Synthesis, Biological Evaluation, and Quantitative Structure−Activity Relationship Analysis of New Schiff Bases of Hydroxysemicarbazide as Potential Antitumor Agents†
TL;DR: Quantitative structure-activity relationship (QSAR) analysis showed that, besides the essential pharmacophore (-NHCONHOH), hydrophobicity, molecular size/polarizability, and the presence of an oxygen-containing group at the ortho position (I) were important determinants for the antitumor activities.
Abstract: Thirty Schiff bases of hydroxysemicarbazide (Ar−CHNNHCONHOH) have been synthesized and tested against L1210 murine leukemia cells. The IC50 values were found to be in a range from 2.7 × 10-6 to 9.4 × 10-4 M. A total of 17 out of the 30 compounds had higher inhibitory activities than hydroxyurea (an anticancer drug currently used for the treatment of melanoma, leukemia, and ovarian cancer) against L1210 cells. Six compounds with IC50 values in micromolar range were 11- to 30-fold more potent than hydroxyurea (IC50 = 8.2 × 10-5 M). The partition coefficient (log P) and ionization constants (pKa) of a model compound [1-(3-trifluoromethylbenzylidene)-4-hydroxysemicarbazide, 1] were measured by the shake-flask method, and the measured log P was used to derive Hansch−Fujita π constant of −CHNNHCONHOH. On the basis of the newly derived π and those of other moieties, the partition coefficients (SlogP) of the other 29 compounds were calculated by the summation of π values. Quantitative structure−activity relations...
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TL;DR: The discovery of p53R2, a p53-inducible form of the small subunit of RR, raises the interest to develop subunit-specific RR inhibitors for cancer treatment, and compiles recent studies on the structure, function, and regulation of two forms of RR.
Abstract: Ribonucleotide reductase (RR) is a multisubunit enzyme responsible for the reduction of ribonucleotides to their corresponding deoxyribonucleotides, which are building blocks for DNA replication and repair. The key role of RR in DNA synthesis and cell growth control has made it an important target for anticancer therapy. Increased RR activity has been associated with malignant transformation and tumor cell growth. Efforts for new RR inhibitors have been made in basic and translational research. In recent years, several RR inhibitors, including Triapine, Gemcitabine, and GTI-2040, have entered clinical trial or application. Furthermore, the discovery of p53R2, a p53-inducible form of the small subunit of RR, raises the interest to develop subunit-specific RR inhibitors for cancer treatment. This review compiles recent studies on (1) the structure, function, and regulation of two forms of RR; (2) the role in tumorigenesis of RR and the effect of RR inhibition in cancer treatment; (3) the classification, mechanisms of action, antitumor activity, and clinical trial and application of new RR inhibitors that have been used in clinical cancer chemotherapy or are being evaluated in clinical trials; (4) novel approaches for future RR inhibitor discovery.
277 citations
TL;DR: Results about the mechanisms involved in the anticancer activities of thiosemicarbazones will aid in the rational design of novel topoisomerase II-targeted drugs and will provide insights into the discovery and development of novel cancer therapeutics based on the dual activity to chelate iron and to inhibit the catalytic activity of topoisomersase IIalpha.
Abstract: A series of novel thiosemicarbazone derivatives bearing condensed heterocyclic carboxaldehyde moieties were designed and synthesized. Among them, TSC24 exhibited broad antiproliferative activity in a panel of human tumor cells and suppressed tumor growth in mice. The mechanism research revealed that TSC24 was not only an iron chelator but also a topoisomerase IIalpha catalytic inhibitor. Its inhibition on topoisomerase IIalpha was due to direct interaction with the ATPase domain of topoisomerase IIalpha which led to the block of ATP hydrolysis. Molecular docking predicted that TSC24 might bind at the ATP binding site, which was confirmed by the competitive inhibition assay. These results about the mechanisms involved in the anticancer activities of thiosemicarbazones will aid in the rational design of novel topoisomerase II-targeted drugs and will provide insights into the discovery and development of novel cancer therapeutics based on the dual activity to chelate iron and to inhibit the catalytic activity of topoisomerase IIalpha.
171 citations
TL;DR: The biological applications of CSBs including antimicrobial activity, anticancer activity, drug carrier ability, antioxidant activity and tissue engineering capacity are discussed and the applications in other fields such as catalysis, adsorption and sensors are demonstrated.
165 citations
TL;DR: This work has focussed its attention on the collected synthetic simple Schiff bases of aldimine- and ketIMine-types revealing anticancer activities in vitro, that have been described in the scientific literature during the last decade, and on structural variations whose affect the antiproliferative activity in sets of the designed molecules.
127 citations
TL;DR: In this paper, the Schiff base derived from vanillin and dl-alpha-aminobutyric acid was synthesized and characterized by elemental analysis, IR, electronic spectra, conductance measurements, magnetic measurements, powder XRD and biological activity.
112 citations
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411 citations
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378 citations
TL;DR: The findings demonstrate the superiority of Triapine over hydroxyurea as an anticancer agent and suggest that prevention byTriapine of repair of DNA lesions created by agents that damage DNA may result in efficacious drug combinations for the treatment of cancer.
340 citations
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323 citations
TL;DR: In this paper, the authors examined the factors that can affect the measurement of partition coefficient, and made recommendations as to good practice, and recommended that partitioning be carried out at constant temperature using either a stirred flask technique or the filter probe.
Abstract: Partition coefficient (P) is a widely-measured property, yet there is considerable variation among published log P values. This paper examines the factors that can affect the measurement of partition coefficient, and makes recommendations as to good practice. Accuracy of partition coefficient determination can be affected by temperature, lack of mutual phase saturation, pH, buffer type and concentration, phase miscibility, solute concentration, solute and solvent purity, solute stability, phase volume ratio, solute adsorption and failure to reach equilibrium conditions. It is recommended that partitioning be carried out at constant temperature using either a stirred flask technique or the filter probe.
233 citations