Claims
- 1. The antitumor antibiotic BBM-1675D which in substantially pure form:
- (a) appears as an amorphous solid;
- (b) is soluble in methanol, ethanol, acetone and tetrahydrofuran, and slightly soluble in chloroform;
- (c) exhibits in silica gel thin-layer chromatography an R.sub.f value of 0.22 with the solvent system chloroform:methanol (5:0.5, v/v) and exhibits in reverse phase silica gel thin layer chromatography an R.sub.f value of 0.37 with the solvent system methanol:water (70:30, v/v);
- (d) has an apparent molecular weight of 695 as determined by high resolution FAB mass spectroscopy;
- (e) has an ultraviolet absorption spectrum in methanol solution substantially as shown in FIG. 2 exhibiting ultraviolet absorption maxima and absorptivities at 214 nm (a=27,000), 274 nm (a=12,800), and 325 nm (a=5,400) with no significant change upon addition of acid or base;
- (f) has an infrared absorption spectrum (KBr, film) substantially as shown in FIG. 4 exhibiting principal absorption peaks at
- 735, 755, 910, 960, 1000, 1020, 1085, 1150, 1195, 1250, 1310, 1335, 1365, 1385, 1445, 1510, 1685, 1720, 1735, 2880, 2930, 2960, and 3400 reciprocal centimeters;
- (g) has a low resolution mass spectrum substantially as shown in FIG. 6 exhibiting a molecular ion [M+H].sup.+ of 696;
- (h) has a 360 MHz proton magnetic resonance spectrum in CDCl.sub.3 +10% CD.sub.3 OD substantially as shown in FIG. 8 exhibiting signals at 6.43 (1H, dd, J=4.4, 10.3); 6.13 (1H, s); 5.81 (1H, d, J=8.8); 5.70 (1H, d, J=8.8); 5.48 (1H, 6 brs); 4.48 (1H, d, J=8.1); 4.02 (1H, d, J=2.0); 3.95-3.80 (solvent background); 3.77 (1H, t, J=9.0); 3.70-3.40 (11H, brm); 3.35 (1H, m); 3.28 (3H, s); 3.22 (3H, brs); 2.66-2.55 (2H, m); 2.38 (3H, s); 2.23-2.12 (2H, m); 1.42 (1H, brdt); 1.22 (3H, d, J=5.9); 0.94 (3H, d, J=6.6); and 0.87 (3H, d, J=5.9) parts per million downfield from tetramethylsilane;
- (i) has a 90.6 MHz carbon-13 magnetic resonance spectrum in CDCl.sub.3 +10% CD.sub.30 OD substantially as shown in FIG. 10 (FIG. 10A+10B) exhibiting signals at 17.5, 21.6, 22.2, 23.0, 33.4, 39.2, 46.4, 52.3, 55.8, 62.1, 67.8, 69.8, 70.1, 71.3, 75.8, 77.1, 78.1, 82.4, 83.3, 88.2, 97.4, 99.6, 122.6, 124.8, 130.1, 130.8, 134.3, 148.7, and 192.8 parts per million downfield from tetramethylsilane.
- 2. A pharmaceutical composition comprising an effective antimicrobial amount of BBM-1675D in combination with a pharmaceutical carrier or diluent.
- 3. A pharmaceutical composition comprising an effective tumor-inhibiting amount of BBM-1675D in combination with a pharmaceutical carrier or diluent.
- 4. A method for therapeutically treating an animal host affected by a microbial infection, which comprises administering to said host an effective antimicrobial dose of BBM-1675D.
CROSS-REFERENCE TO RELATED APPLICATION
This application is a divisional of our prior, co-pending application Ser. No. 770,335, filed Aug. 27, 1985, now abandoned.
1. Field of the Invention
This invention relates to new antitumor antibiotic substances and to their production and isolation. 2. Disclosure Statement
The antitumor compounds of the present invention have not yet been identified in terms of structure. In view of their unique physical, chemical and biological properties, however, applicant believes that the BBM-1675C and BBM-1675D antibiotics are novel substances.
