Edinburgh Napier University

  The present invention relates to compounds which are based on an anthraquinone nucleus for use in medicine, particularly as anti-cancer agents which exert their effects through their interaction with the activity of topoisomerases. The inhibition of DNA topoisomerases, particularly topoisomerase II (topo II) is now considered to be an important component in the mechanism of action of a large number of the most clinically active anticancer drugs presently available...

By "derivatives" of the compounds of the invention, we include salts (acid or base addition), esters, amides, hydrazides and hydroxamic acids of the group B and other derivatives which do not diminish to an unacceptable extent the fundamental topoisomerase mediated activity, ie. anti-tumour properties of the compounds. Further preferred derivatives include those in which functional groups on the peptide group, which may be side groups or the terminal group, are capped.

It is an object of this invention to provide improved clinically active anticancer agents preferably having one or more of the following properties: (i) reduced or eliminated capacity to induce generation of free radical species, (ii) reduced or eliminated capacity to bind to DNA or RNA, (iii) different relative activity against topoisomerases I, IIa and IIb (3 as compared to the known prior art compounds and (iv) activity, particularly being improved as compared to known compounds of this type, against drug resistant cell lines.

Compounds demonstrate non-cross resistant activity against resistant cell lines ... have broad spectrum activity and shrink MAC15A tumours in vivo in test animals. Furthermore, initial screening in the NCI screen shows compounds of the invention to be cytotoxic against NCI-H460 (lung), MCF7 (breast) and SF-268 (CNS) tumour lines.
It should be noted that while many of the results presented relate to trifluoroacetic acid salts, corresponding salts, eg. acetates, have been found to have equivalent activities.