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US 6,274,551 B1Granted
Cytotoxic and antiviral compound
AssigneePharmaMar, S.A.
InventorsPaul J Scheuer, Mark T Hamann, Dolores G. Gravalos
Life of this patent
Estimating the term…
Abstract
Kalahide F, of formula I below, may be isolated from a sacoglossan. The compound may be used in the manufacture of pharmaceutical compositions or in the treatment of tumors or viral conditions.
Claims10
A substially pure compound Kahalalide F, said compound hag a molecular formula of C75H124N14O16, and consisting of five valines, two isoleucines, two threonines, ornithine, dehydroaminobutynic acid, proline, phenylalanine and 5-methylhexanoic acid;
- said compound further exhibiting the following physical and chemical properties:
- [α]D −8° (c 4.32, MeOH;
- 1H NMR (500 MHz, TFA/DMF);
- amino acid unit, δ (carbon position, mult, J):
- Val-1 4.16 (2, t, J=9.0 Hz), 7.11 (NH on 2, d, J=8,9 Hz), 1.77 (3, m), 0.95 (4, m), 0.95(5, m), Dhb 9.20 (NH on 2, s), 6.48 (3, q, J=6.9 Hz), 1.43 (4, d, J=6.6 Hz);
- Phe 4.68 (2, q, J=6.6 Hz), 8.62 (NH on 2, d, J=6.6 Hz), 3.2 (3, dd, J=13.7, 7.2 Hz), 3.0 (3, dd, J=13.7, 9.0 Hz), 7.32 (5, d, J=7.2 Hz), 7.28 (6, t J=7.5 Hz), 7.21 (7, t, J=7.2 Hz);
- Vol-2 4.36 (2, m), 7.82 (NH on 2, d, J=6.6 Hz), 2.12 (3, m), 0.85 (4, m), 0.77 (5, d, J=6.6 Hz);
- Ileu-1 4.53 (2, m), 8.38 (NH on 2, d, J=9.6 Hz), 1.98 (3, m), 0.92 (4, d, J=6.6 Hz), 1.40 (5, m), 1.13 (5, m), 0.88 (6, t, J=7.2 Hz);
- Thr-1 4.63 (2, t, J=9.3 Hz), 8.12 (HN on 2, d, J=5.7), 5.07 (3, dq, 9.6, 6.0 Hz), 1.18 (4, d, J=6.3 Hz);
- Ilue-2 4.52 (2, m), 7.72 NH on 2, d, J=8.4 Hz), 1.88 (3, m), 0.88 (4, d, J-6.3 Hz), 1.40 (5, m) 1.13 (5, m), 0.88 (6d, J=7.2 Hz) Orn 4.48 (2, m), 7.92 (NH on 2, d, J=7.8 Hz), 1.76 (3, m), 1.83 (4, m), 3.10 (5, p, J=5.1 Hz);
- Pro 4.42 (2, m), 2.12 (3, m), 1.97 (3, m), 2.02 (4, m), 1.88 (4, m), 3.75 (5, m), 3.68 (5, m);
- Val-3 4.41 (2, m), 7.90 (NH on 2, d, J=7.2 Hz), 2.12 (3, m), 0.95 (4, m), 0.85 (5, m);
- Val-4 4.34 (2, m), 7.68 (NH on 2, d, J=8.1 Hz), 2.17 (3, m), 0.95 (4, m), 0.90 (5, m);
- Thr-2 4.46 (2, m), 7.77 (NH on 2, d, J=8.1Hz), 4.21 (3, dq, 6.3, 3.6 Hz), 1.12 (4, d, J=6.6 Hz);
- Val-5 4.32 (2, m), 7.85, (HN on 2, d, J=8.1 Hz), 7.82 (NH on (second conformation), d, J=8.1 Hz), 2.14 (3, m), 0.95(4, m), 0.90 (5, m);
- 5-MeHex 2.26 (2, m), 1.60 (3, m), 1.20 (4, m), 1.55 (5, m), 0.87 (6, d, J=7.2 Hz), 0.87 (7, d, J=72 Hz);
- 5-MeHex 2.29 (2, m), 1.65 (3, m), 1.40 (3, m), 1.13 (4, m),1.35 (5, m), 0.90 (6, m), 0.90 (7, m);
- 13C NMR (125 MHz TFA/DMF):
- amino acid unit, δ (carbon position);
- Val-1 170.40 (1), 60.31 (2), 30.75 (3), 19.58 (4), 18.76 (5);
- Dhb 164.54 (1), 130.30 (2), 131.26 (3), 126.6 (4);
- Phe 171.31 (1), 56.27 (2), 36.79 (3), 138.23 (4), 129.86 (5), 128.77 (6), 126.98 (7);
