Isoalloxazine derivatives to neutralize biological contaminants

Details Isoalloxazine derivatives to neutralize biological contaminants Isoalloxazine derivatives to neutralize biological contaminants

1999-10-19

2001-07-31

Shah, Mukund J. (Department: 1611)

Chemistry: molecular biology and microbiology

Maintaining blood or sperm in a physiologically active state...

C544S251000, C514S251000

Reexamination Certificate

active

06268120

ABSTRACT:

BACKGROUND OF THE INVENTION
Contamination of blood supplies with infectious microorganisms such as HIV, hepatitis and other viruses and bacteria presents a serious health hazard for those who must receive transfusions of whole blood or administration of various blood components such as platelets, red cells, blood plasma, Factor VIII, plasminogen, fibronectin, anti-thrombin III, cryoprecipitate, human plasma protein fraction, albumin, immune serum globulin, prothrombin complex plasma growth hormones, and other components isolated from blood. Blood screening procedures currently available may miss contaminants. Thus, there is a need for sterilization procedures that effectively neutralize all infectious viruses and other microorganisms but do not damage cellular blood components, do not degrade desired biological activities of proteins, and preferably do not need to be removed prior to administration of the blood product to the patient.
The use of photosensitizers, compounds which absorb light of a defined wavelength and transfer the absorbed energy to an energy acceptor, has been proposed for blood component sterilization. Various photosensitizers have been proposed for use as blood additives. A review of some photosensitizers including psoralens, and some of the issues of importance in choosing photosensitizers for decontamination of blood products is provided in Goodrich, R. P., et al. (1997), “The Design and Development of Selective, Photoactivated Drugs for Sterilization of Blood Products,” Drugs of the Future 22:159-171.
Some photosensitizers that have been proposed for use for blood component sterilization have undesirable properties. For example, European Patent Application 196,515 published Oct. 8, 1986, suggests the use of non-endogenous photosensitizers such as porphyrins, psoralens, acridine, toluidines, flavine (acriflavine hydrochloride), phenothiazine derivatives, and dyes such as neutral red and methylene blue, as blood additives. Another molecule, chlorpromazine, has been used as a photosensitizer; however its usefulness is limited by the fact that it should be removed from any fluid administered to a patient after the decontamination procedure because it has a sedative effect. Protoporphyrin, which occurs naturally within the body, can be metabolized to form a photosensitizer; however, its usefulness is limited in that it degrades the desired biological activities of proteins.
In addition to molecules which can serve as photosensitizers, alkylating agents have been proposed for use as blood contaminant neutralizers. Alkylating agents are believed to deactivate microorganisms by alkylating nucleophilic groups of amino acid residues and nucleic bases at a certain pH. Ethyleneimine has been reported to deactivate certain viruses (U.S. Pat. No. 5,891,075 (Budowsky, et al.),WO 97/07674 (published Mar. 6, 1997)).
U.S. patent application Ser. No. 09/119,666 and continuation in part Ser. No. 09/357,188, hereby incorporated by reference to the extent not inconsistent with the disclosure herein, describes methods and apparatus for neutralization of biological contaminants using endogenous photosensitizers, including 7,8-dimethyl-10-ribityl isoalloxazine (riboflavine).
7,8-dimethyl-10-ribityl isoalloxazine
7,8-dimethyl-10-ribityl isoalloxazine (Riboflavine or vitamin B2) absorbs light from about 200 to 500 nm. The ring system core of 7,8-dimethyl-10-ribityl isoalloxazine is resistant to photodegradation but the ribityl side chain of riboflavin undergoes photodegradation. Photolysis of 7,8-dimethyl-10-ribityl isoalloxazine may form lumichrome (7,8-dimethylalloxazine) depending on conditions. 7,8-dimethylalloxazine strongly absorbs ultraviolet (UV) light and only weakly absorbs visible light.
7,8-dimethylalloxazine
