s, 2 lines), 168.58 (s), 153.91 (d), 125.43 (d), 72.14 (d), 68.25 (d), 59.07 (d), 58.14 (d, 2 lines), 53.81 (d), 52.85 (d), 51.88 (d), 41.89 (t), 37.09 (t), 35.83 (t), 34.43 (t), 33.78 (t), 30.76 (d), 30.40 (q), 30.33 (q), 29.14 (t), 27.32 (d), 24.82 (d), 23.36 (q), 22.88, (q), 21.57 (q), 20.96 (q), 20.94 (q), 19.56 (q), 18.81 (q), 18.48 (q), 18.24 (q), 17.45 (q), 17.33 (q), 14.10 (q). 10-Ketomicrocolin A (4).…”

“…A solution of 2 (4.8 mg) in ethanol (1.0 mL) was added, and the mixture was stirred under hydrogen for 24 h. The reaction mixture was filtered and the catalyst washed with 20 mL of ethanol followed by 10 mL of CH2CI2. The original filtrate and washings were combined and evaporated to give 4.0 mg of pure (by NMR) 4 (85%): HRLSIMS (MH+) caled for CggHesNsOs 734.507, found 734.499, 8 mmu; NMR (500 MHz, CDCls), ó 6.94 (d, 1H, J = 8.9, N ), 5.41 (dd, 1H, J = 5.3, 8.7, aPro), 5.25 (dd, 1H, J = 10.5, 5.8, oNMeLeu), 5.23 (dd, 1H, J = 6.3, 3.4, /SThr), 5.02 (d, 1H, J = 11.3, aNMeVal), 4.96 (dd, 1H, J = 8.9, 3.7, aThr), 4.43 (m, 1H, H-4), 3.77 (ddd, 1H, J = 16.5, 10.0, 6.8, ó Pro), 3.68 (ddd, 1H, J = 16.5,10.0, 7.1, óPro), 3.10 (s, 3H, NMeVal), 2.95 (s, 3H, NMeLeu), 2.84 (m, 1H, H-36), 2.74 (ddd, 1H, J = 17.6, 11.0, 9.2, H-2), 2.46 (ddd, 1H, J = 17.6, 8.9, 2.6, H-2), 2.37 (ddd, 1H, J = 13.9, 12.6, 7.1, /SPro), 2.26 (m, 1H, /SNMeVal), 2.19 (m, 1H, H-3), 1.99 (bm, 2H, yPro), 1.99 (s, 3H, OAcThr), 1.87 (m, 1H, H-37), 1.84 (m, 1H, /SPro), 1.71 (ddd, 1H, J = 14.6, 10. H-39), 1.25 (bm, 4H, H-40, 41)), 1.18 (m, 1H, H-39), 1.15 (d, 3H, J = 6.3, yThr), 1.12 (d, 3H, J = 6.8, H-44), 0.94 (d, 3H, J = 6.6, yNMeVal), 0.87 (d, 3H, J = 6.6, ÓNMeLeu), 1.09 (m, 1H, H-37), 0.99 (d, 3H, J = 6.6, ÓNMeLeu)), 0.88 (t, 3H, J = 6.8, H-42), 0.84 (d, 3H, J = 6.8, yNMeVal), 0.80 (d, 3H, J = 6.6, H-43); 13C NMR (125 MHz, CDC13) ó 177.84 (s), 175.17 (s), 172.92 (s), 171.24 (s), 169.67 (s, 2 lines), 168.23 (s), 68.80 (d), 60.49 (d), 59.28 (d), 53.88 (d), 53.31 (d), 51.98 (d), 47.83 (d), 41.91 (t), 37.06 (t), 35.97 (t), 33.79 (d), 31.93 (t), 30.76 (d), 30.52 (q), 30.35 (q), 29.12 (t), 29.05 (t), 27.29 (d), 25.32 (d), 24.86 (d), 24.52 (t), 23.29 (q), 22.88 (t), 21.62 (q), 20.95 (q), 19.58 (q), 19.30 (q), 18.87 (q), 18.38 (q), 18.17 (q), 17.13 (q), 14.07 (q).…”

