Isolation and structural elucidation of the cytostatic linear and cyclo-depsipeptides dolastatin 16, dolastatin 17, and dolastatin 18
AssigneeArizona Board of Regents
InventorsGeorge R. Pettit, Jun-ping Xu
Life of this patent
Estimating the term…
Abstract
Cytostatic linear and cyclo-depsipeptides, “Dolastatin 16”, “Dolastatin 18”, and “Dolastatin 17”, are disclosed which are obtained from Indian Ocean shelless mollusk Dolabella auricularia. Methods of using the substances to inhibit malignant cell growth associated with neoplastic diseases in animals and humans are also disclosed, as well as pharmaceutical preparations containing Dolastatin 16, Dolastatin 17, and Dolastatin 18.
Claims10
An isolated and purified substance which inhibits neoplastic cell growth denominated Dolastatin 16 and having the following characteristics:
- Physical Data for Dolastatin 16
- IR (cm−1), KBr:
- 3300, 1600 and 1540;
- UV (nm), MeOH:
- 250, and 240-210;
- MS, HRFAB:
- 871.525713 [M+H]+;
- and
- NMR, 500 MHZ, CLCl3;
- The 1H and 13C- MNR Spectral Data Assignments of Dolastatin 16 (in CDCl3) 13C 1H J HMBC No. ppm ppm (Hz) (1H to 13C) Pro1CO 172.24 s α 61.28 d 4.62 dd (7.2, 2.0) CO, β, γ, δ β 30.70 t 2.18 m 2.26 m CO, α, γ, γ 24.78 t 1.99 m 2.08 m β δ 47.55 t 3.45 m γ 3.91 m α, β, γ Dpv2CO 171.31 s α 50.59 d 4.95 d (7.2) Pro1CO, CO, β, γ, γ′ β 40.90 d 1.75 m γ γ 40.95 t 2.39 m α, β, γ, 1, {fraction (2/6)} 2.52 d (7.6) α, β, γ, 1, {fraction (2/6)} γ′ 15.13 q 0.80 d (5.2) α, β, γ 1 140.60 s {fraction (2/6)} 129.66 d 7.35 d (6.0) γ, 4 ¾ 128.33 d 7.27 d (6.0) 1 5 126.15 d 7.17 d (6.0, 6.0) {fraction (2/6)} NH 6.73 d (7.2) Pro1CO, CO Pro3CO 171.01 s α 58.84 d 4.55 d (6.0) CO, β, γ, δ β 25.49 t 1.51 m CO γ 25.01 t 1.73 m α 1.84 m δ 45.89 t 2.52 m β 2.83 m γ Dml4CO 174.64 s α 38.67 d 2.85 m CO, β′ β 56.35 d 3.66 m Pro3, CO, CO, α, γ β′ 14.89 q 1.01 d (5.6) CO, α, β γ 32.31 d 1.53 m δ 19.73 q 0.87 d (5.6) β, γ, δ′ δ′ 20.29 q 0.88 d (5.6) β, γ, δ NH 7.68 d (8.0) Pro3CO Lac5CO 169.02 s α 66.64 d 5.18 q (7.0) Dml4CO, CO, β β 17.02 q 1.44 d (7.0) CO, α Pro6CO 171.01 s α 57.82 d 4.45 d (6.4) CO, β, γ, δ β 30.82 t 2.20 m CO 2.30 m CO, δ γ 21.77 t 1.95 m 2.07 m β δ 46.43 t 3.42 m γ 3.67 m Hiv7CO 169.57 s α 76.37 d 5.42 d (2.8) Pro6CO, CO, β, γ, γ′ β 28.29 d 2.18 m γ, γ′ γ 16.08 q 1.04 d (7.0) α, β, γ′ γ′ 19.73 q 1.06 d (7.2) α, β, γ MeVal8 CO 169.30 s α 59.46 d 5.16 (8.8) CO, β, γ, γ′, CH3N β 25.63 d 2.36 m α, γ, γ′ γ 19.73 q 0.91 d (5.6) α, β, γ′ γ′ 17.75 q 0.83 d (5.2) α, β, γ CH3N 29.26 q 3.09 s Hiv7CO, CO
An isolated and purified substance which inhibits neoplastic cell growth denominated Dolastatin 17 and having the following characteristics:
- Physical Data for Dolastatin 17
- IR (cm−1), KBr:
- 3350,2900,2116,1740,1643, and 1520;
- MS, HRFAB:
- 774.500914 [M+H]+;
- and
- NMR, 500 MHZ, CDCl3;