U.S. Pat. No. 5,811,144 discusses the treatment of beer with visible light under substantially anaerobic conditions to reportedly reduce the riboflavin content of the beer.
Small molecules such as those shown below which are derived from the ribityl side chain are expected to be products from the photolysis of riboflavin.
Incomplete photolysis of riboflavin leads to isoalloxazine-containing intermediates (Smith, E. C. and Metzler, D. E. (1963) J. Am. Chem. Soc. 85:3285-3288; Carins, W. L. and Metzler, D. E. (1971) J. Am. Chem. Soc. 93:2772-2777; Treadwell, G. E. et al. (1968) J. Chromatog. 35:376-388). Some of the identified compounds are:
These compounds absorb visible light and may convert to either lumichrome or another riboflavin metabolite, lumiflavin (7,8,10-trimethylisoalloxazine) upon complete photolysis, depending on the experimental conditions.
7,8,10-trimethylisoalloxazine
Lumichrome and lumiflavin are reported to be produced by the photolysis of milk (Parks, O. W. and Allen, C. (1977) Dairy Sci. 61:1038-1041; Toyosaki, T. and Hayashi, A. (1993) Milewissenschaft 48:607-609).
As a result of the degradation of 7,8-dimethyl-10-ribityl isoalloxazine upon exposure to light, a combination of visible and ultraviolet light is preferred in decontamination procedures using 7,8-dimethyl-10-ribityl isoalloxazine. Since UV light has a higher energy per photon than visible light, and because UV light is absorbed more strongly than visible light by useful compounds in the biological fluid, more damage to the useful components in the biological fluid containing the contaminants will occur when ultraviolet light is used in combination with visible light than when visible light can be used alone.
There is a need for compounds that neutralize microorganisms with visible light alone.
All publications referred to herein are hereby incorporated by reference to the extent not inconsistent with the disclosure herein.
BRIEF SUMMARY OF THE INVENTION
Methods are provided for treating a fluid or other material to neutralize at least some of the microorganisms and white cells which may be present therein or thereon. Such fluids may also contain one or more components selected from the group consisting of protein, e.g. biologically active protein such as a therapeutic protein, blood and blood constituents, without destroying the biological activity of such components. The methods comprise:
(a) mixing a neutralization-effective amount of a microorganism neutralizer of formula:
with the fluid, wherein R1, R2, R3, R4, R5 and R6 are, independently from one another, selected from the group consisting of hydrogen, optionally substituted hydrocarbyl, alcohol, amine, polyamine, sulfate, phosphate, halogen selected from the group consisting of chlorine, bromine and iodine, salts of the foregoing, and —NR
a
—(CR
b
R
c
)
n
—X wherein X is a halogen selected from the group consisting of chlorine, bromine and iodine, R
a
, R
b
and R
c
are, independently of each other, selected from the group consisting of hydrogen, optionally substituted hydrocarbyl, and halogen selected from the group consisting of chlorine, bromine and iodine, and n is an integer from 0 to 20;
provided that R1 is not —OH or a straight chain alkyl group where the second carbon of the chain is substituted with —OH or ═O and R1, R4 and R5 are not all methyl groups when R2, R3 and R6 are all hydrogen;
(b) exposing the fluid to a triggering event, whereby at least some of the microorganisms are neutralized.
In one group of compounds, n is an integer between 0 and 5. In another group of compounds, n is an integer from 0 to 10. In another group of compounds, n is an integer from 0 to 20.
A fluid is provided comprising biologically active protein, blood or blood constituents, and microorganism neutralizer, made by the method above. The fluid may also contain neutralized microorganisms. A blood product is also provided comprising a microorganism neutralizer made by the method above.
Compounds are provided having the structure:
wherein R1, R2, R3, R4, R5 and R6 are, independently from one another, selected from the group consisting of hydrogen, optionally substituted hydrocarbyl, alcohol, amine, polyamine, sulfate, phosphate, halogen selected from the group consisting of chlorine, bromine and iodine, salts of the foregoi

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