Porphyrin derivatives and their use in photodynamic therapy
Inventors
Love, William • Brundish, Derek • Rhys-Williams, William • Feng, Xiang Dong • Pugin, Benoit
Assignees
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Publication Number
US-8084602-B2
Publication Date
2011-12-27
Expiration Date
Abstract
A compound of formula I: wherein X1, X2, X3, X4, Y1, Y2, Y3, Y4 and Z have meanings given in the description, and metallated forms of such compounds, which are useful in the treatment of medical conditions for which a photodynamic compound is indicated. Pharmaceutical formulations and methods of treatment of a medical condition for which a photodynamic agent is indicated are also disclosed. Sterilizing solutions comprising a compound of the invention, and the use thereof, are also disclosed.
Core Innovation
The invention relates to a method for selectively killing bacteria by administering a compound of formula I or II. The compounds are defined with variable substituents X1, X2, X3 and X4, where at least one of X1, X2, X3 and X4 is a cationic group and at least one of X1, X2, X3 and X4 is a hydrogen atom. The structures further include optional linker moiety L, a flexible definition of Z as —CH or N, and variable groups Y1, Y2, Y3 and Y4 that may be absent or independently represent aryl, lower alkyl, lower alkenyl or lower alkynyl.
The compound definitions further require that R1 represents lower alkylene, lower alkenylene or lower alkynylene, optionally substituted by specified substituent classes, while R2, R3 and R4 independently represent H, aryl, lower alkyl, lower alkenyl or lower alkynyl with optional substituents from the same selected classes. The provided material also describes porphyrin compounds prepared with aryl substitutions, including long alkoxy/alkyl chains and cationic ammonium side chains, with named examples and 1H-NMR characterization.
The disclosed approach is directed to selective killing based on phototoxicity versus dark toxicity and an intended therapeutic window between bacterial and mammalian toxicity. The description states that the compounds can provide low micromolar toxicity and at least two-fold bacterial over mammalian toxicity, and frames illumination as a component of photodynamic therapy. The disclosure also provides examples of specific porphyrin compounds and salt forms, and describes pharmaceutical formulations and illumination/wavelength ranges associated with porphyrin absorption.
Claims Coverage
The independent claim explicitly recites a method for selectively killing bacteria by administering a compound of formula I or II, with multiple structural limitations including cationic group presence, defined scaffold variables, optional linking moiety, Z as —CH or N, and a metal or metalloid element M. The claim coverage centers on this antibacterial administration method and its defined substitution pattern.
Selectively killing bacteria by administering a compound of formula I or II
A method for selectively killing bacteria comprising administering a compound of formula I or II, wherein X1, X2, X3 and X4 independently represent hydrogen atom, a lipophilic moiety, a phenyl group, a lower alkyl, alkaryl or aralkyl group, or a cationic group, and wherein M is a metallic element or a metalloid element.
Defined structural variables with optional linking moiety and Z definition
The compound includes a linking moiety L or is absent, with Z being —CH or N, and Y1, Y2, Y3 and Y4 being absent or independently aryl, lower alkyl, lower alkenyl or lower alkynyl with optional substituents selected from the specified classes.
At least one cationic group and at least one hydrogen atom among X1–X4
The compound is defined such that at least one of X1, X2, X3 and X4 is a cationic group and at least one of X1, X2, X3 and X4 is a hydrogen atom.
R1 flexible chain with specified optional substituent classes
R1 represents lower alkylene, lower alkenylene or lower alkynylene and is optionally substituted by one or more substituents selected from lower alkyl, lower alkylene optionally interrupted with oxygen, fluoro, OR5, C(O)R6, C(O)OR7, C(O)NR8R9, NR10R11 and N+R12R13R14.
R2–R4 group definition with shared optional substituent classes
R2, R3 and R4 independently represent H, aryl, lower alkyl, lower alkenyl or lower alkynyl, the latter three of which are optionally substituted by one or more substituents selected from lower alkyl, lower alkylene optionally interrupted with oxygen, aryl, OR5, C(O)R6, C(O)OR7, C(O)NR8R9, NR10R11 and N+R12R13R14.
The claim coverage centers on a method that selectively kills bacteria through administration of a formula I or II compound, defined by cationic-group inclusion alongside at least one hydrogen atom among X1–X4, specified scaffold variables L, Z, X1–X4, Y1–Y4, and R1–R4, and selection of a metallic or metalloid element M.
Stated Advantages
Selective killing of bacteria.
Low micromolar toxicity.
At least two-fold bacterial over mammalian toxicity.
Therapeutic window based on phototoxicity versus dark toxicity.
Low-dose, light-dependent killing of both Gram-positive and Gram-negative bacteria.
Contrasting dark toxicity and photodynamic activity.
Documented Applications
Photodynamic therapy use for selectively killing bacteria and microorganisms, including antibiotic-resistant bacteria.
Administration of compounds for selectively killing bacteria.
Light-dependent antibacterial activity testing.
Assays with growth inhibition (%) and CFU survival.
Selectivity and mechanistic studies related to singlet-oxygen mediation and distribution and subcellular localization within skin compartments.
Pharmaceutical formulations and illumination/wavelength ranges associated with porphyrin absorption.
In vitro microorganism killing and sterilising solutions using surfactant-containing formulations with photosensitive porphyrin compounds.
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