Phorbol derivatives having antivirus activity

Details Phorbol derivatives having antivirus activity Phorbol derivatives having antivirus activity

2000-05-03

2001-07-31

Carr, Deborah D. (Department: 1621)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Ester doai

C554S229000

Reexamination Certificate

active

06268395

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to phorbol derivatives having antiviral activity, more particularly to an antiviral agent effective against virus such as human immunodeficiency virus (HIV) containing a phorbol derivative as an active ingredient, and to novel phorbol derivatives.
2. Description of the Related Art
Since the discovery of human immunodeficiency virus, the causative agent of the acquired immunodeficiency syndrome (AIDS), significant progress has been made towards the development of effective anti-HIV drugs and recently considerable progress has been made in this field. In the research and development of AIDS therapeutics, research for natural substances having anti-HIV activity has been made besides research and development of novel chemical drugs. For example, a variety of compounds having various chemical structures derived from plants have been reported to be effective in inhibiting the replication of HIV-1 or its essential enzymes (cf. for example, Che, 1991; Schinazi, 1992; Nasr, Cradock & Johnson, 1992; El-Mekkawy et al., 1995; El-Mekkawy, Meselhy, Kusumoto, Kadota, Hattori, Namba, 1998; Ng, Huang, Fong & Yeung, 1997; Kusumoto & Hattori, 1999).
Plant-derived bioactive substances are relatively easily available from plants. There are many plants which are used as materials for Japanese-Chinese medicines or folk medicines over the world so that many pieces of information on bioactivity have accumulated and the plants are greatly expected to be also potent anti-HIV drugs.
However, none of the plant-derived compounds that have anti-HIV effects is sufficient in its activity. Since some of the above-mentioned plant-derived substances show deleterious side effects such as cytotoxicity or carcinogenicity, it is very difficult to select most suitable antiviral agents such as, for example, anti-HIV drugs, taking into consideration both useful bioactivity and harmful bioactivity. Therefore, it has been keenly desired to find plant-derived bioactive substances having high antiviral effects (for example, anti-HIV effects) and having less deleterious side effects and develop effective antiviral agents, for example anti-HIV agents, based thereon.
SUMMARY OF THE INVENTION
The present invention has been made with view to solving the above-described defects of the prior art.
It is an object of the present invention to provide an antiviral agent (for example anti-HIV agent) having higher antiviral effects and less deleterious side effects as compared with conventionally known antiviral agents.
Another object of the present invention is to provide a novel substance that can be used as an active ingredient for the antiviral agent.
The present inventor has conducted extensive research for the screening of about several hundreds to about one thousand kinds of Japanese-Chinese medicines and plant-derived natural raw materials for their antiviral activities. As a result, he has found that the components contained in the seeds of Croton tiglium, particularly phorbol derivatives, have potent inhibitory effect against proliferation of AIDS virus, thus having achieved the present invention.
Accordingly, in a first aspect, the present invention relates to an antiviral agent comprising as an active ingredient a phorbol derivative of formula (I):
(wherein R
1
, R
2
, R
3
, R
4
, and R
5
, independently one another, represent a hydrogen atom, an aliphatic carboxylic acid residue , or an aromatic carboxylic acid residue)
having a ratio r=CC
0
/IC
100
, i.e., ratio of concentration CC
0
at which survival of MT-4 cells is decreased upon cell proliferation tests to concentration IC
100
at which HIV-1-induced cytopathic effect(CPE) on MT-4 cells is inhibited by 100%, of 2 or more and
having a protein kinase C(PKC) activation of 30% or less at a concentration of 10 ng/mL.
