Thiosemicarbazones of Formyl Benzoic Acids as Novel Potent Inhibitors of Estrone Sulfatase

Thiosemicarbazones of the microbial metabolite madurahydroxylactone, a polysubstituted benzo[a]naphthacenequinone, have been previously reported by us as potent nonsteroidal inhibitors of the enzyme estrone sulfatase (cyclohexylthiosemicarbazone 1, IC50 0.46 μM). The active pharmacophore of 1 has no...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2007-07, Vol.50 (15), p.3661-3666
Main Authors: Jütten, Peter, Schumann, Winfried, Härtl, Albert, Dahse, Hans-Martin, Gräfe, Udo
Format: Article
Language:English
Subjects:
Animals
Antineoplastic agents
Antineoplastic Agents - chemical synthesis
Antineoplastic Agents - chemistry
Antineoplastic Agents - pharmacology
Biological and medical sciences
Breast Neoplasms - drug therapy
Chickens
Female
General aspects
Humans
In Vitro Techniques
Medical sciences
Microsomes - drug effects
Microsomes - enzymology
Neoplasms, Hormone-Dependent - drug therapy
Pharmacology. Drug treatments
Placenta - enzymology
Salicylates - chemical synthesis
Salicylates - chemistry
Salicylates - pharmacology
Structure-Activity Relationship
Sulfatases - antagonists & inhibitors
Thiosemicarbazones - chemical synthesis
Thiosemicarbazones - chemistry
Thiosemicarbazones - pharmacology
Toxicity Tests, Acute
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Summary:Thiosemicarbazones of the microbial metabolite madurahydroxylactone, a polysubstituted benzo[a]naphthacenequinone, have been previously reported by us as potent nonsteroidal inhibitors of the enzyme estrone sulfatase (cyclohexylthiosemicarbazone 1, IC50 0.46 μM). The active pharmacophore of 1 has now been identified to be 2-formyl-6-hydroxybenzoic acid cyclohexylthiosemicarbazone (25, IC50 4.2 μM). The active partial structure was derivatized in the search for novel agents against hormone-dependent breast cancer. Further substantial increases in activity were achieved by reversal of functional groups leading to the 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 be noncompetitive inhibitors of estrone sulfatase with K i values of 0.13 μM and 0.12 μM, respectively. The compounds showed low acute toxicity in the hen's fertile egg screening test.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm0611657