Search results for "prodrug"
showing 9 items of 89 documents
Indirect oxidation of the antitumor agent procarbazine by tyrosinase—Possible application in designing anti-melanoma prodrugs
2008
The interaction of tyrosinase with the anticancer drug procarbazine has been investigated. In the presence of the enzyme alone no oxidation of this dialkylhydrazine above the background level was observed. However, when phenolic substrates (4-tert-butylcatechol or N-acetyl-l-tyrosine) were included in the reaction mixture, procarbazine was rapidly degraded. Oxygen consumption measurements showed that in a mixture both the phenolic substrate and the drug were oxidized. The major product of procarbazine degradation was isolated and identified as azoprocarbazine, the first active metabolite of this drug detected in previous in vivo and in vitro studies. This indirect oxidation of the hydrazine…
Studies of macromolecular prodrugs of zidovudine.
2000
Abstract The current problems in controlling severe viral infections such as AIDS as well as the lack of effective and safe therapeutic measures for such diseases have caused interest in systems such as macromolecular prodrugs potentially able to solve heavier drawbacks of conventional antiviral therapy. This review focuses on various approaches proposed in the literature in this field. Neoglycoproteins and synthetic protein-like structure polymers have been mainly proposed. In the first group, the possibility of incorporating into the polymeric structures a determined amount of sugar molecules make them interesting candidates for targeting of infected blood cells. The conjugate of zidovudi…
New Bioprecursor Prodrugs of Sulfadiazine: Synthesis, X-ray Structure and Hirshfeld Analysis
2022
Sulphonamide motif is found extensively in numerous chemotherapeutic drug candidates, it acts by stopping the production of folate inside the bacterial cell. Current research has established the synthesis and characterization of new bioprecursor prodrugs of sulfadiazine. The first prodrug, 3, was synthesized via the coupling of diazonium salt of sulfadiazine with ethyl acetoacetate in AcONa at 0 °C. The second prodrug, sulfadiazine-pyrazole, 5, was furnished via cyclocondensation of the hydrazono derivative, 3, and 2-pyridyl hydrazine, 4. The generated data from the X-ray analysis is interpreted and refined to obtain the crystal structure of the target compound, 5. Density functional th…
Catalysis Concepts in Medicinal Inorganic Chemistry
2018
Catalysis has strongly emerged in the field of medicinal inorganic chemistry as a suitable tool to deliver new drug candidates and to overcome drawbacks associated to metallodrugs. In this Concept article, we discuss representative examples of how catalysis has been applied in combination with metal complexes to deliver new therapy approaches. In particular, we explain key achievements in the design of catalytic metallodrugs that damage biomolecular targets and in the development of metal catalysis schemes for the activation of exogenous organic prodrugs. Moreover, we discuss our recent discoveries on the flavin-mediated bioorthogonal catalytic activation of metal-based prodrugs; a new cata…
Prodrugs of sulfacetamide: Synthesis, X-ray structure, Hirshfeld analysis, antibacterial assessment, and docking studies
2022
Abstract New prodrugs of sulfacetamide as azo compounds were synthesized and have been evidenced through elemental and spectral analyses. Their synthesis was carried out by coupling the diazonium salt of sulfacetamide with activated carbanion salt of ethyl acetoacetate at 0 ˚C to afford the hydrazono derivative 3. Other prodrugs as sulfacetamide-pyrazoles, 5a, 5b and 5c were furnished via cyclocondensation of 3 with aryl/heteroaryl hydrazines. X-ray diffraction for single crystal was used to confirm the molecular and supramolecular structures of 3. In addition, DFT studies were performed to analyze the geometric parameters and compute the electronic properties of 3 and 5a-c. Hirshfeld analy…
Chemical conjugation of dexamethasone to a polyaspartamide and in vitro evaluation studies
2004
Two macromolecular conjugates of dexamethasone containing different drug amounts were synthesized using PHEA as the polymeric carrier and a succinic group as spacer. The content of linked drug was equal to 25.3% w/w (conjugate A) and 12.7% w/w (conjugate B). Both polymeric conjugates, unlike the free drug, were water-soluble and the amount of unlinked drug was evaluated to be approximately about 0.01% w/w. Both conjugates were relatively stable in vitro at pH 7.4 whereas in the presence of esterase only the conjugate B was able to release drug under the used experimental conditions. This dissimilar behavior has been attributed to the distinct macromolecular conformations assumed in aqueous …
Structure and properties of pharmacologically active polymers
1975
Although the concept of using pharmacologically active macromolecular compounds as drugs is still regarded with much skepticism for both theoretical and practical reasons, interest in this field has grown in recent years because of the opportunity to take advantage of the specific properties of polymeric materials. For low molecular weight drugs, changes in structure often lead to a loss of specific activity. On the other hand, the properties of macromolecular drugs depend on the structure of the polymer used and this can be varied over a wide range by the incorporation of comonomer units, by the application of polymer-analogous reactions, or by related structural changes. A new model is pr…
Targeting a Targeted Drug: An Approach Toward Hypoxia-Activatable Tyrosine Kinase Inhibitor Prodrugs
2016
Tyrosine kinase inhibitors (TKIs), which have revolutionized cancer therapy over the past 15 years, are limited in their clinical application due to serious side effects. Therefore, we converted two approved TKIs (sunitinib and erlotinib) into 2-nitroimidazole-based hypoxia-activatable prodrugs. Kinetics studies showed very different stabilities over 24 h; however, fast reductive activation via E. coli nitroreductase could be confirmed for both panels. The anticancer activity and signaling inhibition of the compounds against various human cancer cell lines were evaluated in cell culture. These data, together with molecular docking simulations, revealed distinct differences in the impact of …
Development and biological investigations of hypoxia-sensitive prodrugs of the tyrosine kinase inhibitor crizotinib
2019
Despite the huge success of tyrosine kinase inhibitors as anticancer agents, severe side effects are a major problem. In order to overcome this drawback, the first hypoxia-activatable 2-nitroimidazole-based prodrugs of the clinically approved ALK and c-MET inhibitor crizotinib were developed. The 2-aminopyridine functionality of crizotinib (essential for target kinase binding) was considered as ideal position for prodrug derivatization. Consequently, two different prodrugs were synthesized with the nitroimidazole unit attached to crizotinib either via carbamoylation (A) or alkylation (B) of the 2-aminopyridine moiety. The successful prodrug design could be proven by docking studies and a dr…