United Kingdom Patent Application No. 2,141,425, published Dec. 19, 1984, discloses fermentation of Actinomadura verrucosospora strain H964-92 (ATCC 39334) or Actinomadura verrucosospora strain A1327Y (ATCC 39638) to produce a new antitumor antibiotic complex designated as BBM-1675. Two major bioactive components of the BBM-1675 complex described therein were designated as BBM-1675A.sub.1 and BBM-1675A.sub.2. The structures of the BBM-1675A.sub.1 and BBM-1675A.sub.2 antibiotics, also known as esperamicin A.sub.1 and esperamicin A.sub.2, respectively, have not yet been elucidated, but both components exhibit excellent antimicrobial and antitumor activity.
U.S. Pat. No. 4,530,835, issued July 23, 1985 to Bunge et al., discloses fermentation of an unidentified Actinomycete isolate WP-444 (ATCC 39363) to produce antitumor antibiotics designated CL-1577A and CL-1577B. The structures of the CL-1577 antibiotics have not yet been elucidated, but the characterizing properties given for the antibiotics indicate that CL-1577A and CL-1577B are similar in structure to the BBM-1675 antibiotics, and especially BBM-1675A.sub.1 and A.sub.2 mentioned above in United Kingdom Patent Application No. 2,141,425.
There is disclosed by R. H. Bunge et al., in J. Antibiotics, 37(12), 1566-1571 (1984) the fermentation of Actinomadura sp. (ATCC 39363) to produce a bioactive complex from which two major components, PD 114,759 and PD 115,028, were isolated. In J. Chem. Soc. Chem. Commun., 919-920 (1985), J. H. Wilton et al. described the partial structural elucidation of the antibiotics PD 114,759 and PD 115,028. The production, isolation and characterization of the PD 114,759 and PD 115,028 antibiotics appear to be identical to the above-mentioned CL-1577A and CL-1577B antibiotics, respectively.
European Patent Application No. 95,154, published Nov. 30, 1983, discloses fermentation of Actinomadura pulveraceus sp. nov. No. 6049 (ATCC 39100) to produce antitumor antibiotics designated WS 6049-A and WS 6049-B. The structures of the WS 6049 antibiotics have not yet been elucidated, but the characterizing properties given for the antibiotics indicate that WS 6049-A and WS 6049-B are related in structure to the BBM-1675 antibiotics of United Kingdom Patent Application No. 2,141,425 and to the CL-1577 antibiotics of U.S. Pat. No. 4,530,835. Spectral data show, however, that neither WS 6049-A nor WS 6049-B is identical to any of the BBM-1675 components. Moreover, the producing organism described in European Patent Application No. 95,154 may be clearly differentiated from Actinomadura verrucosospora employed in United Kingdom Patent Application No. 2,141,425 in the color of its aerial mycelium on ISP Medium Nos. 2, 3 and 4, in its positive milk peptonization and in its positive utilization of D-fructose, D-mannitol, trehalose and cellulose.
There is provided by the present invention new antitumor antibiotic substances designated herein as BBM-1675C and BBM-1675D, also known as BMY-27305 and BMY-27307, respectively, said substances being produced by selective chemical hydrolysis of the bioactive components BBM-1675A.sub.1 (esperamicin Al) or BBM-1675A.sub.2 (esperamicin A.sub.2), which are themselves produced by cultivating a BBM-1675-producing strain of Actinomadura verrucosospora. The bioactive substances BBM-1675C and BBM-1675D may be separated and purified by conventional chromatographic procedures, and both substances exhibit excellent antimicrobial and antitumor activity.
US Referenced Citations (3)
| Number |
Name |
Date |
Kind |
|
4594248 |
Wilton et al. |
Jun 1986 |
|
|
4661353 |
Wilton et al. |
Apr 1987 |
|
|
4675187 |
Konishi et al. |
Jun 1987 |
|
Divisions (1)
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Number |
Date |
Country |
| Parent |
770335 |
Aug 1985 |
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Patent Grant
4921700