- Val-2 172.94 (1), 58.57 (2), 32.38 (3), 18.92 (4), 17.60 (5);Ileu-1 171.87 (1), 57.48 (2), 38.78 (3), 14.56 (4), 26.78 (5), 11.67;
- Thr-1 169.68 (1), 57.37 (2), 71.05 (3), 17.34 (4);
- Ileu-2 171.92 (1), 57.29 (2), 38.01 (3), 14.78 (4), 26.55 (5), 11.63 (6);
- Orn 172.01 (1), 52.87 (2), 29.63 (3), 24.39 (4), 40.05 (5);
- Pro 172.55 (1), 60.23 (2), 29.58 (3), 25.38 (4), 48.03 (5);
- Val-3 171.28 (1), 57.57 (2), 30.54 (3), 19.61 (4), 18.80 (5);
- Val-4 171.83 (1), 59.10 (2), 31.26 (3), 19.45 (4), 18.08 (5);
- thr-2 170.97 (1), 58.89 (2), 67.36 (3), 19.66 (4);
- Val-5 172.67 (1), 59.64 (2), 30.66 (3), 19.61 (4), 18.43 (5);
- 5-MeHex 173.83 (1), 36.28 (2), 23.99 (3), 38.96 (4), 28.10 (5), 22.54 (6), 22.50 (7);
- 5-MeHex (second conformation) 174.08 (1), 33.86 (2), 32.84 (3), 29.75 (4), 34.54 (5), 19.51 (6), 11.20 (7);
- IR neat (NaCl):
- 3287 (s, br), 2964 (s, br), 1646 (s), 1528 (s), 1464 (s), 1388 (m), 1228 (m), cm−1;
- mass spectrum HRFAB m/z (fragment, %) 1477.9408 (M++1, 85);
- UV (MeOH):
- λmax 204 (89,630) nm.
35 more elements
A pharmaceutical compostion comprising a pharmaceutical carrier or diluent and the substantially pure compound Kahalalide F, said compoumd having a molecular formula of C75H124N14O16, and conng of five valines, two isoleucines, two threonines, ornithine, dehydroamiobutyric acid, proline, phenylalanine and 5-methylhexoic acid;
- said compound further exhibiting the following physical and chemical properties:
- [α]D −8° (c 4.32, MEOH;
- 1H NMR (500 MHz, TFA/DMF);
- amino acid unit, δ (carbon position, mult, J):
- Val-1 4.16 (2, t, J=9.0 Hz), 7.11 (NH on 2, d, J=8,9 Hz), 1.77 (3, m), 0.95 (4, m), 0.95 (5, ma);
- Dhb 9.20 (NH on 2, s), 6.48 (3, q, J=6.9 Hz), 1.43 (4, d, J=6.6 Hz,);
- Phe 4.68 (2, q, J=6.6 HZ), 8.62 (NH on 2, d, J=6.6 Hz), 3.2 (3, dd, J=13.7, 7.2 Hz), 3.0 (3, dd, J=13.7, 9.0 Hz), 7.32 (5, d, J=7.2 Hz), 7.28 (6, t J=7.5 Hz), 7.21 (7, t, J=7.2 Hz);
- Val-2 4.36 (2, m), 7.82 (NH on 2, d, J=6.6 Hz), 2.12 (3, m), 0.85 (4, m), 0.77 (5, d, J=6.6 Hz);
- Ilue-1 4.53 (2, m), 8.38 (NH on 2, d, J=9.6 Hz), 1.98 (3, m), 0.92 (4, d, J=6.6 Hz), 1.40 (5, m), 1.13 (5, m), 0.88 (6, t, J=7.2 Hz);
- Thr-1 4.63 (2, t, J=9.3 Hz), 8.12 (NH on 2, d, J=5.7), 5.07 (3, dq, 9.6, 6.0 Hz), 1.18 (4, d, J=6.3 Hz);
- Ileu-2 4.52 (2, m), 7.72 (NH on 2, d, J=8.4 Hz), 1.88 (3, m), 0.88 (4, d, J-6.3 Hz), 1.40 (5, m) 1.13 (5, m), 0.88 (6, d, J=7.2 Hz) Orn 4.48 (2, m), 7.92 (NH on 2, d, J=7.8 Hz), 1.76 (3, m), 1.83 (4, m), 3.10 (5, p, J=5.1 Hz);
- Pro 4.42 (2, m), 2.12 (3, m), 1.97 (3, m), 2.02 (4, m), 1.88 (4, m), 3.75 (5, m), 3.68 (5, m);
- Val-3 4.41 (2, m), 7.90 (NH on 2, d, J=7.2 Hz), 2.12 (3, m), 0.95 (4, m), 0.85 (5, m);
