Bis(phenazine-1-carboxamides):  Structure−Activity Relationships for a New Class of Dual Topoisomerase I/II-Directed Anticancer Drugs

Abstract

Ring-substituted bis(phenazine-1-carboxamides), linked by a -(CH(2))(3)NMe(CH(2))(3)- chain, were prepared from the corresponding substituted phenazine-1-carboxylic acids by reaction of the intermediate imidazolides with bis(3-aminopropyl)methylamine. The compounds were evaluated for growth inhibitory activity in a panel of tumor cell lines, including P388 leukemia, Lewis lung carcinoma, and wild-type (JL(C)) and mutant (JL(A) and JL(D)) forms of human Jurkat leukemia. The latter mutant lines are resistant to topoisomerase (topo) II targeted agents because of lower levels of the enzyme. Analogues with small, lipophilic substituents (e.g., Me, Cl) at the 9-position were the most potent inhibitors, superior to the corresponding dimeric bis(acridine-4-carboxamides) (bis-DACA analogues). Several of the compounds were preferentially (up to 2-fold) more cytotoxic toward the mutant Jurkat lines than the wild-type. To test whether this selectivity was related to topoisomerase action, the most potent of the compounds (9-methyl) was evaluated in a cell-free system. It poisoned topo I at drug concentrations of 0.25 and 0.5 microM and inhibited the catalytic activity of both topo I and topo II at concentrations of 1 and 5 microM, respectively. Results from the NCI human tumor cell line panel showed the compounds had preferential activity toward colon tumor lines (on average 9.5-fold more active in the HT29 line than in the cell line panel as a whole). Several analogues produced significant growth delays in the relatively refractory subcutaneous colon 38 tumor model in vivo. In particular, the 9-methyl compound was substantially more potent in this tumor model than the clinical dual topo I/II poison DACA (total dose 90 versus 400 mg/kg) with comparable activity. The bis(phenazine-1-carboxamides) are a new and interesting class of dual topo I/II-directed anticancer drugs.

Synthesis and Antispasmodic Activity Evaluation of Bis-(Papaverine) Analogues

“…Table 1 summarizes the concentration of papaverine and test compounds producing 50% relaxation (IC 50 ) of acetylcholine induced contraction for compounds 6-13 and (6)(7)(8)(9)(10)(11)(12)(13). Second category has piperazinyl, substituted piperazinyl ring placed between two acetyl groups, as linkers (15)(16)(17)(18). Third category consists of piperazinyl, substituted piperazinyl ring placed between two carbamoyl groups, as linkers (21)(22)(23)(24).…”

“…bis-(triazoloacridinones), 11) bis-(anthracyclines), 12,13) bis-(acridine-4-carboxamides), 14) bis-(phenazine-1-carboxamides) 15,16) and bis-(indeno [1,2-b]quinoline-6-carboxamides). 17) A comparative study of a variety of bis analogues with their monomeric counterparts has revealed that there are variable but significant gains in potency for the dimeric species.…”

Considerations for Treatment Development in Rhabdomyosarcoma: In Vitro Assessment of Novel DNA Binding Drugs

“…With the linker chains laying in the minor groove of the DNA helix they play a crucial role in the overall activity of the compound by placing a physical block in the path of DNA tracking enzymes (Wakelin et al, 2003). The second class of transcription inhibitors ( Figure 1B,C) contain representatives of phenazine-1-carboxamide dimers bridged via their side chains with alkylamino linkers of various structures (Spicer et al, 2000). Within this class, the clinical candidate MLN944/XR5944 bisintercalates with its linker in the DNA major groove making hydrogen bonding interactions to guanines in a sequence specific manner.…”

“…This generalized resistance to the bisacridines also extends to the bis(phenazinecarboxamide) dimers, with one important exception. These compounds were designed as bisintercalating topoisomerase I and II poisons (Spicer et al, 2000), but their actual mechanism of action is complex and appears to involve both transcription inhibition, along with topoisomerase I poisoning (Byers et al, 2005). The three compounds studied here are potently cytotoxic in mouse leukemia P388, mouse Lewis lung and Jurkat human leukemia cells (Gamage et al, 2001).…”

DFT Calculation on 76 Polychlorophenazines: Their Thermodynamic Function and Implication of Cl Substituted Position

“…Natural and synthetic phenazines have attracted considerable attention because of their interesting biological activities [3], that is, antibiotic and anticancer agents [4,5]. Halosubstituted phenazines are useful as herbicides [6].…”