Cytotoxic and antiviral compound

Details Cytotoxic and antiviral compound Cytotoxic and antiviral compound

1994-02-03

2001-08-14

MacMillan, Keith D. (Department: 1618)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

C530S321000, C530S317000, C514S009100, C514S002600, C930SDIG722, C930SDIG722

Reexamination Certificate

active

06274551

ABSTRACT:

This invention is concerned with a cytotoxic and antiviral compound isolated from the sacoglossan,
Elysia rafescens.
According to the invention there is provided, a new compound, the peptide, Kahalalide F, of the formula:
The antitumor activities of this compound has been determined “in vitro” in cell cultures of human lung carcinoma A-549 and human colon carcinoma HT-29. The procedure was carried out using the metnhodology described by Raymond J. Bergeron et al.
Biochem. Bioph. Res. Comm
. 1984, 121(3), 848-854 and by Alan C. Schroeder et al.
J. Med. Chem
. 1981, 24 1078-1083.
The antiviral activities of this compound have also been determined “in vitro” against HSV (Herpes simplex virus) and VSV (Vesicular stomatitis virus). The methodology used to carry out this determination is described by Raymond J. Bergeron et al.
Biochem. Bioph. Res. Comm
. 1984, 121(3), 848-854 and by Alan C. Schroeder et al.
J. Med. Chem
. 1981, 24 1078-1083.
Therefore, the present invention also provides a method of treating any mammal affected by a malignant tumor sensitive to compounds above described, which comprises administering to the affected individual a therapeutically effective amount of these compounds or a pharmaceutical composition thereof; and a method of treating viral infections in mammals, comprising administering to a patient in need of such treatment, an antiviral effective amount of the compounds described in the present invention.
The present invention also relates to pharmaceutical preparations which contain as active ingredient these compounds, or a pharmaceutically acceptable acid addition salt thereof, as well as the process for its preparation.
Examples of pharmaceutical compositions include any solid (tablets, pills, capsules, granules, etc.) or liquid (solutions, suspensions or emulsions) suitable composition for oral, topical or parenteral administration, and they may contain the pure compound or in combination with any carrier or other pharmacologically active compounds. These compositions may need to be sterile when administered parenterally.
The correct dosage of a pharmaceutical composition of these compounds will vary according to the particular formulation, the mode of application and particular site, host and tumor being treated. Other factors like age, body weight, sex, diet, time of administration, rate of excretion, condition of the host, drug combinations, reaction sensitivities and severity of disease shall be taken in account. Administration can be carried out continuously or periodically within the maximum tolerated dose. Kahalalide F was isolated from the sacoglossan, Elysia rufescens (family Plakobranchidae, order Sacoglossa), collected near Black point, Oahu. This animal varies in size between 1 and 4 cm; it is dark red-brown in color with light-colored spots. There is orange fringing of the parapodia, which have very small dark green spots from sequestered chloroplasts.
Elysia rufescens
feeds on the delicate, feather-like green alga Bryopsis sp.
1
Kahalalide F can also be isolated from this alga. Two hundred animals were collected over the period of several weeks during spring, 1991 and extracted with EtOH. The extracts were then chromatographed by silica gel flash chromatography (hexane, hexane/EtOAc (1:1), EtOAc, EtOAc (1:1), MeOH and MeOH/HOAc (98:2). The peptides were eluted with EtOAc/MeOH (1:1). Final purification was accomplished by repeated HPLC (RP C18) using MeCN/H
2
O with 0.1% TFA (70-45% H
2
O).
ISOLATION SCHEME
Elysia rufescens
The structures of the peptides were elucidated by 2D NMR experiments (HMQC, HMBC, TOCSY, COSY and ROESY).
Kahalalide F was isolated as a white amorphous powder in 0.02% yield. A molecular formula of C
75
H
124
N
14
O
16
was deduced from detailed analyses of the
13
C and
1
H NMR spectra and the high resolution FAB mass spectrum. The 14 substructures in this compound arise from five valines, two isoleucines, two threonines, ornithine, dehydroaminobutyric acid. proline, phenilalanine and 5-methythexanoic acid (5-MeHex). Kahalalide F is the largest peptide in this series of compounds.


REFERENCES:
UMI Dissertation Services, “Biologically Active Constituents of Some Marine Invertebrates”, Hamaii, Mark Todd, Ph.D., University of Hawaii, 1992.
Hamann et al, J. Am. Chem. Soc., 115, pp. 5825-5826 (1993).
Merck Manual, 11thed., pp. 761-763; 1368-1371; pp. 456-459.

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