Methods of using bis-indolylquinones

Details Methods of using bis-indolylquinones Methods of using bis-indolylquinones

2000-05-03

2004-06-15

Qazi, Sabiha (Department: 1616)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C514S416000, C514S300000, C514S312000, C548S455000, C548S460000, C548S468000

Reexamination Certificate

active

06750240

ABSTRACT:

1. INTRODUCTION
The present invention relates to novel synthetic methods for the preparation of both known and novel indolylquinones. Many indolylquinones, in particular the class of indolylquinones known as the asterriquinones, have utility, in the treatment of cell proliferative disorders such as cancer. In addition, many indolylquinones are known to be useful as dyes. Finally, indolylquinones are also known to exhibit antifungal and antibacterial properties. However, in general, indolylquinones are isolated from natural sources and are not prepared synthetically. The present invention is directed to a synthetic method for the preparation of indolylquinones, and to novel compounds prepared using said method. In particular, the methods of the present invention are directed to synthetic reactions involving indoles and halo-quinones in solvent and in the presence of a metal carbonate. These methods provide a direct and simple means of preparing the compounds of interest, indolylquinones.
2. BACKGROUND OF THE INVENTION
2.1 Isolation from Natural Sources and Therapeutic Utility of Indolylquinones
Research interest concerning indolylquinones grew out of early observations that extracts of Chaetomium exhibited antibiotic properties. These observations led researchers to attempt the isolation of active species from cultures of these microorganisms. For example, Brewer et al. disclose the isolation of a purple pigment, which was termed cochliodinol, from isolates of
Chaetomium cochliodes
and
Chaetoinium globosum
(1968, “The Production of Cochliodinol and a Related Metabolite by Chaetomium Species,”
Can. J. Microbiol.
14:861-866). Brewer et al. also disclose the synthetic conversion of cochliodinol to a diacetate compound. Id. Further, the antifungal properties of cochliodinol have also been documented (Meiler et al., 1971, “The Effect of Cochliodinol, a Metabolite of Chaetomium cochliodes on the Respiration of Microspores of
Fusarium oxysporum,” Can. J. Microbiol.
17: 83-86).
The structure of cochliodinol was elucidated by Jerram et al. in 1975. (1975, “The Chemistry of Cochliodinol, a Metabolite of Chaetomium spp.,”
Can. J. Chem.
53:727-737). Jerram et al. reported the structure of cochliodinol as: 2,5-dihydroxy-3,6-di(5′-(2″-methylbut-&Dgr;
2
″-ene)-indolyl-3′)-cyclohexadiene-1,4-dione. The conversion of cochliodinol to various other derivatives, including its dimethyl and diacetyl analogues, was also disclosed. Id. Some of these derivatives were highly colored and suitable for use as dyes, while others were colorless. Id. Sekita discloses the isolation of other bis(3-indolyl)-dihydroxybenzoquinones, including isocochliodinol and neocochliodinol from
Chaetoinium muroum
and
C. amygdalisporum
(1983, “Isocochliodinol and Neocochliodinol, Bis(indolyl)-benzoquinones from Chaetomium spp.,”
Chem. Pharm. Bull.
31(9): 2998-3001).
Despite the therapeutic potential of cochliodinol and its derivatives, efficient methods suitable for large scale production of these compounds have remained elusive. U.S. Pat. No. 3,917,820 to Brewer et al. discloses the purple pigment cochliodinol and a process for its production by culturing various types of Chaetomium under aerobic conditions. However, the methods of Brewer require long incubation periods for cochliodinol production (2-8 days), the use of benzene, a known carcinogen, to effect chromatographic separation of cochliodinol from the culture and are limited to the few naturally occurring compounds. Moreover, Brewer discloses the isolation of only small quantities (0.75 grams) of cochliodinol from Chaetomium.
Another class of indolylquinones known as the asterriquinones in which the nitrogen of the indole ring is substituted, has been shown to exhibit antitumor activity. Arai et al. proposed the general name “asterriquinones” for the class of indolylquinones based upon asterriquinone (1981, “Metabolic Products of
