Phenylamidine cationic groups linked by a furan ring (furamidine) and related compounds bind as monomers to AT sequences of DNA. An unsymmetric derivative (DB293) with one of the phenyl rings of furamidine replaced with a benzimidazole has been found by quantitative footprinting analyses to bind to GC-containing sites on DNA more strongly than to pure AT sequences. NMR structural analysis and surface plasmon resonance binding results clearly demonstrate that DB293 binds in the minor groove at specific GC-containing sequences of DNA in a highly cooperative manner as a stacked dimer. Neither the symmetric bisphenyl nor bisbenzimidazole analogs of DB293 bind significantly to the GC containing sequences. DB293 provides a paradigm for design of compounds for specific recognition of mixed DNA sequences and extends the boundaries for small molecule-DNA recognition. O rganic cations that bind in the DNA minor groove have biological activities that range from anti-opportunistic infection to anticancer properties (1-5). Such compounds have also provided a wealth of fundamental information about nucleic acid recognition properties, and they continue to be important models in the study of nucleic acid complexes (1, 2, 6-8). Netropsin ( Fig. 1) was the first minor-groove-binding compound crystallized with a B-form DNA, and the structure of the complex provided clear suggestions about the molecular basis for AT base pair sequence-specific recognition (9). The structure also lead to proposals by the Dickerson and Lown groups for minor-groove binding netropsin analogs, lexitropsins, that could specifically recognize GC base pairs and could, thus, have extended sequence recognition capability (10-12). Initial efforts in the design of analogs of netropsin that could recognize GC base pairs, however, yielded compounds of limited specificity. A breakthrough in this area occurred with the discovery that the monocationic relative of netropsin, distamycin ( Fig. 1), could bind into the minor groove of some AT sequences of DNA as a stacked, antiparallel dimer (7,13,14). Replacement of pyrrole groups in distamycin by imidazole provided lexitropsins with improved GC recognition specificity through dimer complexes, and current design efforts in the pyrrole-imidazole polyamide system have reached a high level of success (15-18). With recent developments by the Dervan group, AT and TA as well as GC and CG base pairs can now be effectively distinguished in DNA sequences by polyamides (15-18).Interestingly, the polyamide system is the only one of the well known minor-groove binding motifs that has yielded conclusive evidence for formation of the stacked-dimer recognition unit, although recent evidence indicates that some monocationic cyanine dyes can form an array of stacked dimers in the DNA minor groove (19). No dications have been found to form the stacked-dimer recognition motif. Netropsin, the first minorgroove-binding agent to be characterized in detail and a dicationic relative of the monocation distamycin (Fig. 1), for example, does n...

Twenty analogues of pentamidine, 7 primary metabolites of pentamidine, and 30 dicationic substituted bis-benzimidazoles were screened for their inhibitory and fungicidal activities againstCandida albicans and Cryptococcus neoformans. A majority of the compounds had MICs at which 80% of the strains were inhibited (MIC80s) comparable to those of amphotericin B and fluconazole. Unlike fluconazole, many of these compounds were found to have potent fungicidal activity. The most potent compound against C. albicans had an MIC80 of ≤0.09 μg/ml, and the most potent compound against C. neoformans had an MIC80 of 0.19 μg/ml. Selected compounds were also found to be active againstAspergillus fumigatus, Fusarium solani,Candida species other than C. albicans, and fluconazole-resistant strains of C. albicans and C. neoformans. It is clear from the data presented here that further studies on the structure-activity relationships, mechanisms of action and toxicities, and in vivo efficacies of these compounds are warranted to determine their clinical potential.

The inclusion of phenolic compounds enhanced growth performance, decreased lipid oxidation, decreased cholesterol value and increased beneficial fatty acids content. Positive effects varied depending on phenolic compound used and, therefore, it would be interesting to further investigate synergistic effects of investigated phenolic compound.

The syntheses of nine new derivatives of 2, 5-bis[4-(N-alkylamidino)phenyl]furans with extended aromatic systems are reported. The interaction of these dicationic furans with poly(dA)poly(dT) and with the duplex oligomers d(CGCGAATTCGCG)2 and d(GCGAATTCGC)2 was determined by Tm measurement, and the effectiveness of these compounds against the immunosuppressed rat model of Pneumocystis carinii was evaluated. At a screening dose of 10 micromol/kg, 4 of the 12 amidino furans described here are more active than the parent compound 1. In general, extension of the aromatic system in the absence of a substitution of the amidino nitrogens resulted in higher affinity for DNA than the parent compound as judged by the larger DeltaTm values and suggests enhanced van der Waals interactions in the amidino furan-DNA complex. Three of the compounds, 3, 5, and 11, yield cysts counts of less than 0.1% of control when administered at a dosage of 10 micromol/kg. Compound 3, which does not have an extended aromatic system, is the most active derivative. Although a direct correlation between anti-P. carinii activity and DNA binding affinity was not observed, all compounds which have significant activity have large DeltaTm values.