- Val-4 4.34 (2, m), 7.68 (NH on 2, d, J=8.1 Hz), 2.17 (3, m), 0.95 (4, m), 0.90 (5, m);
- Thr-2 4.46 (2, m), 7.77 (NH on 2, d, J=8.1), 4.21 (3, dq, 6.3, 3.6 Hz), 1.12 (4, d, J=6.6 Hz);
- Val-5 4.32 (2, m), 7.85, (NH on 2, d, J=8.1 Hz), 7.82 (NH on (second conformation), d, J=8.1 Hz), 2.14 (3, m), 0.95 (4, m), 0.90 (5, m);
- 5MeHex 2.26 (2, m), 1.60 (3, m), 1.20 (4, m), 1.55 (5, m), 0.87 (6, d, J=7.2 Hz), 0.87 (7, d, J=7.2 Hz);
- 5MeHex 2.29 (2, m), 1.65 (3, m), 1.40 (3, m) 1.13 (4, m), 1.35 (5, m), 0.90 (6, m), 0.90 (7, m);
- 13C NMR (125 MHz TFA/DMF):
- amino acid unit, δ (carbon position);
- Val-1 170.40 (1), 60.31 (2), 30.75 (3), 19.58 (4), 18.76 (5);
- Dhb 164.54 (1), 130.30 (2), 131.26 (3), 12.68 (4);
- Phe 171.31 (1), 56-27 (2), 36.79 (3), 138.23 (4), 129.86 (5), 128.77 (6), 126.98 (7);
- Val-2 172.94 (1), 58.57 (2), 32.38 (3), 18.92 (4), 17.60 (5);
- Ileu-1 171.87 (1), 57.48 (2), 38.78 (3), 14.56 (4), 26.78 (5), 11.67;
- Thr-1 169.68 (1), 57.37 (2), 71.05 (3), 17.34 (4);
- Ileu-2 171.92 (1), 57.29 (2), 38.01 (3), 14.78 (4), 26.55 (5), 11.63 (6);
- Orn 172.01 (1), 52.87 (2), 29.63 (3), 24.39 (4), 40.05(5);
- Pro 172.35 (1), 60.23 (2), 29.58 (3), 25.38 (4), 48.03 (5);
- Val-3 171.28 (1), 57.57 (2), 30.54 (3), 19.61 (4), 18.80 (5);
- Val-4 171.83 (1), 59.10 (2), 31.26 (3), 19.45 (4), 18.08 (5);
- Thr-2 170.97 (1), 58.89 (2), 67.36 (3), 19.66 (4);
- Val-5 172.67 (1), 59.64 (2), 30.66 (3), 19.61 (4), 18.43 (5);
- 5-MeHex 173.83 (1), 36.28 (2), 23.99 (3), 38.96 (4), 28.10 (5), 22.54 (6), 22.50 (7);
- 5-MeHex (second conformation) 174.08 (1), 33.86 (2), 32.84 (3), 29.75 (4), 34.54 (5), 19.51 (6), 11.20 (7);
- IR neat (NaCl):
- 3287 (s, br), 2964 (s, br), 1646 (s), 1528 (s), 1464 (s), 1388 (m), 1228 (m), cm−1;
- mass spectrum HRFAB m/z (fragment, %) 1477.9408 (M++1, 85);
- UV (MeOH):
- λmax 204 (89,630) nm.
37 more elements
A method of treating fungal infections in mammals comprising administering to patient in need of such treatment, an amount of the substantially puxe compound Kahalalide F or a pharmaceutically acceptable salt thereof, sufficient to slow or stop the growth of the fungal infection;
- said compound having a molecula formula of C75H124N14O16, and consisting of five valines, two isoleucines, two theonines, ornithine, dehydroaminobutiric acid, proline, phenylalanie and 5-methylhexanoic acid;
- said compound further exhibiting the folowing physical and chemical properties:
- [α]D −8° (c 4.32, MEOH;
- 1H NMR (500 MHz, TFA/DMF);
- amino acid unit, δ (carbon position, mult, J):
- Val-1 4.16 (2, t, J=9.0 Hz), 7.11 (NH on 2, d, J=8,9 Hz), 1.77 (3, m), 0.95 (4, m), 0.95 (5, ma);
- Dhb 9.20 (NH on 2, s), 6.48 (3, q, J=6.9 Hz), 1.43 (4, d, J=6.6 Hz,);
