Hypoxia, a state of low oxygen, is a common feature of solid tumors and is associated with disease progression as well as resistance to radiotherapy and certain chemotherapeutic drugs. Hypoxic regions in tumors, therefore, represent attractive targets for cancer therapy. To date, five distinct classes of bioreactive prodrugs have been developed to target hypoxic cells in solid tumors. These hypoxia-activated prodrugs, including nitro compounds, N-oxides, quinones, and metal complexes, generally share a common mechanism of activation whereby they are reduced by intracellular oxidoreductases in an oxygen-sensitive manner to form cytotoxins. Several examples including PR-104, TH-302, and EO9 are currently undergoing phase II and phase III clinical evaluation. In this review, we discuss the nature of tumor hypoxia as a therapeutic target, focusing on the development of bioreductive prodrugs. We also describe the current knowledge of how each prodrug class is activated and detail the clinical progress of leading examples.
Anthraquinones ; chemistry ; pharmacology ; Antineoplastic Agents ; chemistry ; pharmacology ; Aziridines ; chemistry ; pharmacology ; Cell Hypoxia ; drug effects ; Humans ; Indolequinones ; chemistry ; pharmacology ; Molecular Structure ; NAD(P)H Dehydrogenase (Quinone) ; chemistry ; pharmacology ; Neoplasms ; drug therapy ; pathology ; Nitrogen Mustard Compounds ; chemistry ; pharmacology ; Nitroimidazoles ; chemistry ; pharmacology ; Phosphoramide Mustards ; chemistry ; pharmacology ; Prodrugs ; chemistry ; pharmacology ; Triazines ; chemistry ; pharmacology

A series of valproic acid salicylanilide esters were designed and synthesized based on the principle of prodrug. The structures of the target compounds were confirmed by MS, 1H NMR and 13C NMR. Anti-tumor activities of these compounds against K562, A549, A431 cells in vitro were investigated by MTT assay and SRB assay. The results indicated that the compounds 6h-6j were found to have stronger cell growth inhibitory action than gefitinib, and comparable to niclosamide, which are worth to be intensively studied further.
Antineoplastic Agents ; chemical synthesis ; chemistry ; pharmacology ; Cell Line, Tumor ; Cell Proliferation ; drug effects ; Drug Design ; Esters ; Humans ; Inhibitory Concentration 50 ; K562 Cells ; Molecular Structure ; Prodrugs ; chemical synthesis ; chemistry ; pharmacology ; Salicylanilides ; chemical synthesis ; chemistry ; pharmacology ; Structure-Activity Relationship ; Valproic Acid ; chemical synthesis ; chemistry ; pharmacology

To design and synthesize a series of novel scutellarein 4'-L-amino acid prodrugs with more potent anti-oxidative activity and improved physicochemical properties. Scutellarein was used as lead compound, according to successful experience of improving bioavailability of oral administration drugs by active transport mechanism, principle of hybridization was used to introducing L-amino acid structural fragments at 4'-position of scutellarein to design and synthesize target scutellarein 4'-L-amino acid prodrugs. The synthetic compounds were tested on their physicochemical properties and in vitro anti-oxidative activity against H202 induced oxidative damage in PC12 cells. Five compounds were found to have more potent anti-oxidative activity than positive control VE. Moreover the physicochemical properties of synthesized compounds were evaluated, and the results revealed that L-amino acid ether derivatives are more stable (t1/2 9-92 h) than their corresponding ester derivatives (t1/2 0.5 h). Water solubility of scutellarein 4'-L-amino acid ester and ether derivatives were 1 796-4 100 microg.mL-1 and 27.7-81.1 microg.mL-1 respectively, in comparison with scutellarin, the solubility of compounds 18, 19 and 22, 24-27 increased about 120-280 fold and 2-6 fold respectively. All these results suggested that L-amino acid prodrug strategy has significant potential in scutellarein prodrug design.
Amino Acids ; chemistry ; Animals ; Antioxidants ; chemical synthesis ; chemistry ; pharmacokinetics ; pharmacology ; Apigenin ; chemical synthesis ; chemistry ; pharmacokinetics ; pharmacology ; Biological Availability ; Drug Design ; L-Lactate Dehydrogenase ; metabolism ; PC12 Cells ; Prodrugs ; chemical synthesis ; chemistry ; pharmacokinetics ; pharmacology ; Rats

