Synthesis and Ribonucleotide reductase inhibitory activity of thiosemicarbazones

• Published in: Bioorganic & medicinal chemistry Vol. 18; no. 23; pp. 6248 - 6250
• Main Authors: KRISHNAN, Kesavan, PRATHIBA, Kumari, JAYAPRAKASH, Venkatesan, BASU, Arijit, MISHRA, Nibha, BINGSEN ZHOU, SHUYA HU, YUN YEN
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier 01-12-2008
• Subjects: Analytical, structural and metabolic biochemistry; Biological and medical sciences; Enzymes and enzyme inhibitors; Fundamental and applied biological sciences. Psychology; Humans; Hydroxyurea - pharmacology; Medical sciences; Miscellaneous; Molecular Structure; Oxidation-Reduction; Oxidoreductases; Pharmacology. Drug treatments; Protein Subunits - chemistry; Ribonucleotide Reductases - antagonists & inhibitors; Ribonucleotide Reductases - chemistry; Thiosemicarbazones - chemical synthesis; Thiosemicarbazones - chemistry; Thiosemicarbazones - pharmacology; Human; Thiosemicarbazone; Enzyme; Benzene derivatives; p-Hydroxybenzaldehyde thiosemicarbazones; In vitro; Human recombinant RR subunit; Structure activity relation; Ribonucleoside-triphosphate reductase; RR inhibitory activity; Oxidoreductases; [3H]CDP reduction assay; hRRMI and hRRM2; Ribonucleoside-diphosphate reductase; Chemical synthesis
• ISSN: 0960-894X; 0968-0896; 1464-3405; 1464-3391
• DOI: 10.1016/j.bmcl.2008.09.097

Ribonucleotide reductase (RR) is an important therapeutic target for anticancer drugs. The structure of human RR features a 1:1 complex of two homodimeric subunits, hRRM1 and hRRM2. Prokaryotically expressed and highly purified recombinant human RR subunits, hRRM1 and hRRM2, were used for holoenzyme-based [(3)H]CDP reduction in vitro assay. Ten new thiosemicarbazones (7-16) were synthesized and screened for their RR inhibitory activity. Two thiosemicarbazones derived from p-hydroxy benzaldehyde (9 and 10) were found to be active but less potent than the standard, Hydroxyurea (HU). Guided by the activity of compounds 9 and 10, 11 new thiosemicarbazones (17-27) derived from p-hydroxy benzaldehyde were prepared and screened for their RR inhibitory activity. All the 11 compounds were more potent than HU.