Terpenoidic derivatives useful as antitumor agents

Details Terpenoidic derivatives useful as antitumor agents Terpenoidic derivatives useful as antitumor agents

1997-01-15

1999-02-09

Stockton, Laura L.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

5483114, A61K 31415, C07D23364

Patent

active

058695141

DESCRIPTION:

BRIEF SUMMARY
This application is a 371 of PCT/EP96/01688 filed Apr. 23, 1996.
The present invention relates to terpenoidic derivatives, known in the art as Sarcodictyins (Helvetica Chimica Acta Vol. 70, 1987, 2019-2027 and Helvetica Chimica Acta, Vol. 71, 1988, 964-976), which can be useful as therapeutic agents.
A possible therapeutic application of the Sarcodictyins mentioned in the present application was not reported earlier.
In particular, according to the present invention, Sarcodictyins, in view of their cytotoxic activity, can be of use as therapeutic antineoplastic agents in the treatment of cancers in human or animal beings.
Accordingly, the present invention refers to a compound selected from the group consisting of: hydro-7-hydroxy-6-(methoxy carbonyl)-1,10-dimethyl-4-(1-methylethyl)benzo cyclodecen-11-yl(E)-3-(1-Methyl-1H-imidazol-4yl) acrylate (Sarcodictyin A); 10-Epoxy-6-(ethoxycarbonyl)-3,4,4a,7,10,11,12,12a-octahydro-7-hydroxy-1,10 -dimethyl-4-(1-methylethyl)benzocyclodecen-11-yl(E)-3-(1-Methyl-1H,imidazol -4-yl)acrylate (Sarcodictyin B); ctahydro-3,7-dihydroxy-6-(methoxycarbonyl)-1,10-dimethyl-4-(1-methylethyl) benzocyclodecen-11-yl(E)-3-(1-Methyl-1H-imidazol-4-yl) acrylate (Sarcodictyin C); 1,12,12a-octahydro-7-hydroxy-6-(methoxycarbonyl)-1,10-dimethyl-4-(1-methyle thyl) benzocyclodecen-11-yl(E)-3-(1-Methyl-1H-imidazol-4-yl) acrylate (Sarcodictyin D); 7,10,11,12,12a-octahydro-3,7-dihydroxy-6-(methoxycarbonyl)-1,10-dimethyl-4 -(1-methylethyl) benzocyclodecen-11-yl(Z)-3-(1-Methyl-1H-imidazol-4-yl) acrylate (Sarcodictyin E); and ctahydro-1,7-dihydroxy-6-(methoxycarbonyl)-1,10-dimethyl-4-(1-methylethyl) benzocyclodecen-11-yl(E)-3-(1-Methyl-1H-imidazol-4-yl) acrylate (Sarcodictyin F);
The structural formulae of the above listed compounds is reported in Table 1 below, with reference to the following formulae: ##STR1##


TABLE 1 ______________________________________ COMPOUND (A) R.sub.1 R.sub.2 R.sub.3 ______________________________________ Sarcodictyin A (A.sub.1) Me H (E)u Sarcodictyin B (A.sub.1) Et H (E)u Sarcodictyin C (A.sub.1) Me OH (E)u Sarcodictyin D (A.sub.1) Me OAC (E)u Sarcodictyin E (A.sub.1) Me OH (Z)u Sarcodictyin F (A.sub.2) Me OH (E)u ______________________________________
In the above Table 1: urocanoyl moiety of formula ##STR2##
In particular, the above reported Sarcodictyins A to F may be useful as therapeutic agents in the treatment of cancers in human or animal beings, by virtue of their cytotoxic, antitumor activity. The cancer may be selected from sarcomas, carcinomas, lymphomas, neuroblastomas, melanomas, myelomas, Wilms tumor, leukemias and adenocarcinomas. The Sarcodictyins of the invention may be obtained by isolation from the Mediterranean Stoloniferan Coral "Sarcodictyon Roseum" (Rolandia rosea) (Forbes 1847) according to the method reported in Helvetica Chimica Acta Vol. 70, 1987, page,2025.
The biolgical activity of the Sarcodictyins of the invention was demonstrated by (a) "in vitro" test to evaluate their activity in promoting the tubulin assembly and (b) "in vitro" test to evaluate their cytotoxic activity both on L 1210 cells and L 1210 cells resistant to Doxorubicin (L 1210/Dx).
As an example, the activity of Sarcodictyin A (internal code FCE 29123) and Sarcodictyin C (internal code FCE 29119) was evaluated according to the methods described in tests (a) and (b).
Calf brain tubulin was prepared by two cycles of assembly-disassembly (Shelanski M. L., Gaskin F. and Cantor C. R., Proc. Natl.Acad.Sci. U.S.A. 70, 765-768, 1973; and stored in liquid nitrogen in MAB (0.1M MES, 2.5 mM EGTA, 0.5 mM MgSO.sub.4, 0.1 mM EDTA, 0.1 mM DTT, pH 6.4).
All the experiments were carried out on protein stored for less than 4 weeks.
Before each experiment, tubulin was kept 30 min at 4.degree. C. Assembly was monitored by the method of Gaskin et al. (Gaskin F., Cantor C. R. and Shelanski M. L., J.Molec.Biol. 89, 737-758, 1974).
The cuvette (1 cm path) containing tubulin (1 mg/ml) and 1 mM GTP was shifted to 37.degree. C. and continuous turbidity measurements were made a

REFERENCES:
patent: 4861776 (1989-08-01), Nelson et al.
patent: 5204364 (1993-04-01), Carganico et al.
D'Ambrosio et al., Helv. Chim. Acta (1988), 71(5), 964-76, 1988.
D'Ambrosio et al., Helv. Chim. Acta (1987), 70(8), 2019-27,1987.
Honda et al., Prostaglandins, vol. 36, No. 5, Nov. 1988, pp. 621-630.

Affiliated with

Also associated with

Rating

Terpenoidic derivatives useful as antitumor agents does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Terpenoidic derivatives useful as antitumor agents, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Terpenoidic derivatives useful as antitumor agents will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-1948686