Superior Pyrimidine Derivatives as Selective ABCG2 Inhibitors and Broad-Spectrum ABCB1, ABCC1, and ABCG2 Antagonists

In
the search for highly effective modulators addressing ABCG2-mediated
MDR, 23 pyrimidines were synthesized and biologically assessed. Seven
derivatives with (a) nitrogen- and/or halogen-containing residue(s)
had extraordinary potencies against ABCG2 (IC50 < 150
nM). The compounds competitively inhibited ABCG2-mediated Hoechst
33342 transport but were not substrates of ABCG2. The most potent
MDR reverser, compound 19, concentration-dependently
increased SN-38-mediated cancer cell death at 11 nM (EC50), time-dependently doubled SN-38 toxicity in a period of 7 days
at 10 nM, and half-maximally accelerated cell death combined
with SN-38 at 17 nM. No induction of ABCG2 was observed. Furthermore,
11 pyrimidines were revealed as triple ABCB1/ABCC1/ABCG2 inhibitors.
Five possessed IC50 values below 10 μM against each
transporter, classifying them as some of the 50 most potent multitarget
ABC transporter inhibitors. The most promising representative, compound 37, reversed ABCB1-, ABCC1-, and ABCG2-mediated MDR, making
it one of the three most potent ABC transporter inhibitors and reversers
of ABC transporters-mediated MDR.