Design, synthesis, biological testing and QSAR analysis of new Schiff bases of N-hydroxysemicarbazide as inhibitors of tumor cells.

摘要

Ribonucleotide reductase (RR) is a rate-limiting enzyme involved in de novo DNA synthesis, and is considered to be a potential target for cancer chemotherapy. Among all RR inhibitors investigated, only hydroxyurea (HU) is currently used for the treatment of various cancers, but it has several drawbacks. To obtain more potent and selective RR inhibitors, thirty-one title compounds were synthesized. Their molecular structures and purity were established by NMR, IR and MS spectra, and by elemental analyses.;The cytotoxicities of the 31 compounds were first evaluated against murine leukemia L1210 cells using the MTS/PES colorimetric assay. Seventeen of the 31 compounds exhibited higher cytotoxicities than HU against the L1210 cells. Six compounds with IC50 values in the micromolar range (2.7--7.2 muM) were found to be 11 to 30-fold more potent than HU (IC50 = 82 muM).;The active compounds were further tested against human leukemia CCRF-CEM cells and four solid tumor cells. Among these, three new compounds (RWL-4, 21, 35) inhibited the CCRF-CEM cells with IC50 values ranging from 2.7 to 7.0 muM. RWL35 [1-(9-[10-methylanthryl]methylene)-4-hydroxysemicarbazide] was the strongest inhibitor, and showed 74 to 692-fold activity, compared to HU, against the solid tumor cells tested. RWL35 exhibited more favorable selectivity (8--187 fold) than HU, and had no cross-resistance with HU and gemcitabine, two known RR inhibitors.;The log P and pKa values of a model compound, RWL1 [1-(3-trifluoromethylbenzylidene)-4-hydroxysemicarbazide], were measured by the shake-flask method, and then the Hansch-Fujita pi constant of the functional group---CH=NNHONHOH was derived for the calculation of log P of other congeners. Besides the essential pharmacophore (-NHCONHOH), among the physicochemical parameters examined in the QSAR analysis, hydrophobicity (log P), molecular size/polarizability (MR) and the indicator variable (I) for o-oxygen function turned out to be the important determinants of the antitumor activities observed.;Six of the title compounds have been shown to be remarkable inhibitors of various tumor cells including the HU-resistant cells. The most active compounds merit additional investigations for further development as anticancer drugs.