SMALL MOLECULE PHOTOSENSITIZERS FOR PHOTODYNAMIC THERAPY
Field of the invention
The invention relates to small and neutral potent photosensitizers. The invention further relates to processes for the preparation of the compounds and uses of the compounds in optical imaging and photodynamic therapy. Still further the invention relates to a method for making a photosensitive compound starting from a common scaffold selenobenzodiazole modified with electron-donating groups.
Background of the invention
Photodynamic therapy (PDT) is a treatment that uses a photosensitizer and a particular type of light. When photosensitizers are exposed to a specific wavelength of light, they produce a form of oxygen that kills nearby cells.
A wide number of photosensitisers (PS) have been developed. However, a very few are seeing regular use within contemporary clinical practice due to their intrinsic limitations, including lack of selectivity, systemic phototoxicity, and large molecular size that impedes conjugation to small biomolecules like metabolites, peptides or nucleic acids.
For instance, one important strategy in the development of cancer-targeting therapies is to harness the Warburg effect, which is related to a considerable rise in glucose uptake and is observed in the majority of tumours. This metabolic effect is particularly prevalent within glioblastomas, where malignant brain cells take up large amounts of glucose.
Whereas the preparation of PS based on chlorins and porphyrins has been widely described, its conjugation to glucose is hampered by the large size and charges of the photosensitive scaffolds, which leads to a reduction in both the recognition of glucose transporters and limited tissue permeability (e.g., crossing blood brain barrier), which is essential for effective therapies.
Therefore, there is still the need for photosensitizers, which allow conjugation to small biomolecules like metabolites, peptides or nucleic acids, are selective and do not have systemic phototoxicity, Statement of the invention
The present invention provides compounds, which are small enough to retain the transport and uptake properties of small biomolecules including metabolites.
The compound of the invention can be used in photodynamic therapy for ablation of metabolically-active cells. Once the labelled metabolites are uptaken by the target cells, their activation with visible light leads to singlet oxygen generation and concomitant cell death.
The compounds of the invention can also be used to label cancer cells, immune cells as well as stem cells for cell-based therapies or fluorescence-guided surgery. They are also suitable to be used for other optical imaging modalities beyond fluorescence. For example, they can be used as multimodal reagents as they can be readily detected under Surface-Enhanced Raman Scattering upon conjugation to metal surfaces.
In particular, it is hereby provided a compound of formula (I), a derivative or a salt thereof wherein
R1 is selected from the group consisting of amines, anilines, phenols, thiophenols, selenols and aryl groups;
R2 and R3 independently are H or a halogen;
R4 is selected from the group consisting of H, nitro and cyano; and
R5 and R6 independently are either absent, or oxygen or methyl.
Preferably R1 is an amine or an aniline. Preferably R2 and/or R3 are/is H.
Preferably R4 is nitro.
Preferably R5 and/or R6 are/is absent.
The compound is preferably selected from the group consisting of PS-SCOTfluor-1 to PS- SCOTfluor-20 reported below, and a derivative or a salt thereof.
etc.