Aspergillus terreus
IV. Metabolites of the Strain IFO 8835. (2) The Isolation and Chemical Structure of Indolyl Benzoquinone Pigments,”
Chem. Pharm. Bull.
29(4): 961-969). It should be noted that as used herein, the term “asterriquinone” has a more general meaning, and is used interchangeably with the term “indolylquinone.” Yamamoto et al. disclose the antitumor activity of asterriquinone, i.e., 2,5-bis[N-(1″,1″-dimethyl-2″-propenyl)indol-3″-yl]-3,6-dihydroxy-1,4-benzoquinone, and its isolation from the fungus
Aspergillus terreus
(1976, “Antitumor Activity of Asterriquinone, a Metabolic Product from
Aspergillus terreus,” Gann
67:623-624).
Arai et al. disclose the isolation and characterization of 11 different kinds of bisindolyl-dimethoxyl-p-benzoquinones from
Aspergillus terreus.
Id. The isolation and structural determination of a number of other asterriquinones have also been reported. (Arai et al. 1981, “Metabolic Products of
Aspergillus terreus
VI. Metabolites of the Strain IFO 8835. (3) the Isolation and Chemical Structures of Colorless Metabolites,”
Chem. Pharm. Bull.
29(4): 1005-1012; Kaji et al., 1994, “Four New Metabolites of
Aspergillus Terreus”, Chem. Pharm. Bull.
42(8): 1682-1684).
However, the separation of asterriquinones is troublesome because there are so many kinds of homologous pigments in the Aspergillus extracts. Moreover, the chromatographic purification of asterriquinones is typically carried out using benzene, a known carcinogen, as a solvent. Finally, only milligram quantities of asterriquinones have actually been isolated from these natural sources.
In view of their potential as anticancer agents, research has been directed to determination of the relationship between structure and antitumor activity of asterriquinones. For example, Arai et al. reported a study in which hydroxyl benzoquinone derivatives obtained by demethylation of bisindolyl-dimethoxyl-p-benzoquinones were found to have greater antitumor activity than the methoxyl derivatives (1981, “Metabolic Products of
Aspergillus terreus
V. Demethylation of Asterriquinones,”
Chem. Pharm. Bull.
29(4): 991-999). Shimizu et al. noted that the presence of free hydroxyl groups in the benzoquinone moiety, as well the number and position of tert-, isopentenyl, or both pentyl groups, seems to have an effect on the antitumor activity of the compound (1982, “Antitumor Effect and Structure-Activity Relationship of Asterriquinone Analogs,”
Gann
73: 642-648). In an attempt to obtain information towards the development of more potent asterriquinone derivatives, Shimizu et al. conducted an investigation into the structure-activity relationship of asterriquinones in which the action mechanism of asterriquinone in its antitumor activity with reference to its interaction with DNA molecules and the plasma membrane of tumor cells was studied (1990, “Interaction of Asterriquinone with Deoxyribonucleic Acid in Vitro,”
Chem. Pharm. Bull.
38(9): 2617-2619). It was reported that a correlation exists between the pKa value of the asterriquinone derivative and its antitumor activity. Id. Maximum antitumor activity was observed for compounds with pKa's in the range of 6-7. Id.
Analysis of structure-activity relationships has led to attempts to obtain compounds with more potent antitumor activity by chemical modification of asterriquinone and related compounds isolated from natural sources (Shimizu et al., 1982, “Antitumor Activity of Asterriquinones from Aspergillus Fungil IV. An Attempt to Modify the Structure of Asterriquinones to Increase the Activity,”
Chem. Pharm. Bull.
30(5): 1896-1899). Although benzoquinone derivatives having aziridinyl groups in the molecule such as mitomycin C, carbazilquinone or “E 39” are well known potent anticancer agents, replacement of the functional groups at the 3 and 6 positions in the benzoquinone moiety of asterriquinone failed to enhance its antitumor potency. Id. Similarly, the introduction of an ethyleneimino group into the molecule did not increase antitumor activity. A dimethylallyl derivative of asterriquinone showed moderate activity against t

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