Saintopin derivatives

Details Saintopin derivatives Saintopin derivatives

1994-07-21

1996-04-23

Prior, Kimberly J.

Organic compounds -- part of the class 532-570 series

Organic compounds

Tetracyclo naphthacene configured ring system having at...

C07C 49423

Patent

active

055105017

DESCRIPTION:

BRIEF SUMMARY
This application is a 371 of PCT/JP93/01680.


TECHNICAL FIELD

The present invention relates to Saintopin derivatives which have antibacterial and anti-tumor activity and are useful as antibacterial and anti-tumor agents.


BACKGROUND ART

Heretofore, some compounds such as anthracycline have been reported as antibiotics having anthraquinone skeleton CRC Handbook of Antibiotic Compounds, 3, 61 (1981)!.
Further, UCT 1003 (Saintopin) having anti-tumor activity which is represented by the following formula A: ##STR2## has also been known Biochemistry, 30, 5838-5845 (1991); Japanese Published Unexamined Patent Application No. 200655/90!.


DISCLOSURE OF THE INVENTION

The present invention relates to Saintopin derivatives having antibacterial and anti-tumor activity which are represented by the following formula (I): ##STR3## wherein R.sup.1 is hydrogen and R.sup.2 is SO.sub.2 OH (hereinafter, the compound given by the definition is referred to as UCE 1022), or R.sup.1 is acetyl and R.sup.2 is hydrogen (hereinafter, the compound given by the definition is referred to as Saintopin E).
The compounds described above can be produced by culturing a microorganism belonging to the genus Paecilomyces.
The present invention is described in detail below.
The compound UCE 1022 has the following physicochemical properties. m/z; 417(M--H).sup.- alcohol): m/z (.epsilon.); 241 (22,000), 274 (27,500), 306 (16,100), 339 (9,800), 483 (12,300) ; 3360, 3210, 1625, 1600, 1400, 1330, 1265, 1235, 1045 ppm; 108.3, 109.2, 109.3, 111.4, 111.6, 114.8, 116.3, 121.9, 130.0, 137.5, 141.2, 154.3, 161.9, 166.4, 166.5, 166.6, 183.4, 190.8 ppm; 6.57(1H, d), 7.09(1H, d), 7.21(1H, d), 7.41(1H, d), 7.96 (1H, s) (UCT 1003 is sparingly soluble in water) 5715, produced by Merck & Co., Inc.) with a developing solvent composed of n-hexane:ethyl acetate:methanol:acetic acid (6:4:1:1, v/v) (The spot of UCE 1022 is detectable by the absorption in the visible and UV regions).
Saintopin E has the following physicochemical properties. (.epsilon.); 290 (17,100), 338 (8,100), 566 (7,300) ; 3431, 3230, 1622, 1564, 1437, 1387, 1269, 1163 14.10(1H, br.s), 13.43(1H, br.s), 10.76(1H, br.s), 7.46(1H, s), 7.04(1H, d, 2.1 Hz), 6.53(1H, d, 2.1 Hz), 6.34(1H, s), 2.66(3H, s) in chloroform and ethyl acetate, and sparingly soluble in water and n-hexane 5715, produced by Merck & Co., Inc.) with a developing solvent composed of n-hexane:ethyl acetate:methanol:acetic acid (6:4:1:1, v/v) Corporation: Flow rate; 1 ml/min.:
The biological activities of Compounds (I) are described below.


TEST EXAMPLE 1



Antibacterial activity

The minimum inhibitory concentration (MIC) against the growth of various bacteria is shown in Table 1. The antibacterial activity was determined by the agar dilution method using a medium (pH 7) which comprises 3 g/l Bacto-Tryptone (produced by Difco Laboratories), 3 g/l meat extract, 1 g/l yeast extract, 1 g/l glucose and 16 g/l agar.


TABLE 1 ______________________________________ Bacteria tested MIC (.mu.g/ml) (UCE 1022) ______________________________________ Staphylococcus aureus 0.52 ATCC 6538P Enterococcus faecium 0.52 ATCC 10541 ______________________________________


TEST EXAMPLE 2



Anti-tumor activity against HeLaS.sub.3 cells

HeLaS.sub.3 cells (ATCC HTB22) were suspended in a medium comprising 10% fetal calf serum, 2 mM glutamine and MEM medium (produced by Nippon Pharmaceutical Co., Ltd.) (hereinafter referred to as medium A) to a concentration of 3.times.10.sup.4 cells/ml. The cell suspension was put into wells of a 96-well microtiter plate in an amount of 0.1 ml per well. The cells in the plate were cultured at 37.degree. C. for 20 hours in a CO.sub.2 -incubator. Subsequently, the test compound appropriately diluted with medium A was added to the wells in an amount of 0.1 ml/well. The cells were further cultured at 37.degree. C. for 72 hours in the CO.sub.2 -incubator, and then the culture supernatant was removed. To the residue was added a medium comprising medium A and 0.02% Neutral Red in an amount of 0.1 ml per well, f

REFERENCES:
Yamashita, et al, J. Antibiotics, 43(10) 1344-6 (1990).
Fujii, et al, J. Antibiotics, 47(8) 949-51 (1994).
Yamachita, et al. "Induction of Mammalian DNA Topoisomerase I and II Mediated DNA Cleavage by Saintopin . . . ", Biochemistry 30: 5839-5845, 1991.
Berdy, J. "Anthiacyclins" CRC Handbook of Antibiotic Compounds, vol. III, pp. 61-63, 1981.

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