Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:5.99.1.3 (topoisomerase)
 9,911 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A series of over 60 agents representing several different classes of compounds were evaluated for their effects on the ATP pools of Pneumocystis carinii populations derived from immunosuppressed rats. A cytotoxicity assay based on an ATP-driven bioluminescent reaction was used to determine the concentration of agent which decreased the P. carinii ATP pools by 50% versus untreated controls (IC50). A ranking system based on the IC50 value was devised for comparison of relative responses among the compounds evaluated in the cytotoxic assay and for comparison to in vivo efficacy. With few exceptions, there was a strong correlation between results from the ATP assay and the performance of the compound in vivo. Antibiotics, with the exception of trimethoprim-sulfamethoxazole (TMP-SMX), were ineffective at reducing the ATP pools and were not active clinically or in the rat model of P. carinii pneumonia. Likewise, other agents not expected to be effective, e.g., antiviral compounds, did not show activity. Standard anti-P. carinii compounds, e.g., TMP-SMX, pentamidine, and dapsone, dramatically reduced ATP levels. Analogs of the quinone and topoisomerase inhibitor groups were shown to reduce ATP concentrations and hold promise for further in vivo investigation. The cytotoxicity assay provides a rapid assessment of response, does not rely on replicating organisms, and should be useful for assessment of structure-function relationships.
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PMID:A cytotoxicity assay for evaluation of candidate anti-Pneumocystis carinii agents. 902 Nov 95

Nickel(II) complexes of thiosemicarbazons were observed to be potent cytotoxic agents in human and rodent tissue cultured tumor cells. Each compound demonstrated a slightly different profile in the various histological types of tumors. The nickel complex of Appip demonstrated the most potent in vivo activity in the Ehrlich ascites carcinoma. This agent selectively inhibited L1210 DNA and purine syntheses, and DNA polymerase alpha, PRPP-amido transferase, IMP-dehydrogenase, dihydrofolate reductase, TMP-kinase and thymidylate synthetase activities. L1210 DNA strand scission was evident and DNA viscosity was reduced after 24 hr incubation. The nickel complexes were not L1210 DNA topoisomerase II inhibitors.
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PMID:Antineoplastic and Cytotoxic Activities of Nickel(II) Complexes of Thiosemicarbazones. 1847 74

Sodium N-[(trimethylamineboryl)-carbonyl]-L-phenylalanine 2 and {N-[(trimethylamineboryl)-carbonyl]-L-phenylalanyl- carbxylato}-bis-{N-[(trimethylaminebryl)-carbonyl]-L-phenylalanine} dicopper (II) 3 were successfully synthesized. The agents blocked L(1210) leukemic cell DNA and RNA syntheses by inhibiting multiple enzyme activities for nucleic acid synthesis, e.g. PRPP amido transferase, IMP dehydrogenase, DNA polymerase alpha, thymidine kinase, and TMP kinase. The copper (II) complex 3 demonstrated improved ability to inhibit L(1210) partially purified DNA topoisomerase II compared to the parent compound while the sodium salt was inactive at 100 muM.
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PMID:The Synthesis and Antitumor Activity of the Sodium Salt and Copper (II) Complex of N-[(Trimethylamineboryl)-Carbonyl]-L-Phenylalanine Methyl Ester. 1847 18