In this research, phosphate and thiophosphate prodrugs 3a, 3b of anti-HIV agent AZT were synthesized, and their anti-HIV activities and cytotoxicities were investigated in vitro. Results showed that the prodrugs 3a and 3b with an IC50 value of 11.0 and 4.0 micromol x L(-1), respectively, were less toxic than AZT (1.0 micromol x L(-1)). Although the EC50 values of both 3a (0.04 micromol x (L(-1) and 3b (0.16 micromol x L(-1)) were lower than that of AZT (0.01 micromol x L(-1)), the therapeutic index (IC50/EC50) of prodrug 3a (275) was much higher than that of both AZT (100) and prodrug 3b (25). This indicated that the prodrug 3a merited further investigation as an anti-HIV agent.
Anti-HIV Agents ; chemical synthesis ; chemistry ; pharmacology ; CD4-Positive T-Lymphocytes ; cytology ; Cell Proliferation ; drug effects ; Cells, Cultured ; Humans ; Inhibitory Concentration 50 ; Prodrugs ; chemical synthesis ; chemistry ; pharmacology ; Zidovudine ; analogs & derivatives ; chemical synthesis ; chemistry ; pharmacology

A series of adefovir mono-L-amino acid esters, mono non-steroidal anti-inflammatory drugs carboxylic ester prodrugs with more potent anti-HBV activity and lower nephrotoxicity were designed and synthesized. Adefovir bis (L-amino acid) ester was used as lead compound, according to pathological and pharmacological findings that non-steroidal anti-inflammatory drugs can effectively inhibit the organic anion transporter 1 (hOAT1)-mediated adefovir phosphonic acid pairs of anion transport across tubular basement membrane thereby reducing the nephrotoxicity of adefovir. Flatten design principle was used to introducing non-steroidal anti-inflammatory drugs structural fragments to design and synthesize target adefovir mixture ester prodrugs. HepG2 2.2.15 cell line was used as in vitro anti-HBV activity evaluation model. Five compounds exhibited antiviral activity, and compound 18 showed the most potent anti-HBV activity and relatively high selective index (EC50 3.92 micromol L(-1), SI 9.97). HK-2 cell line was used as in vitro model to evaluate nephrotoxicity. Results suggested the target compounds have lower cytotoxicity than the positive control. Moreover, by analyzing the primary structure and activity relationship of these compounds, it could suggest that mono-L-amino acid ester, mono non-steroidal anti-inflammatory drugs carboxylic ester prodrugs strategy has significant potential in the acyclic nucleoside phosphonates prodrug design.
Adenine ; analogs & derivatives ; chemical synthesis ; chemistry ; pharmacology ; Amino Acids ; chemical synthesis ; chemistry ; pharmacology ; Anti-Inflammatory Agents, Non-Steroidal ; chemical synthesis ; chemistry ; pharmacology ; Antiviral Agents ; chemical synthesis ; chemistry ; pharmacology ; Carboxylic Acids ; chemistry ; pharmacology ; Cell Survival ; drug effects ; Drug Design ; Hep G2 Cells ; drug effects ; Humans ; Kidney Tubules, Proximal ; cytology ; metabolism ; L-Lactate Dehydrogenase ; metabolism ; Molecular Structure ; Organophosphonates ; chemical synthesis ; chemistry ; pharmacology ; Prodrugs ; chemical synthesis ; chemistry ; pharmacology

