A focused set of heterocyclic quinones based on the benzothiazole, benzoxazole, benzimidazole, indazole and isoindole was prepared and screened with respect to the inhibition of the phosphatase activity of CDC25C. Benzoxazole- and benzothiazole-diones were at least 50 times more potent in inhibiting CDC25C than their benzimidazole-indazole- or isoindole-dione counterparts. These in vitro activities were in good correlation with the anti-proliferative effects observed with Mia PaCa-2 and DU-145 human tumor cell cultures. The IC(50) values obtained by WST-1 colorimetric assay ranged from 0.10 to 0.50 microM for the benzoxazole- or benzothiazole-diones and were above 10 microM for the other heterocyclic diones. This study further illustrates how the activity of the quinone pharmacophore can be selectively modulated by changing the type of five-membered heterocycle fused to the quinone ring.