Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1988-11-23
1992-01-07
Wax, Robert A.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
548512, A01N 4390, A61K 3147, C07D20932, C07D20946
Patent
active
050792571
DESCRIPTION:
BRIEF SUMMARY
The present investigation relates to new indoloquinone compounds and to methods of preparing them.
Mitomycins.sup.1 have been known for many years to have strong antibacterial and cytostatic activity. In particular, mitomycin C, which has the formula: ##STR1## has been shown to be active against breast, pancreatic and prostatic adenocarcinomas, and notably against colon, bladder, lung and gastro-intestinal cancer.
However, clinically, mitomycin C was found to have disadvantages and consequently many derivatives of mitomycin C have been synthesized in attempts to develop more effective antitumour agents with a higher antitumour activity and a lower toxicity than mitomycin C itself.
Among the derivatives of mitomycin C, 7-methoxymitosene of the formula: ##STR2## is known to have important antibacterial activity in vitro and in mice.sup.2, and this fact prompted the synthesis of a number of related indoloquinones of the general formula.sup.3 : ##STR3## These compounds were found to have antibacterial activity, but none show antitumour activity below the toxic dosis. However the degree of variation in the structure of indoloquinones produced was limited by the method of synthesis used.
The mitomycin antibiotics belong together with the anthracyclines.sup.4, the aziridinyl quinones.sup.5, streptonigrin.sup.6, saframycin.sup.7 and mitoxanthrone.sup.8 to the quinoid antitumour compounds.sup.9, which require reduction to exert their main cytotoxic effects. The following two mechanisms of action may be involved:
A. Redox cycling (Scheme 1 A)
Quinoid cytostatic agents are transformed by an enzymatic one-electron reduction into their corresponding semiquinone radical anions. Because of its ubiquitous existance in many cells and cell compartments NADPH-cytochrome P-450 reductase is regarded as the major enzyme catalyzing these reactions. Depending on the redox potential of the semiquinone radical anion, a reaction with oxygen may occur. The superoxide anion formed can undergo a variety of reactions. It spontaneously dismutates to hydrogen peroxide and singlet oxygen (.sup.1 O.sub.2). Ground state dioxygen is formed when superoxide dismutase is involved in this step. Superoxide anion radicals together with hydrogen peroxide molecules give rise to the formation of cytotoxic hydroxyl radicals in the metal-catalyzed Haber-Weiss cycle. ##STR4## The hydroxyl radical, the most reactive oxygen metabolite, is suggested to be responsible for some of the serious damages occurring during redox cycling processes, e.g. lipid peroxidation, enzyme inactivation and DNA cleavage. Further as can be derived from scheme 1 A, NADPH depletion could also be a critical event.
Tumour cells are deficient in enzymes that normally protect the cell against free radical damage and this may explain part of the selective cytotoxicity of the antitumour quinones.sup.12. The protective mechanism embraces a combined action of either superoxide dismutase and catalase or superoxide dismutase and glutathion peroxidase.
B. Bioreductive alkylation
Several reduced quinoid cytostatic agents are not stable, but decompose into reactive intermediates which can undergo nucleophilic addition reactions with several biologically important nucleophiles.
The concept of "bioreductive alkylation", which applies to the mechanism of action of these antitumour compounds, has been formulated by Lin et al. in 1972.sup.11a, on studying the biological activity of derivatives of methyl substituted benzoquinones and naphthoquinones. The bioreductive activation of quinone containing cytostatic agents in essence comprises the reduction of quinone (4) to its dihydroform (5) after which HX is expelled and the .alpha.-methylene carbonyl structure (6) generated. The latter form supposedly acts as a Michael acceptor and binds the nucleophile (Scheme 1 B). ##STR5## The efficiency of such compouds can be enhanced by the introduction of additional methyl substituents bearing a leaving group. Upon reductions two or more unsaturated moieties are formed, creating possibilities for the crosslin
REFERENCES:
patent: 3265698 (1966-08-01), Allen, Jr. et al.
Oostveen Everardus A.
Speckamp Willem N.
Farley Walter C.
Tsung F.
Wax Robert A.
LandOfFree
Indoloquinone compounds does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Indoloquinone compounds, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Indoloquinone compounds will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-822764