Granulatimide compounds and uses thereof

Details Granulatimide compounds and uses thereof Granulatimide compounds and uses thereof

1999-02-26

2001-09-18

Shah, Mukund J. (Department: 1609)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S283000, C514S393000, C514S394000, C540S469000, C546S048000, C546S052000, C548S301700

Reexamination Certificate

active

06291447

ABSTRACT:

BACKGROUND
Natural products are a rich source of novel organic compounds, many of which have interesting and desirable biological activities. From extracts of an organism of interest, such as marine invertebrates, methods of chemical separation and analysis may be applied to elucidate the structure of biologically active compounds. These chemical structures then form the basis for synthetic modifications to enhance the desired activity.
Marine ascidians, or sea squirts, have a number of unique secondary metabolites with potent biological activity. Colonial ascidians within the family Didemnidae have been particularly prolific, containing nitrogenous amino acid derived metabolites, including various cyclic peptides. The compounds termed didemnimides were isolated from
Didemnum conchyliatum.
These compounds are indole-maleimide-imidazole alkaloids, which could hypothetically be synthesized as a condensation of tryptophan and histidine
The further study of Didemna products, and the characterization of their active agents, is of particular interest for the development of novel therapeutic agents and uses thereof.
Relevant Literature
Didemnimide compounds are described by Vervoot et al. (1997)
J. Org. Chem.
62:1486-1490. In describing synthesis of such didemnimide compounds, Terpin et al. (1998)
Tetrahedron
54:1740-1752 reported a ring closing event that may occur upon irradiation or upon recrystallization from methanol of a Boc protected intermediate used in the didemnimide synthesis scheme.
Known G2 checkpoint inhibitors include purine analogues, e.g. caffeine, pentoxifylline, 2-aminopurine, 6-dimethylaminopurine; and staurosporine with its derivative UCN-01 (7-hydroxystaurosporine). See, for example, Busse et al. (1978)
Radiat. Res.
76:292-307; Schlegel (1986)
Science
232:1264-1266; Downes et al (1990)
J. Cell. Biol.
110:1855-1859; Steinmann et al. (1991)
P.N.A.S.
88:6843-6847; Andreasson et al. (1992)
P.N.A.S.
89:2272-2276; Tam et al. (1992)
Cell Growth Differ.
3:811-817; and Wang et al. 1996)
J. Nat'l Cancer Inst.
88:956-965.
Experiments employing cells deficient in the tumour suppressor protein p53 have demonstrated the value of the two groups of G2 checkpoint inhibitors described above, for selectively sensitizing cancer cells. Pentoxifylline has been shown to enhance cisplatin induced killing of p53-MCF-7 cells 30-fold and radiation induced killing of p53-A549 human lung adenocarcinoma cells 5-fold. For example, see Russell et al. (1995)
Cancer Res.
55:1639-1642; Powell et al. (1995)
Cancer Res.
55:1643-1648; Russell et al. (1996)
Int. J. Radiat. Oncol. Biol. Phys.
36:1099-1106; Yao et al. (1996)
Nature Med.
2:1140-1143; and Bracey et al (1997)
Clin. Cancer Res.
3:1371-1381.
SUMMARY OF THE INVENTION
Granulatimide compounds of Formula I are provided, as defined herein. This invention includes the naturally occurring compounds, granulatimide and iso-granulatimide, in purified or partially purified form, including extracts containing these compounds taken from naturally occurring sources, e.g.
Didemnum granulatum
. In one embodiment of the invention, formulations of the compounds in combination with a physiologically acceptable carrier are provided. The pharmaceutical formulations are useful as a cytotoxic agent; as a protein kinase inhibitor; and to inhibit the G2 checkpoint. This invention also provides the use of compounds of Formula I, e.g. to sensitize cells to the effects of DNA damaging agents; and the use of such compounds in the formulation of agents, including medicaments.