- The 1H- and 13C-NMR Spectral Data Assignments of Dolastatin 17 (in CDCl3) 13C 1H J HMBC No. ppm ppm (Hz) (1H to 13C) Pro1CO 171.81 s α 57.27 d 5.12 dd (9.0, 5.0) CO, β, γ β 29.68 t 1.80 m CO 2.38 m CO γ 24.81 t 2.00 m α, β, δ δ 47.06 t 3.55 dd (9, 7.5) α, β 3.91 m α, β MeVal2 CO 171.27 s α 64.51 d 4.23 d (8.5) Pro1CO, CO, β, γ, γ′, CH3N β 29.47 d 2.35 m α, γ, γ′ γ 20.43 q 1.20 d (6.5) α, β, γ′ γ′ 21.40 q 1.07 d (7.0) α, β, γ CH3N 30.49 q 2.92 s Pro1CO, CO, α Hiv3CO 169.54 α 76.60 d 5.21 d (3.0) MeVal2CO, CO β, γ, γ′ β 28.92 d 2.14 m γ, γ′ γ 20.07 q 1.10 d (7.0) α, β, γ′ γ′ 16.31 q 0.99 d (7.0) α, β, γ MeVal4 CO 168.98 s α 62.15 d 4.68 d (10) Hiv3CO, CO, β, γ, γ′ β 25.58 d 2.30 m α, γ, γ′ γ 17.91 q 0.78 d (6.5) α, β, γ′ γ′ 19.83 q 0.95 d (7.0) α, β, γ CH3N 29.81 q 2.92 s Hiv3CO, CO Lac5CO 172.08 α 51.64 d 4.60 m McVal4CO, CO, β, γ β 38.39 t 1.68 m γ, δ, ι′ γ 24.65 d 1.61 in β, δ, δ′ δ 23.59 q 0.86 q (7.0) β, γ, δ′ δ′ 20.87 q 0.84 q (7.5) β, γ, δ NH 7.25 d (7.8) McVal4CO, α Doy6CO 170.17 s α 39.51 t 2.27 m CO, β, γ 2.79 dd (16.6) CO, β, γ β 45.32 d 4.32 m γ 33.99 t 1.52 m α, β, ε 1.64 m δ 24.48 t 1.52 m ε 18.18 t 2.16 m γ, ζ ζ 68.43 s ξ 84.20 d 1.91 s ε NH 6.10 d (7.8) Leu5CO, α, β Hiv7CO 167.20 s α 76.17 d 5.03 d (3.0) Doy6CO, CO, β, γ, γ′ β 29.47 d 2.35 m γ, γ′ γ 16.21 q 0.98 d (7.0) α, β, γ′ γ′ 20.02 q 1.02 d (7.0) α, β, γ
An isolated and purified substance which inhibits neoplastic cell growth denominated Dolastatin 18 and having the following characteristics:
- Physical Data for Dolastatin 18
- MS, HRFAB;
- 619 [M+H]+;
- and
- NMR, 500 MHZ, CDCl3:
- The 1H- and 13 C- NMR Spectral Data Assignments of Dolastatin 18 (in CDCl3) 13C 1H J HMBC No. ppm ppm (Hz) (1H to 13 C) 2 174.13 s 4 139.41 d 7.50 d 7.5 5 119.96 d 7.38 d 7.5 6 52.40 d 5.63 m 2 6a 40.87 t 3.47 dd 8.0, 19 2, 6, 9b, 9c 3.37 dd 7.5, 19 6b 135.80 s 6c 129.33 d 7.23 m 6a 6d 128.73 d 7.26 m 6e 127.23 d 7.24 m 7 7.81 d 3.5 8 169.86 s 9 57.46 d 5.10 dd 6.5, 7.0 8, 10 9a 33.53 t 3.30 m 9 2.92 m 9 9b 136.41 s 9c 128.66 d 7.28 m 9a 9d 128.50 d 7.22 m 9c 126.75 d 7.18 m 10 31.36 q 2.89 s 9, 11 11 174.04 s 12 48.42 d 4.55 m 11, 12a 12a 41.11 t 1.05 m 0.88 m 12b 24.39 d 1.07 m 17 12c 21.97 q 0.73 d 7.5 12a, 12b, 12d 12d 22.97 q 0.69 d 8.0 12a, 12b, 12c 13 6.29 d 8.0 14 14 172.80 s 15a 55.47 s 15b 22.48 q 1.30 s 14, 15 15c 22.55 q 1.32 s 15, 16 16 210.20 s 17 40.06 t 2.42 dt 4.0, 9.0 16, 18, 19 18 17.10 t 1.52 m 16 19 13.59 q 0.83 t 8.0
A method of inhibiting the growth of neoplastic cells in a host afflicted therewith comprising administering to said host an amount effective to inhibit the growth of said cells of an active ingredient selected from the group consisting of dolastatin 16, dolastatin 17, dolastatin 18 or a pharmaceutically active derivative thereof and a pharmaceutically acceptable carrier.
Dependencies are inferred from the claim text.