Selective cytostatic and cytotoxic anticancer effects of bisfunctional agents: A strategy for the design of DNA binding agents.

Various agents have been synthesized and proved useful for the National Cancer Institute's anticancer testing as potential new drugs, but most agents suffer side effects from their limited selectivity against cancer cells over healthy ones. Therefore, this paper attempts to describe drugs in terms of the level of tumor cell selectivity which they possess to define the features of molecules that are essential for useful cytotoxicity. Selected cyclic amidinothymine analogues (NSC 697864, NSC 697865, and NSC 697869) have nanomolar inhibitory activities against leukemia cell lines: CCRF-CEM, HL-60(TB), while bisfunctional cancer fighters NSC 702408 and NSC 702409, showing larger numbers of cytostatic and cytotoxic effects, in an extended conformation would probably adopt a similar to NSC 715653 conformation leaving both opposite H-bond donor groups at the same distance to interact with DNA in a similar way. Such specific interactions (cell line selectivity to unique mutated patterns) lower considerably the observed dose-response concentrations. This in vitro selectivity is shown to translate into in vivo efficacy indicated by the inflection in the cumulative testing curve.