The invention relates to the inhibition of histone deacetylase. The invention provides compounds and methods for inhibiting histone deacetylase enzymatic activity. The invention also provides compositions and methods for treating cell proliferative diseases and conditions.

Inhibitors of histone deacetylase

https://febs.onlinelibrary.wiley.com/doi/pdf/10.1016/S0014-5793%2897%2901572-X

Resveratrol, a remarkable inhibitor of ribonucleotide reductase.

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.

Ribonucleotide reductase inhibitors and future drug design.

Ribonucleotide reductase activity and growth of glutathione-depleted mouse leukemia L1210 cells in vitro.

EDTA (ethylenediamine tetraacetic acid) and its salts are substituted diamines. HEDTA (hydroxyethyl ethylenediamine triacetic acid) and its trisodium salt are substituted amines. These ingredients function as chelating agents in cosmetic formulations. The typical concentration of use of EDTA is less than 2%, with the other salts in current use at even lower concentrations. The lowest dose reported to cause a toxic effect in animals was 750 mg/kg/day. These chelating agents are cytotoxic and weakly genotoxic, but not carcinogenic. Oral exposures to EDTA produced adverse reproductive and developmental effects in animals. Clinical tests reported no absorption of an EDTA salt through the skin. These ingredients are likely, however, to affect the passage of other chemicals into the skin because they will chelate calcium. Exposure to EDTA in most cosmetic formulations, therefore, would produce systemic exposure levels well below those seen to be toxic in oral dosing studies. Exposure to EDTA in cosmetic formulations that may be inhaled, however, was a concern. An exposure assessment done using conservative assumptions predicted that the maximum EDTA dose via inhalation of an aerosolized cosmetic formulation is below that shown to produce reproductive or developmental toxicity. Because of the potential to increase the penetration of other chemicals, formulators should continue to be aware of this when combining these ingredients with ingredients that previously have been determined to be safe, primarily because they were not significantly absorbed. Based on the available data, the Cosmetic Ingredient Review Expert Panel found that these ingredients are safe as used in cosmetic formulations.

Final report on the safety assessment of EDTA, calcium disodium EDTA, diammonium EDTA, dipotassium EDTA, disodium EDTA, TEA-EDTA, tetrasodium EDTA, tripotassium EDTA, trisodium EDTA, HEDTA, and trisodium HEDTA.

For the purpose of developing an effective anticancer agent with a mode of action directed against ribonucleotide reductase, a number of acyl and aryl hydroxamic acids and their congeners were synthesized and tested for their ability to inhibit ribonucleotide reductase in vitro and to prolong the life span of L1210 leukemia-bearing mice. Benzohydroxamic acid and other six-member aromatic ring hydroxamic acids were found to be as inhibitory as was hydroxyurea in vitro , and they increased the life span of L1210 leukemia-bearing mice. Addition of hydroxy groups to the benzene ring of benzohydroxamic acid increased both inhibition of ribonucleotide reductase and life span of L1210 leukemic mice. Di- and trihydroxybenzohydroxamic acids, particularly when the hydroxyl groups were adjacent, were even more potent both in vitro and in vivo . For example, in comparison to hydroxyurea, 2,3,4-trihydroxybenzohydroxamic acid was 160 times more potent as an inhibitor of ribonucleotide reductase and increased the life span of L1210-leukemic mice at a lower dosage. The hydroxamic acid moiety was not essential for activity, since 2,3,4-trihydroxybenzamide was 100 times more potent than was hydroxyurea in vitro . Of the compounds tested, 3,4-dihydroxybenzohydroxamic acid was most effective in prolonging the life span of L1210-leukemic mice, increasing survival time over 100% and at one-third the dosage of hydroxyurea.

/pdf/new-ribonucleotide-reductase-inhibitors-with-antineoplastic-4b0gy38k5h.pdf

New Ribonucleotide Reductase Inhibitors with Antineoplastic Activity

Benzohydroxamic acids inhibit mammalian ribonucleotide reductase and exhibit antineoplastic activity in L1210 leukemic mice. Five new hydroxy- and amino-substituted benzohydroxamic acids (3,4- and 3,5-OH, 3,4-NH2, 2,3,4- and, 3,4,5-OH) were prepared and tested along with 12 previously reported benzohydroxamic acids (BHA) for enzyme inhibition and antitumor activity. The most potent enzyme inhibitor in this series was 2,3,4-OH-BHA (ID50 = 3.5 microM), which is 140 times more potent than hydroxyurea, but its toxicity limited the antitumor activity to a 30% increase in life span of L1210 bearing mice at 125 (mg/kg)/day ip for 8 days. The most effective antitumor agent in this series was 3,4-OH-BHA which prolonged the life span of L1210 bearing mice 103% at 600 (mg/kg)/day ip for 8 days.

Synthesis of hydroxy- and amino-substituted benzohydroxamic acids: inhibition of ribonucleotide reductase and antitumor activity.

Regulation of ribonucleotide reductase in mammalian cells by chemotherapeutic agents

Trimidox (3,4,5-trihydroxybenzamidoxime), a newly synthesized analog of didox (N,3,4-trihydroxybenzamide) reduced the activity of ribonucleotide reductase (EC 1.17.4.1) in extracts of L1210 cells by 50% (50% growth-inhibitory concentration, IC50) at 5 μM, whereas hydroxyurea, the only ribonucleotide reductase inhibitor in clinical use, exhibited an IC50 of 500 μM. Ribonucleotide reductase activity was also measured in situ by incubating L1210 cells for 24 h with trimidox at 7.5 μM, a concentration that inhibits cell proliferation by 50% (IC50) or at 100 μM for 2 h; these concentrations resulted in a decrease in enzyme activity to 22% and 50% of the control value, respectively. Trimidox and hydroxyurea were cytotoxic to L1210 cells with IC50 values of 7.5 and 50 μM, respectively. Versus ribonucleotide reductase, trimidox and hydroxyurea yielded IC50 values of 12 and 87 μM, respectively. A dose-dependent increase in life span was observed in mice bearing intraperitoneally transplanted L1210 tumors. Trimidox treatment (200 mg/kg; q1dx9) significantly increased the life span of mice bearing L1210 leukemia (by 82 in male mice and 112% in female mice). The antitumor activity appeared more pronounced in female mice than in male mice. Viewed in concert, these findings suggest that trimidox is a new and potent inhibitor of ribonucleotide reductase and that it is a promising candidate for the chemotherapy of cancer in humans.

Biochemical and antitumor activity of trimidox, a new inhibitor of ribonucleotide reductase

A series of amidoximes was prepared and evaluated for possible antitumor activity against L1210 leukemia. Three of the most active compounds in the L1210 system, formamidoxime, acetamidoxime, and 2-aminoacetamidoxime hydrochloride, were also active against P388 leukemia. Acetamidoxime was marginally active against Lewis lung carcinoma. The active amidoximes showed best activity against L1210 leukemia when given two times daily, 5 hours apart, for 8 days. Most of the amidoximes produced excessive central nervous system stimulation.

Bart Van't Riet

Papers

New Ribonucleotide Reductase Inhibitors with Antineoplastic Activity

Synthesis of hydroxy- and amino-substituted benzohydroxamic acids: inhibition of ribonucleotide reductase and antitumor activity.

Regulation of ribonucleotide reductase in mammalian cells by chemotherapeutic agents

Biochemical and antitumor activity of trimidox, a new inhibitor of ribonucleotide reductase

Antitumor Activity of Amidoximes (Hydroxyurea Analogs) in Murine Tumor Systems