- Phe 4.68 (2, q, J=6.6 HZ), 8.62 (NH on 2, d, J=6.6 Hz), 3.2 (3, dd, J=13.7, 7.2 Hz), 3.0 (3, dd, J=13.7, 9.0 Hz), 7.32 (5, d, J=7.2 Hz), 7.28 (6, t J=7.5 Hz), 7.21 (7, t, J=7.2 Hz);
- Val-2 4.36 (2, m), 7.82 (NH on 2, d, J=6.6 Hz), 2.12 (3, m), 0.85 (4, m), 0.77 (5, d, J=6.6 Hz);
- Ilue-1 4.53 (2, m), 8.38 (NH on 2, d, J=9.6 Hz), 1.98 (3, m), 0.92 (4, d, J=6.6 Hz), 1.40 (5, m), 1.13 (5, m), 0.88 (6, t, J=7.2 Hz);
- Thr-1 4.63 (2, t, J=9.3 Hz), 8.12 (NH on 2, d, J=5.7), 5.07 (3, dq, 9.6, 6.0 Hz), 1.18 (4, d, J=6.3 Hz);
- Ileu-2 4.52 (2, m), 7.72 (NH on 2, d, J=8.4 Hz), 1.88 (3, m), 0.88 (4, d, J-6.3 Hz), 1.40 (5, m) 1.13 (5, m), 0.88 (6, d, J=7.2 Hz) Orn 4.48 (2, m), 7.92 (NH on 2, d, J=7.8 Hz), 1.76 (3, m), 1.83 (4, m), 3.10 (5, p, J=5.1 Hz);
- Pro 4.42 (2, m), 2.12 (3, m), 1.97 (3, m), 2.02 (4, m), 1.88 (4, m), 3.75 (5, m), 3.68 (5, m);
- Val-3 4.41 (2, m), 7.90 (NH on 2, d, J=7.2 Hz), 2.12 (3, m), 0.95 (4, m), 0.85 (5, m);
- Val-4 4.34 (2, m), 7.68 (NH on 2, d, J=8.1 Hz), 2.17 (3, m), 0.95 (4, m), 0.90 (5, m);
- Thr-2 4.46 (2, m), 7.77 (NH on 2, d, J=8.1), 4.21 (3, dq, 6.3, 3.6 Hz), 1.12 (4, d, J=6.6 Hz);
- Val-5 4.32 (2, m), 7.85, (NH on 2, d, J=8.1 Hz), 7.82 (NH on (second conformation), d, J=8.1 Hz), 2.14 (3, m), 0.95 (4, m), 0.90 (5, m);
- 5MeHex 2.26 (2, m), 1.60 (3, m), 1.20 (4, m), 1.55 (5, m), 0.87 (6, d, J=7.2 Hz), 0.87 (7, d, J=7.2 Hz);
- 5MeHex 2.29 (2, m), 1.65 (3, m), 1.40 (3, m) 1.13 (4, m), 1.35 (5, m), 0.90 (6, m), 0.90 (7, m);
- 13C NMR (125 MHz TFA/DMF):
- amino acid unit, 6 (carbon position);
- Val-1 170.40 (1), 60.31 (2), 30.75 (3), 19.58 (4), 18.76 (5);
- Dhb 164.54 (1), 130.30 (2), 131.26 (3), 12.68 (4);
- Phe 171.31 (1), 56-27 (2), 36.79 (3), 138.23 (4), 129.86 (5), 128.77 (6), 126.98 (7);
- Val-2 172.94 (1), 58.57 (2), 32.38 (3), 18.92 (4), 17.60 (5);
- Ileu-1 171.87 (1), 57.48 (2), 38.78 (3), 14.56 (4), 26.78 (5), 11.67;
- Thr-1 169.68 (1), 57.37 (2), 71.05 (3), 17.34 (4);
- Ileu-2 171.92 (1), 57.29 (2), 38.01 (3), 14.78 (4), 26.55 (5), 11.63 (6);
- Orn 172.01 (1), 52.87 (2), 29.63 (3), 24.39 (4), 40.05(5);
- Pro 172.35 (1), 60.23 (2), 29.58 (3), 25.38 (4), 48.03 (5);
- Val-3 171.28 (1), 57.57 (2), 30.54 (3), 19.61 (4), 18.80 (5);
- Val-4 171.83 (1), 59.10 (2), 31.26 (3), 19.45 (4), 18.08 (5);
- Thr-2 170.97 (1), 58.89 (2), 67.36 (3), 19.66 (4);
- Val-5 172.67 (1), 59.64 (2), 30.66 (3), 19.61 (4), 18.43 (5);
- 5-MeHex 173.83 (1), 36.28 (2), 23.99 (3), 38.96 (4), 28.10 (5), 22.54 (6), 22.50 (7);
- 5-MeHex (second conformation) 174.08 (1), 33.86 (2), 32.84 (3), 29.75 (4), 34.54 (5), 19.51 (6), 11.20 (7);
- IR neat (NaCl):
- 3287 (s, br), 2964 (s, br), 1646 (s), 1528 (s), 1464 (s), 1388 (m), 1228 (m), cm−1;
- mass spectrum HRFAB m/z (fragment, %) 1477.9408 (M++1, 85);
- UV (MeOH):
- λmax 204 (89,630) nm.
38 more elements
Dependencies are inferred from the claim text.