To design and synthesize the hepatic targeting anticancer prodrug with norcantharidin (NCTD-Gal) conjugating structure, galactosylated NCTD derivatives were synthesized from NCTD analogues modified by a series of amino acids via acylation, hydrolysis, glycosylation and deacetylation. Seven new compounds were synthesized as beta-O-glycosides and characterized by IR, MS, NMR and element analysis. The compound 4a was chosen for the inchoate antitumor experiments on mice. The result showed that the antitumor inhibition rate of 4a groups with medium and high dose are clearly higher than that of NCTD group, which suggests that anticancer effect of NCTD is improved at a certain degree by galactosylation.
Animals ; Antineoplastic Agents ; chemical synthesis ; pharmacology ; Bridged Bicyclo Compounds, Heterocyclic ; chemical synthesis ; chemistry ; pharmacology ; Carcinoma, Hepatocellular ; pathology ; Cell Line, Tumor ; Drug Delivery Systems ; Female ; Galactose ; chemistry ; Humans ; Liver Neoplasms ; pathology ; Male ; Mice ; Neoplasm Transplantation ; Prodrugs ; chemical synthesis ; pharmacology

To design and synthesis a series of novel L-amino acid esters prodrugs of acyclic nucleoside phosphonates with more potent anti-HBV activity, adefovir dipivoxil was used as lead compound, according to the results of enhanced oral bioavailability and antiviral activities of nucleoside L-amino acid ester prodrugs. Eleven novel L-amino acid ester prodrugs of acyclic nucleoside phosphonates were designed and synthesized, their anti-HBV activities were evaluated in HepG2 2.2.15 cells. Eight compounds exhibited antiviral activity, and compound 11 showed the most potent anti-HBV activity and highest selective index in vitro (EC50 0.0952 micromol x L(-1), SI 69523). Moreover, by analyzing the primary structure and activity relationship of these compounds, it could be suggested that L-amino acid ester strategy has significant potential in the acyclic nucleoside phosphonates prodrug design.
Amino Acids ; chemistry ; Antiviral Agents ; chemical synthesis ; pharmacology ; Cell Line, Tumor ; Hepatitis B virus ; drug effects ; Humans ; Liver Neoplasms ; pathology ; virology ; Nucleosides ; chemical synthesis ; pharmacology ; Organophosphonates ; chemical synthesis ; pharmacology ; Prodrugs ; chemical synthesis ; pharmacology

Histone deacetylase (HDAC) has been highlighted as one of key players in tumorigenesis and angiogenesis. Recently, several derivatives of psammaplin (Psams) from a marine sponge have been known to inhibit the HDAC activity, but the molecular mechanism for the inhibition has not fully understood. Here, we explored the mode of action of Psams for the inhibition of HDAC activity in the molecular and cellular level. Among the derivatives, psammaplin A (Psam A) showed the potent inhibitory activity in enzyme assay and anti-proliferation assay with IC50 value of 0.003 and 1 microM, respectively. Psam A selectively induced hyperacetylation of histones in the cells, resulting in the upregulation of gelsolin, a well-known HDAC target gene, in a transcriptional level. In addition, reduced Psam A showed a stronger inhibitory activity than that of non-reduced one. Notably, glutathione-depleted cells were not sensitive to Psam A, implying that cellular reduction of the compound is responsible for the HDAC inhibition of Psam A after uptake into the cells. Together, these data demonstrate that Psam A could exhibit its activity under the reduced condition in the cells and be a new natural prodrug targeting HDAC.
Tyrosine/*analogs & derivatives/chemistry/pharmacology ; Prodrugs/chemistry/*pharmacology ; Oxidation-Reduction ; Molecular Structure ; Humans ; Histones/metabolism ; Histone Deacetylases/*antagonists & inhibitors/*classification/genetics/metabolism ; Hela Cells ; Enzyme Inhibitors/chemistry/*pharmacology ; Disulfides/chemistry/*pharmacology ; Cell Proliferation ; Biological Products/chemistry/*pharmacology ; Acetylation

