A number of new 4'-O-demethylepipodophyllotoxin derivatives possessing various 4 beta-N- or 4 beta-O-benzyl groups have been synthesized and evaluated for their inhibitory activity against the human DNA topoisomerase II as well as for their activity in causing cellular protein-linked DNA breakage. The 4 beta-N-benzyl derivatives 9-22 are, in general, as active or more active than etoposide (1). The most active compounds are 14, 16, and 17, which are more than 2-fold more potent than 1. The results indicated that a basic unsubstituted 4 beta-benzylamino moiety is structurally required for the enhanced activity. Replacement of the benzyl nitrogen with oxygen gave compounds (23 and 24) which are inactive. The ability of these compounds to inhibit human DNA topoisomerase II and to cause protein-linked DNA breakage appears to have no direct correlation with cytotoxicity in KB cells.

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The trans-fused gamma-lactone ring of etoposide is readily epimerized to its cis epimer, which is biologically inactive, or is metabolized to the inactive ring-opened hydroxy acids. Modification of this gamma-lactone ring of 4 beta-(arylamino)-4'-O-demethyl-4-desoxypodophyllotoxin resulted in several compounds (15-16, 21-22, and 24) that should block this epimerization and the resulting biological deactivation. In a topoisomerase II inhibition assay, compounds 21, 22, and 24 showed comparable activity to etoposide. In a protein-linked DNA complex formation assay, compounds 21 and 22 were more active than etoposide.

In this paper, we study homological dimensions of algebras linked by recollements of derived module categories, and establish a series of new upper bounds and relationships among their finitistic or global dimensions. This is closely related to a longstanding conjecture, the finitistic dimension conjecture, in representation theory and homological algebra. Further, we apply our results to a series of situations of particular interest: exact contexts, ring extensions, trivial extensions, pullbacks of rings, and algebras induced from Auslander-Reiten sequences. In particular, we not only extend and amplify Happel's reduction techniques for finitistic dimenson conjecture to more general contexts, but also generalise some recent results in the literature.

A series of ortho-quinone analogues 1-28 of podophyllotoxin possessing various C-4 beta-aniline moieties have been synthesized and evaluated for their inhibitory activity against human DNA topoisomerase II, their activity in causing cellular protein-linked DNA breakage, and their cytotoxicity against KB cells. Compounds 8-12, 15, 19, and 23-28 are better than or comparable to etoposide in their inhibition of the human DNA topoisomerase II, while compounds 8-10 and 22 are comparable to or more potent than etoposide in causing DNA breakage. There is an apparent lack of correlation between cytotoxicity and the ability of these compounds to cause protein-linked DNA breaks or inhibit DNA topoisomerase II. This suggests that in addition to the mechanism of the topoisomerase II involving DNA breakages, other mechanisms of action, such as the radical mechanism or the direct adduct formation of the ortho-quinone with DNA or protein, may also involve and account for the apparent KB cytotoxicity. Two different modes of DNA topoisomerase II inhibition for 8-28 were proposed.