Macrolides with antitumor activity

Details Macrolides with antitumor activity Macrolides with antitumor activity

2000-04-17

2002-05-28

Peselev, Elli (Department: 1623)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Carbohydrate doai

C435S076000, C435S867000, C514S033000, C514S468000, C536S065000, C549S298000

Reexamination Certificate

active

06395711

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to a novel macrolide compound isolated from the culture broth of a new marine microbial organism. The present invention further relates to the production of the novel compound by aerobic fermentation under controlled conditions and its isolation and purification, as well as to derivative compounds, and to additional aspects based on the discovery of antitumor and other activities.
BACKGROUND OF THE INVENTION
The macrolides called oligomycins and homooligomycins are known from J. Antibiotics 46: 1334~1341. 1993; J. Antibiotics 45: 171~179, 1992; and J. Antibiotics 49: 1275~1277, 1996.
OBJECTS OF THE INVENTION
New antiproliferative compounds are still needed for treatment of several human tumors, due to the fact that a high number of cancer cell lines. including those displaying MDR phenotype, are not efficiently treated by any drugs
Yet another objective of this invention is to provide pharmaceutical compositions for administering to a patient in need of treatment with the active compound.
Microbial products are interesting because industrial production is well established at present times. Therefore, another objective of this invention is directed to the production of the active compound and to its isolation and purification from the resulting fermentation broth, as well the hydrolysis to an aglycone compound and derivatisation to related compounds.
SUMMARY OF THE INVENTION
This invention provides a compound with a macrolide-like structure, designated IB-96212, of the following formula,
A process of obtaining IB-96212 is also provided, and the preferred process comprises cultivating a strain of a micro-organism capable of producing IB-96212 in an aqueous nutrient medium with assimilable carbon and nitrogen sources and salts, under controlled submerged aerobic conditions. The resultant broth itself, either unpurified or partly purified and having antitunor activity, is also part of this invention. The compound IB-96212 can be recovered and purified from the cultured broth. The compound and the fermentation broth demonstrate interesting activity against several human cancer cells, among them sensitive and multi-drug resistant (MDR) leukaemia cells. Additionally, IB-96212 presents antibiotic activity against some Gram-positive bacteria.
From this compound IB-96212, a trideoxy sugar identified as L-rhodinose can be removed by hydrolysis, leaving the active aglycone compound IB-96212B which has the core 26-membered macrolide ring system of the parent IB96212.
Thus, the invention further provides the compound IB-96212B with the structure:
IB-96212B has activity comparable to the parent IB-96212.
In the compound IB-96212, the trideoxy sugar which we identify as L-rhodinosc can itself be derivatised or the sugar can be replaced, in either case giving further derivatives of IB-96212 having a group other than L-rhodinose at the position of the sugar. Thus, more broadly, the present invention provides a compound of the general formula:
where R is hydrogen or a substituent group.
Illustratively, R is hydrogen or a group selected from a saccharide group, a hydrocarbyl group, an acyl group, a heterocyclyl group, or some other suitable substituent The nature of the substituent group is not crtical. The sacchaide group is suitably a mono-, di- or tri-saccharide which may be a deoxysaccharide. The hydrocarbyl can be alkyl, cycloalkyl, aryl, aralkyl, or alkylaryl, especially C
1
-C
6
atkyl, cyclo-(C
4
-C
8
)alkyl, phenyl, naphthyl or benzyl. The heterocyclyl group can be a 4 to 8 membered ring having 1 to 4 heteroatoms, especially a 5 or 6 membered ring having 1 or 2 hetero atoms chosen from oxygen, sulphur or nitrogen. The hydrocarbyl group, acyl group or heterocyclyl group can itself be substituted, for example with 1, 2 or 3 subsituents chosen among C
1
-C
6
alkyl, C
1
-C
6
alkoxy, halogen, hydroxy, amino or other groups.
The preferred culture to obtain IB-96212 is a new strain designated ES25-008, and its chemical, biochemical and morphological chambers show that it belongs to the genus Micromonospora, being taxonomically classified as Micromonospora sp.
As described above, the compounds IB-96212 and IB-96212B have been found to be effective in the inhibition of the proliferative activity of several human and murine leukaemia cell-multidrug resistant (MDR) as well as sensitive cell lines—as well as against other human tumors. It follows that other compounds of the given general formula will retain such activity.


REFERENCES:
patent: 4639467 (1987-01-01), Celino
patent: 5003056 (1991-03-01), Nishikiori et al.
patent: 0164207 (1985-12-01), None
patent: 0322748 (1994-04-01), None
Laatsch et al., “Oligomycin F, A New Immunosuppressive Homologue of Oligomycin A”,The Journal of Antibiotics, vol. 46, No. 9, pp. 1334-1341 (1993).
Yamazaki et al., “44-Homooligomycins A and B, New Antitumor Antibiotics From Sreptomyces bottropensis”,The Journal of Antibiotics, vol. 45, No. 2, pp. 171-179 (1992).

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