other nitroimidazooxazines were found to be significantly more effective than P

A set of these substances differed from 1 in the glycosylation sample, and showed lower antitumor activity in vitro. This result was relating to what it'd been previously noted for other glycosylated analogues of 1, which showed a decrease in its anti-tumor activity and also lacked one or two deoxysugars. Some exceptions to this principle were materials that missing one deoxysugar Cyclopamine still included a D mycarose residue. They don't include this saccharide residue, which matches with their anticipated lower activity, since substances 5 to 8 were developed in a mutant defective in D mycarose bio-synthesis. A second pair of compounds being in compounds 11 and 9 about 5-fold more active than 10, and showed high anti-tumor activity, combined changes in the glycosylation pattern and within the 3 side chain. Compounds 9 and 11 showed similar anti-tumor action Papillary thyroid cancer in vitro, and were also more potent than 1 for some tumor cell lines, though in average they were slightly less potent. These two compounds combined two structural features that had been previously found to enhance mithramycin pharmacological behavior: a D digitoxose residue in place of D mycarose in the E position of the chain, and an altered 3 carbon side chain. It has been noted that the oligosaccharide moieties be involved in the binding of this family of compounds to DNA, being the sugar E of the trisaccharide sugar chain one of the main interaction points. Also, adjustments at the 3 side chain have unveiled to influence the capacity of inhibiting Sp1 binding to DNA, the energy of binding to DNA, and the cellular uptake of mithramycins. Since compounds 9 and 11 are modified just at the sugar E and at the 3 side chain, it would be likely to show various properties, as it is the case. Moreover, FK866 substance 9 showed a better behavior in vivo than 1 and 11 in hollow fiber assays, both on intraperitoneal and subcutaneous implants. Currently, it is unclear the main reason for this; a better bioavailability and/or differences in DNA specificity, and therefore differences on inhibition of gene transcription mediated by Sp1 and/or other transcription factors, could account for this behavior. In this sense, compounds 3 and 4, which only change from 1 in the 3 side chain, also showed a much better action in vivo in prostate and ovarian tumor xenografs. 6,42 About the other hand, pharmacokinetics of compound 9 doesn't seem the main reason for its better behavior in vivo in comparison to the compound 1, because similar pharmacokinetics were revealed by studies in mice for both substances. Moreover, although substance 9 is cleared rapidly in the bloodstream, it s efficacious in melanoma and colon xenografs, particularly at higher, more spaced doses, indicating that maximum concentration, not half life, will be the key for efficacy.