Triptycenes: a novel synthetic class of bifunctional anticancer drugs thatinhibit nucleoside transport, induce DNA cleavage and decrease the viability of leukemic cells in the nanomolar range in vitro

In contrast to their inactive parent compound triptycene (code name TT0), s everal triptycene (TT) analogs (code names TT1 to TT13), most of them new c ompounds, were synthesized and shown to prevent L1210 leukemic cells from s ynthesizing macromolecules and growing in vitro. The most potent rigid tetr acyclic quinones synthesized so far are TT2 and its C2-brominated derivativ e, TT13, The antitumor activity of TT2 has been compared to that of daunomy cin (DAU), a clinically valuable anthracycline antibiotic which is structur ally different from TT2 but also contains a quinone moiety, TT2 inhibits th e proliferation (IC50: 300 nM at day 2 and 150 nM at day 4) and viability ( IC50: 250 nM at day 2 and 100 nM at day 4) of L1210 cells to the same maxim al degree as DAU, suggesting that the cytostatic and cytotoxic activities o f TT2 are a combination of drug concentration and duration of drug exposure . Since TT2 does not increase the mitotic index of L1210 cells at 24 h like vincristine, it is unlikely to be an antimitotic drug that disrupts microt ubule dynamics. Like DAU, a 1.5-3 h pretreatment with TT2 is sufficient to inhibit the rates of DNA, RNA and protein syntheses determined over 30-60 m in periods of pulse-labeling in L1210 cells in vitro (IC50: 6 mu M) In cont rast to DAU, which is inactive, a 15 min pretreatment with TT2 has the adva ntage of also inhibiting the cellular transport of nucleosides occuring ove r a 30 s period in vitro (IC50: 6 mu M), suggesting that TT2 prevents the i ncorporation of [H-3]thymidine into DNA because it rapidly blocks the uptak e of [H-3]thymidine by the tumor cells. After 24 h, TT2 induces as much DNA cleavage as camptothecin and DAU, two anticancer drugs producing DNA stran d breaks and known to respectively inhibit DNA topoisomerase I and II activ ities. Interestingly, the abilities of TT2 to block nucleoside transport, i nhibit DNA synthesis and induce DNA fragmentation are irreversible upon dru g removal, suggesting that this compound may rapidly interact with various molecular targets in cell membranes and nuclei to disrupt the functions of nucleoside transporters and nucleic acids, and trigger long-lasting antitum or effects which persist after cessation of drug treatment. Because inhibit ion of nucleoside transport is highly unusual among DNA-damaging drugs, the use of bifunctional TTs with antileukemic activity in the nM range in vitr o might provide a considerable advantage in polychemotherapy to potentiate the action of antimetabolites and sensitize multidrug-resistant tumor cells . [(C) 1999 Lippincott Williams & Wilkins].