REFERENCES:
patent: 5438050 (1995-08-01), Kleinschroth
patent: 5489608 (1996-02-01), Kleinschroth
patent: 5604219 (1997-02-01), Murakata
patent: 5807882 (1998-09-01), Coudert et al.
patent: 35 35 842 A1 (1987-04-01), None
patent: 0 328 000A2 (1989-02-01), None
patent: 0 434 057 A2 (1991-06-01), None
patent: 0 657 458 A1 (1995-06-01), None
patent: 0 672 668 A1 (1995-09-01), None
patent: 0 735 038 A1 (1996-10-01), None
patent: 0 841 337 A1 (1998-05-01), None
patent: WO 91/09034 (1991-06-01), None
patent: WO 94/04541 (1994-03-01), None
patent: WO 94/07895 (1994-04-01), None
patent: WO 95/32976 (1995-12-01), None
patent: WO 95/32974 (1995-12-01), None
patent: WO 95/32975 (1995-12-01), None
patent: WO 96/11933 (1996-04-01), None
patent: WO 97/19080 (1997-05-01), None
patent: WO 97/18809 (1997-05-01), None
Roberge et al., High-Throughput Assay for G2 Checkpoint Inhibitors, Cancer Research, 58(24), pp. 5701-5706, Dec. 1998.*
Berlinck et al., Granulatimide and Isogranulatimide, J. Org. Chem. vol. 63, No. 26, pp. 9850-9856, Dec. 1998.*
Harris et al., Oxidative Cyclasations with Palladium Acetate, Tetrahedron Letters, vol. 34, No. 51, pp. 8361-8364, 1993.*
Terpin, et al Synthesis and Cyclisation of Didemnimide C and its Imidazol-1-yl Isomer1(1997) Tetrahedron vol. 54:1740-1752.
Russell, et al “Abrogation of the G2Checkpoint Results in Differential Radiosensitization of G1Checkpoint-deficient and G1Checkpoint-competent Cells1”, (1995) Cancer Res. vol. 55:1639-1642.
Powell,et al “Differential Sensitivity of p53(−)and p53(+)Cells to Caffeine-induced Radiosensitization and Override of G2Delay1”., (1995) Cancer Res. vol. 55:1643-1648.
Wang, et al. “UCN-01:a Potent Abrogator of G2Checkpoint Function in Cancer Cells With Disrupted p53”, (1996) J. Nat'l. Cancer Inst. vol. 88:956-965.
Downes, et al. “Caffeine Overcomes a Restriction Point Associated with DNA Replication, but Does Not Accelerate Mitosis”, (1990) J. Cell Biol. vol. 110:1855-1859.
Bracey, et al. “Inhibition of Radiation-induced G2Delay Potentiates Cell Death by Apaptosis and/or the Induction of Giant Cells in Colorectal Tumor Cells with Disrupted p53 Function1”, (1997) Clin. Cancer Res. vol 3:1371-1381.
Steinman, et al. “Chemically induced premature mitosis: Differential response in rodent and human cells and the relationship to cyclin B synthesis and p34cdc2/cyclin B complex formation”, (1991) P.N.A.S. vol. 88:6843-6847.
Schlegel “Caffeine-Induced Uncoupling of Mitosis form the Completion of DNA Replication in Mammalian Cells” (1986) Science vol. 232:1264-1266.
Yao et al “Selective radiosensitization of p53-deficient cells by caffeine-mediated activation of p34cdc2kinase”., (1996) Nature Med.vol.2:1140-1143.
Russell, et al. “Preferential Radiosensitization of G1 Checkpoint-Deficient Cells by Methylxanthines”, (1996) Int. J.Radiat. Oncol. Biol. Phys. vol.36:1099-1106.
Tam, et al. “Staurosporine Overrides Checkpoints for Mitotic Onset in BHK Cells1” (1992) Cell Growth Differ. vol.3:811-817.
Andreasson,et al. “2-Aminopurine overrides multiple cell cycle checkpoints in BHK cells”, (1992) P.N.A.S. vol.89:2272-2276.
Busse, et al. “The Action of Caffeine on X-Irradiated HeLa Cells” (1978) Radiat. Res. vol. 76:292-307.
Vervoot et al. “Didemnimides A-D: Novel, Predator-Deterrent Alkaloids from the Caribbean Mangrove AscidianDidemnum conchyliatum”, (1997) J. Org.Chem. vol 62:1486-1490.
Smith, et al. “The Chemistry of 3-(∝-Cyanobenzylidene)-1-phenyltriazenes and Their Conversion to Diarylmaleimides and Phenanthrene-9, 10-dicarboximides”, (1990) J. Organic Chemistry, vol. 55, No. 10, pp 3351-3361.

Affiliated with

Also associated with

Rating

Granulatimide compounds and uses thereof does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Granulatimide compounds and uses thereof, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Granulatimide compounds and uses thereof will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-2444190