| Abstract
| - Thiosemicarbazones of the microbial metabolite madurahydroxylactone, a polysubstituted benzo[a]naphthacenequinone, have been previously reported by us as potent nonsteroidal inhibitors of the enzymeestrone sulfatase (cyclohexylthiosemicarbazone 1, IC50 0.46 μM). The active pharmacophore of 1 has nowbeen identified to be 2-formyl-6-hydroxybenzoic acid cyclohexylthiosemicarbazone (25, IC50 4.2 μM). Theactive partial structure was derivatized in the search for novel agents against hormone-dependent breastcancer. Further substantial increases in activity were achieved by reversal of functional groups leading tothe cyclohexylthiosemicarbazones of 5-formylsalicylic acid (35, IC50 0.05 μM) and 3-formylsalicylic acid(34, IC50 0.15 μM) as the most potent analogues identified to date. Both compounds were shown to benoncompetitive inhibitors of estrone sulfatase with Ki values of 0.13 μM and 0.12 μM, respectively. Thecompounds showed low acute toxicity in the hen's fertile egg screening test.
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