DEPSIPEPTIDES AND THEIR THERAPEUTIC USE

摘要

The invention relates to compounds of structure III or IV, isosteres and pharmaceutically acceptable salts thereof, wherein R1, R2, R3, R4, R5, R6, R7and R9are hydrogen or a natural or unnatural amino acid side-chain moiety; R10is hydrogen, alkyl, alkenyl or alkynyl; R8is -CR11R11-CR11R11-(CH2)n-R12, -CR11=CR11-(CH2)n-R12or -C=C-(CH2)n-R12; R11is hydrogen, alkyl, alkenyl, alkynyl or heteroaryl; R12is a linear or cyclic metal chelating moiety; and n=0-7; with the proviso that R12is not -SH nor -SPr2, Pr2being a thiol protecting group. Examplified R1and R2are hydrogen or isopropyl, or together form a cyclopropyl; R3, R4= hydrogen or methyl; R5, R6= thiazol-4-ylmethyl or pyridin-3-yl-methyl; R7= R9= R10= hydrogen; and R8= -(CH2)4CO2H, -(CH2)4CO2Me, -(CH2)4CO2tBu, -(CH2)4CONHOH or -(CH2)4CONHOTBS. The compounds may be useful as histone deacetylase (HDAC) inhibitors, for the treatment of cancer, cardiac dystrophy, chronic heart failure, skin inflammatory conditions, haemoglobinopathy, thalassemia, sickle cell disease, CNS disorders, autoimmune diseases, diabetes and other HDAC-mediated conditions. Methods for assaying HDAC inhibition are outlined.