Second generation tumour photosensitisers: the synthesis and biological activity of octaalkyl chlorins and bacteriochlorins with graded amphiphilic character

Abstract

Routes to hydroxychlorin derivatives of two distinct categories (nuclear hydroxy substituent; side-chain hydroxy substituent) are developed. Such substances, covering a range of amphiphilic character depending on the number of hydroxy groups, are seen as potential sensitisers for photodynamic therapy. Osmylation of octaethylporphyrin gives the dihydroxyoctaethylchlorin 2 and the tetrahydroxybacteriochlorin 3. Pinacol–pinacolone rearrangement of 2 gives the octaethyl-β-oxochlorin 4, borohydride reduction of which gives the secondary alcohol 6. This is converted via the bromochlorin 7(prepared using 50% HBr/HOAc at room temperature) into a series of ethers, including those, 10, 11, 12, derived from glycerol, D-glucose, and D-mannitol respectively. Alkylation of these unprotected polyols with the highly hindered bromide 7 occurs preferentially at the primary alcohol functions in each case. Some of these hydroxychlorins are found in animal assays to be highly effective sensitisers of tumour photonecrosis. In this respect the most effective compounds in each category are the most highly hydroxylated. However, the D-glucose derivative 11 proves also to be an effective sensitiser of skin and muscle, i.e. it does not show the selectivity shown by 5,10,15,20-tetra(m-hydroxyphenyl)chlorin.