“…2.4-Dimethyloctanoyl-NMeLeu-Thr-NMeVal-Hyp-OMe (8) (0.3 mg): eluted with k' = 1.8; HRLSIMS (MH+) caled for C33H60N4O8 641.449, found 641.437, 12 mmu; NMR (500 MHz, CDCls) ó 6.94 (d, 1H, J = 9.1, N ), 5.20 (t, 1H, J = 8.0, aLeu), 4.95 (d, 1H, J = 11.2, aVal), 4.72 (brd, 1H, J =7.7, aThr, or aHyp), 4.46 (dd, 1H, J = 2.0, 10.2, aThr or aHyp), 4.40 (m, 1H, yHyp), 4.04 (dq, 1H, J = 2.4, 6.5, /?Thr), 3.85 (m, 2H, ÓHyp), 3.78 (s, 3H), 3.09 (s, 3H), 2.95 (s, 3H), 2.81 (m, 1H), 2.30 (m, 2H, ^Val and ySHyp), 2.07 (brd, 1H, J = 13.9, ,3Hyp), 1.83 (ddd, 1H, J = 4.7, 9.4,13.6), 1.65 (dt, 1H, J = 1.6, 7.6), 1.2-1.45 (m), 1.10 (d, 3H, J = 6.5), 1.02 (d, 3H, J = 6.4), 1.00 (d, 3H, J = 6.1), 0.93 (d, 3H, J = 6.8), 0.86 (d, 3H, J = 6.4), 0.86 (t, 3H, J = 6.8), 0.82 (d, 3H, J = 6.4), 0.81 (d, 3H, J = 6.4).…”

“…37, No. 19 3185 NMR (500 MHz, CDC13) ó 6.87 (brs, 1H, Thr-ß ), 5.25 (dq, 1H, J = 6.4,9.0, ¿3Thr), 4.70 (dd, 1H, J = 6.3,8.5, aLeu), 3.87 (dd, 1H, J = 3.0, 9.0, aThr), 3.59 (d, 1H, J = 5.7, aVal), 3.07 (s, 3H, NMe-Leu), 2.98 (s, 3H, ß-Val), 2.81 (m, 1H), 2.23 (m, 1H, jSVal), 1.6-1.9 (m, ySLeu), 1.49 (m, 1H, yLeu), 1.39 (d, 3H, J = 6.4, yThr (Me)), 1.2-1.3 (m), 1.12 (d, 6H, J = 7.0, dimethyloctanoyl-Me and Val-Me), 1.06 (d, 3H, J = 6.8, Val-Me), 0.95 (d, 3H, J = 6.6, Leu-Me), 0.90 (d, 3H, J = 6.5, Leu-Me), 0.85 (d, 3H, J = 6.6, dimethyloctanoyl-Me), 0.83 (t, 3H, J = 6.5, dimethyloctanoyl-Me), key NOESY correlations: H/9Thr/H/S,HyMeVal; 13C NMR (125 MHz, CDCls) ó 178.5 (dimethyloctanoyl C=0), 171.6 (Leu C=0), 166.2 (Val C=0), 163.2 (Thr C=Q), 72.6 (jSThr), 68.4 (aVal), 59.7 (aThr), 56.6 (aLeu), 41.7 (t, C-3, dimethyloctanoic group), 37.8 (/7Leu), 37.1 (t, C-5, dimethyloctanoic group), 35.6 (NMe-Val), 33.9 (d, C-2, dimethyloctanoic group), 32.9 (NAfe-Leu), 32.7 (/3Val), 30.7 (d, C-4, dimethyloctanoic group), 29.1 (t, C-6, dimethyloctanoic group), 25.2 (yLeu), 23.0 (t and q, C-7, dimethyloctanoic group and Leu-Me), 21.8 (Leu-Me), 19.9 (Val-Me), 19.7 (dimethyloctanoyl-Me), 19.0 (Val-Me), 17.8 (Thr-Me), 17.6 (dimethyloctanoyl-Me), 14.1 (dimethyloctanoyl-Me).…”

“…The limited amounts of pure natural product on hand prompted us to begin by preparing a few simple derivatives (Chart 1) to test the role of oxygen functionality on the proline ring. Microcolin A (1) was acetylated by treatment with acetic anhydride in pyridine at room temperature to give the corresponding C-10 acetate (3) in good yield.…”