Cellular penetration

Zl. Zack, D. J., Stempniak, M., Wong, A. L., Taylor, C., andWeisbart, R. H., Mechanisms of cellular penetration and nuclear localization of an anti-double strand DNA autoantibody. J. Immunol. 157, 2082-2088 (1996). 

The oh.scT ation that certain catechol-substituted cephalo-.sporins exhibit marked broad-spectrum antibacterial activity l to the discovery that such compounds and other analogues capable of chelating iron could mimic natural sidero-phores (iron-chelating peptides) and thus be actively transported into bacterial cells via the roiiB-dependent iron-transport sy.stem." This provides a meaas of attacking bacterial strains that resist cellular penetration of eephalo-.sporins. 

Other conceivable explanations for the lack of cellular activity concerned cellular penetration and active efflux. Our data in the Caco-2 penetration model indicated the compounds should have significant cellular penetration. Although the data from our active efflux studies were not conclusive this also did not appear to be a problem with the compounds as a class. 

Tenofovir is a derivative of adenosine 5 -monophosphate lacking a complete ribose ring and is the only nucleotide analog currently marketed for the treatment of HIV infection. Because the parent compound had very poor oral bioavailability, tenofovir is available only as the disoproxil fumarate prodrug, which has improved oral absorption and cellular penetration substantially. Like lamivudine and emtricitabine, tenofovir is active against HIV-1, HIV-2,... 

Piper et al. [368] acylated the terminal amino group in the MTX analogues (VIII.268)-(VIII.270) with 4-chlorobenzoyl chloride to form the amides (VIII.281)-(VIII.283). More recently a series of A -acyl derivatives of the AMT analogue (VIII.275) were prepared from A -(4-amino-4-deoxy-A °-formylpteroyl-L-ornithine (VIII.274) by reaction with appropriate anhydrides to give the A -disubstituted derivatives (VIII.284)-(VIII.289) [370]. Selective hydrolysis at N ° with dilute NaOH then gave the A -acyl derivatives (VIII.290)-(VIII.295). The impetus behind these studies was a desire to improve cellular penetration, which is hindered in the parent compounds by protonation of the side-chain amino group at physiologic pH. 

Flanagan, W., et al.. Cellular penetration and antisense activity by a phenoxazine-substituted heptanucleotide. Nature Biotechnology, 1999, 17, 48-52. 

The 6-fluorine provides a significant enhancement in antibacterial activity for many quinolones presumably by increasing cellular penetration (11,20) and the inhibitory activity against the enzyme. In the case of norfloxacin, a fluorine at the 6-position provides a compound which is 16-fold more potent against. E. CoS than the nonfluorinated derivative (21—24). Substituents other than fluorine at the 6-position have provided some enhancement in activity over the 6-H compound, but this has been less than that provided by fluorine (11). In some cases the effect of the 6-fluorine is much smaller, depending on the group at the 7-position (25,26). 

Table 43.2. Antiviral Agents Interfering with Cellular Penetration and Early Replication ...

Bioisosteric replacement is often considered when tbe aims are to maintain enzyme potency wbUe optimizing additional properties, sudi as cellular penetration, solubility, metabolism, toxidty, and so on. This prindple is often referred to as multiobjective optimization (MOOP) or multiparameter optimization (MPO) [12]. There are many ways in which one can address multiple objectives, but it is important to understand the landscape of the trade-off surface between each of the important... 

The 7-0-j3-D-glucosamine derivative of daunomycinone was the first compound prepared in which the daunosamine residue is replaced [70]. The compound is however inactive in vivo [223] due to its inability to bind to DNA [213]. Esterification of the 7-OH group of daunomycin has also been attempted, for example compounds (89-93) show some activity in vivo [86,224]. It is interesting to compare the related compounds (94) and (95). The latter appears to have the greater degree of cellular penetration since it is about three times more active as an inhibitor of cellular nucleic acid synthesis, yet it shows no in vivo activity whereas compound (94) shows low activity [72]. The simpler analogue (95) therefore has an unfavourable distribution or is more rapidly hydrolysed. 

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