Deaza compounds with carbon insertion in the bridge

8-Deaza compounds with carbon insertion in the bridge 

4- diamino-5-chloro-5,8-dideazaAMT (IC5o = 46nM), while IV.273 (IC50 = 60 nM) and the 5-methyl analogue (IV.274) (IC50 = 63 nM) were somewhat less inhibitory. Finally, in a more recent study [47], the binding of 

In assays against S. faecium DHFR, (IV.273) and (IV.274) had IC50 values of0.032 and 0.0083 /iM, respectively, while the diesters (IV.279) and (IV.280) had comparable or, in the latter instance, somewhat greater activity [54]. In assays against cultured L1210 murine leukaemic cells, (IV.280) had an IC50 

As with other classical antifolates, the ability of 5,8-dideazaisoAMT (IV.273) and its 5-substituted derivatives to cross the cell membrane is an important determinant of growth-inhibitory potency. Susten et al [50] addressed this issue by measuring the kinetics of transport of [ H]MTX in the presence of the quinazolines. The IC50 of IV.273 as an inhibitor of 1.0 /xM MTX influx was 1.6 /xM, whereas the IC50 values of (IV.274), (IV.275), and MTX (unlabelled) were 2.0, 1.4, and 1.0 uM. Thus substitution at position 5 caused a slight decrease in binding of the quinazolines for the MTX/reduced folate carrier protein. 

The 2-amino-4(377)-oxo compound lAHQ (IV.281) has been reported by Scanlon et al. [159] and by Fernandes et al. [160] to be a reasonably potent inhibitor of purified TS from L1210 cells. With (6-i ,S )-5,10-methylenetetrahy-drofolate as the substrate, lAHQ behaved as a linear non-competitive inhibitor with a Xj(app) of 8.4 /xM [160]. Binding of dUMP to TS was stimulated by lAHQ and, to a greater degree, by 5,8-dideazaisopteroyl triglutamate. Scatchard plots showed that one molecule of dUMP was bound per mole of enzyme. Dissociation of dUMP from the ternary complex was found in 

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