Kahalalide F and compositions and uses thereof

Abstract

KalahideKahalalide 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

1. A substially  Substantially pure compound  Kahalalide F compound, said compound hag  having a molecular formula of C 75 H 124 N 14 O 16 , and consisting of five valines, two isoleucines, two threonines, ornithine, dehydroaminobutynic  dehydroaminobutyric acid, proline, phenylalanine and 5-methylhexanoic acid; said compound further exhibiting the following physical and chemical properties: [α] D -8° (c 4.32, MeOH);  1 H 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 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), 3.23 (3, dd, J=13.7, 7.2 Hz), 3.00 (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  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); 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  NH on 2, d, J=5.7), 5.07 (3, dq, J=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  t , 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 Hz), 4.21 (3, dq, J=6.3, 3.6 Hz), 1.12 (4, d, J=6.6 Hz); Val-5 4.32 (2, m), 7.85 (HN  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); 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 7.2 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);   13 C 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  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 (   6   ); 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  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): λ max  204 (89,630) nm. 
     
     
       2. The compound  Kahalalide F compound of  claim 1 , which further has the folowing  following non-stereospecific structure: 
                 
 
     
     
       3. A pharmaceutical compostion  composition comprising a pharmaceutical carrier or diluent and the  substantially pure compound  Kahalalide F, said compoumd  compound having a molecular formula of C 75 H 124 N 14 O 16 , and conng  consisting of five valines, two isoleucines, two threonines, ornithine, dehydroamiobutyric  dehydroaminobutyric acid, proline, phenylalanine and 5-methylhexoic   5 - methylhexanoic  acid; said compound further exhibiting the following physical and chemical properties:
 [α] D -8° (c 4.32, MEOH);  1 H 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 8.9 Hz), 1.77 (3, m), 0.95 (4, m), 0.95 (5, ma  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), 3.23 (3, dd, J=13.7, 7.2 Hz), 3.00 (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); Ileu- 1  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 (NH on 2, d, J=5.7), 5.07 (3, dq, J=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  t, 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, J=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); 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);   13 C 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  56.27 (2), 36.79 (3), 138.23 (4), 129.86 (5), 128.77 (6), 126.98 (7); Val-2 172.94 (1), 58.27 (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 (   6   ); 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  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): λ max  204 (89,630) nm.  
 
     
     
       4. The pharmaceutical composition of  claim 3 , wherein the compound  Kahalalide F compound further has the folowing non-streospecific  following non- stereospecific  structure 
                 
 
     
     
       5. A method of treating fungal infections in mammals comprising administering to a patient in need of such treatment, an amount of the substantially puxe compound  pure Kahalalide F compound or a pharmaceutically acceptable salt thereof, sufficient to slow or stop the growth of the fungal infection; said compound having a molecula  molecular formula of C 75 H 124 N 14 O 16 , and consisting of five valines, two isoleucines, two theonines  threonines, ornithine, dehydroaminobutiric  dehydroaminobutyric acid, proline, phenylalanie  phenylalanine and 5-methylhexanoic acid; said compound further exhibiting the folowing  following physical and chemical properties:
 [α] D -8° (c 4.32, MEOH);  1 H 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 8.9 Hz), 1.77 (3, m), 0.95 (4, m), 0.95 (5, ma  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), 3.23 (3, dd, J=13.7, 7.2 Hz), 3.00 (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  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 (NH on 2, d, J=5.7), 5.07 (3, dq, J=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  t, 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, J=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);   13 C 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  56.27 (2), 36.79 (3), 138.23 (4), 129.86 (5), 128.77 (6), 126.98 (7); Val-2 172.94 (1), 58.27 (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 (   6   ); 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  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): λ max  204 (89,630) nm.  
 
     
     
       6. The method of treatment of  claim 5 , wherein compound Kahalalide F has the following non-stereospecific structure: 
                 
 
     
     
       7. The method of  claim 5 , wherein the fungal infection is caused by Aspergillus oryzae. 
     
     
       8. The method of  claim 5 , wherein the fungal infection is caused by Penicillium notatum. 
     
     
       9. The method of  claim 5 , wherein the fungal infection is caused by Trichophyton mentagrophy. 
     
     
       10. The method of  claim 5 , wherein the fungal infection is caused by Candida albicans.