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We have synthesized a series of bis(9-aminoacridine-4-carboxamides) linked via the 9-position with neutral flexible alkyl chains, charged flexible polyamine chains, and a semirigid charged piperazine-containing chain. The carboxamide side chains comprise N,N-dimethylaminoethyl and ethylmorpholino groups. The compounds are designed to bisintercalate into DNA by a threading mode, in which the side chains are intended to form hydrogen-bonding contacts with the O6/N7 atoms of guanine in the major groove, and the linkers are intended to lie in the minor groove. By this means, we anticipate that they will dissociate slowly from DNA, and be cytotoxic as a consequence of template inhibition of transcription. The dimers remove and reverse the supercoiling of closed circular DNA with helix unwinding angles ranging from 26 degrees to 46 degrees, confirming bifunctional intercalation in all cases, and the DNA complexes of representative members dissociate many orders of magnitude more slowly than simple aminoacridines. Cytotoxicity for human leukemic CCRF-CEM cells was determined, the most active agents having IC(50) values of 35-50 nM in a range extending over 20-fold, with neither the dimethylaminoethyl nor the ethylmorpholino series being intrinsically more toxic. In common with established transcription inhibitors, the morpholino series, with one exception, have no effect on cell cycle distribution in randomly dividing CCRF-CEM populations. By contrast, the dimethylaminoethyl series, with two exceptions, cause G2/M arrest in the manner of topoisomerase poisons, consistent with possible involvement of topoisomerases in their mode of action. Thus, the cellular response to these bisintercalating threading agents is complex and appears to be determined by both their side chain and linker structures. There are no simple relationships between structure, cytotoxicity, and cell cycle arrest, and the origins of this complexity are unclear given that the compounds bind to DNA by a common mechanism.

Seven isonitrogenous and isolipidic diets containing fish meal (FM) protein replaced by corn gluten meal (CGM) protein at 0% (the control, C0), 10% (C10), 20% (C20), 30% (C30), 40% (C40), 50% (C50) and 60% (C60) were fed to juvenile Pseudobagrus ussuriensis for 8-weeks to evaluate the effects of FM protein replaced by CGM protein on growth, feed utilization, nitrogen (N) and phosphorus (P) excretion and IGF-I gene expression of juvenile P. ussuriensis. The results showed that the replacement level up to 40% did not affect the weight gain, specific growth rate (SGR), feed intake and protein efficiency ratio, whereas these parameters were depressed by further replacement level. Apparent digestibility coefficients (ADC) of dry matter, crude protein significantly decreased, but ADC of phosphorus significantly increased with increasing dietary CGM levels (p < .05). Fish fed diets with FM protein replaced by CGM protein led to an increase in nitrogen excretion, but led to a reduction in phosphorus excretion. No significant differences were observed in alpha-amylase and lipase activities of intestine (p > .05). The lowest pepsin activity was found in C60 group. Fish fed diet C40, C50 and C60 had significantly lower serum lysozyme activity compared with fish fed diet C0 (p < .05).The lowest plasma alkaline phosphatase activity and the highest plasma alanine aminotransferase and aspartate aminotransferase activities were observed in C60 group. Fish fed diet C60 had significantly lower hepatic IGF-I gene expression compared with fish fed diet C10 (p < .05). Broken-line model analysis based on SGR against the CGM substitution level indicated that the appropriate replacement level was 37.7%.