In a second aspect, the present invention relates to an antiviral agent comprising as an active ingredient a phorbol derivative of formula (II):
(wherein R
1
, R
2
, R
3
, R
4
, and R
5
, independently one another, represent a hydrogen atom, an aliphatic carboxylic acid residue, or an aromatic carboxylic acid residue)
having a ratio r=CC
0
/IC
100
, i.e., ratio of concentration CC
0
at which survival of MT-4 cells is decreased upon cell proliferation tests to concentration IC
100
at which HIV-1-induced cytopathic effect(CPE) on MT-4 cells is inhibited by 100%, of 2 or more and
having a protein kinase C(PKC) activation of 30% or less at a concentration of 10 ng/mL.
In a third aspect, the present invention relates to a phorbol derivative of formula (I):
(wherein
R
1
, R
4
, and R
5
represent each a hydrogen atom, R
2
represents an acetyl group, R
3
represents a linoleic acid residue, or
R
1
, R
4
, and R
5
represent each a hydrogen atom, R
2
represents a tigloyl group, R
3
represents a linoleic acid residue, or
R
1
represents an acetyl group, R
2
represents a tigloyl group,R
3
, R
4
, and R
5
represent each a hydrogen atom, or
R
1
represents a decanoyl group, R
2
represents a 2-methyllactic acid residue, R
3
, R
4
, and R
5
represent each a hydrogen atom, or
R
1
represents a tigloyl group, R
2
represents a decanoyl group, R
3
, R
4
, and R
5
represent each a hydrogen atom).
DETAILED DESCRIPTION OF THE INVENTION
Hereinafter, the present invention will be described in detail. For the convenience's sake, the following explanation will be focused mainly on HIV.
In the course of search for anti-HIV-1 agents from natural products, a number of extracts of plants used in Egyptian folk medicine were evaluated for possible anti-HIV properties, and it revealed that the methanol and water extracts of the seeds of Croton tiglium significantly inhibited the infectivity and HIV-1-induced cytopathic effect(CPE) on MT-4 cells at concentrations (IC
50
values of 0.025 and 2.0 &mgr;g/mL, respectively) below the cell toxic concentration (selectivity indices of 34.4 and 50.0, respectively) (Kawahata, Otake, Mori, Morimoto, Ueba, Kusumoto et al., 1996). Croton tiglium belongs to the family Euphorbiaceae and is known to contain tigliane phorbol esters. These compounds have been shown to be responsible for eliciting a remarkable range of biochemical effects on a variety of biological systems (cf. Evans & Taylor, 1983; Evans & Soper, 1978; De Chaffoy de Courcelles, Roevens & van Belle, 1984; Hecker, 1978; Blumberg, 1980; Blumberg 1981; Blumberg, 1988; Kupchan, Uchida, Branfman, Daily & Yu-Fei, 1979; Gustafson, Cardellina, II, McMahon, Gulakowski, Ishitoya, Szallasi et al., 1992; Gschwendt & Hecker, 1974).
That is, these include tumor promotion, cell proliferation, platelet aggregation, antitumor and anti-HIV-1 effects. Much of what is known about how these effects are transmitted inside cells come from the study of tumor promoting and platelet aggregating phorbol esters like 12-O-tetradecanoylphorbol-13-acetate (Compound 8, TPA) . Although the ability of these compounds to promote tumors presents one potential limitation to their utility, it should be stressed that there are many phorbol esters that exert profound effects without being tumor promoters.
12-O-tigloylphorbol-13-decanoate isolated from croton oil demonstrated antileukemic activity against the P-388 leukemia in mice (Kupchan et al., 1976). 12-Deoxyphorbol-13-acetate having an anti-HIV activity was isolated from a Samoan plant, Homolanthus nutans (Gustafson et al., 1992). Although structurally belonging to the phorbol esters, it does not exhibit a tumor promoting effect, while 12-deoxyphorbol-13-tetradeconoate isolated from Euphorbia triangularis possesses the same tumor promoting activity as TPA (Geschwendt et al., 1974). These findings suggested that the difference among tumor promoting, antitumor and anti-HIV-1 effects of an ester is associated with the specific structure of the entire molecule, and that particular structural features are necessary for phorbol esters to provoke these diverse effects.
It has been reported that these compounds interact with and activate protein kinase C(PKC), and that

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