Oxidative stress plays critical roles in airway inflammation that is usually accompanied by increased vascular permeability and plasma exudation. VEGF increases vascular permeability and leads to airway inflammation. In addition, VEGF has been shown to enhance receptor activator of NF-kappaB (RANK) expression in endothelial cells. An aim of the study was to determine the potential role of antioxidant in the regulation of RANK expression in murine model of asthma. We have used a C57BL/6 mouse model of allergic asthma to evaluate the effect of L-2-oxothiazolidine-4-carboxylic acid (OTC), a prodrug of cysteine, which acts as an antioxidant, and VEGF receptor inhibitor on RANK mRNA expression. The mice develop the following pathophysiological features of asthma in the lungs: increased expression of RANK mRNA, increased number of inflammatory cells of the airways, increased vascular permeability, and increased levels of VEGF. Administration of OTC and VEGF receptor inhibitor markedly reduced plasma extravasation and VEGF levels in allergen-induced asthmatic lungs. We also showed that the increased RANK mRNA expression at 72 h after ovalbumin inhalation were reduced by the administration of OTC or VEGF receptor inhibitor. The results indicate that OTC and VEGF receptor inhibitor which inhibit up-regulation of VEGF expression modulate RANK expression that may be in association with the regulation of vascular permeability, and suggest that VEGF may regulate the RANK expression. These findings provide a crucial molecular mechanism for the potential use of antioxidants to prevent and/or treat asthma and other airway inflammatory disorders.
Vascular Endothelial Growth Factor A/analysis/antagonists & inhibitors/metabolism ; Thiazolidines ; Thiazoles/*pharmacology ; Reverse Transcriptase Polymerase Chain Reaction ; Receptors, Vascular Endothelial Growth Factor/antagonists & inhibitors ; Receptors, Tumor Necrosis Factor/genetics/*metabolism ; Receptors, Cytoplasmic and Nuclear/genetics/*metabolism ; Reactive Oxygen Species/metabolism ; RNA, Messenger/genetics/metabolism ; Pyrrolidonecarboxylic Acid ; Proto-Oncogene Proteins c-akt/metabolism ; Protein Kinase Inhibitors/pharmacology ; Prodrugs/pharmacology ; Phosphorylation/drug effects ; Ovalbumin/immunology ; Osteoprotegerin ; Mice, Inbred C57BL ; Mice ; Immunohistochemistry ; Glycoproteins/genetics/*metabolism ; Gene Expression/drug effects ; Female ; Capillary Permeability/drug effects ; Bronchoalveolar Lavage Fluid/chemistry/cytology ; Blotting, Western ; Asthma/*drug therapy/immunology/metabolism ; Antioxidants/*pharmacology ; Animals

AIMTo demonstrate the specific killing of folate receptor (FR)-positive tumor cells can be achieved by folate-targeted penicillin-G amidase (PGA) combined with its prodrug substrate N-(phenylacetyl) doxorubicin (DOXP).

METHODSFolic acid was covalently linked to PGA and folate content value was determined by quantitative UV spectrophotometry. The ability of folate conjugated PGA to hydrolyze DOXP was measured by RP-HPLC. Visual demonstration of uptake by FR (+) HeLa and SKOV3 cells was detected by using FITC labeled folate-PGA and a fluorescence microscopy. The cytotoxicity of DOXP towards the cells in the presence or absence of folate-PGA was assayed by using MTT method.

RESULTSThe folate-PGA has a specific activity of 29. 8 U x mg(-1) (protein). FR selectivity was confirmed by fluorescence microscopy. The combination of DOXP prodrug with folate-PGA generated higher cytotoxicity towards the FR (+) cells than free doxorubicin. The IC50 was 0.72 micromol x L(-1) for HeLa cells and 0.75 micromol x L(-1) for SKOV3 cells, respectively. Further, the enhanced cytotoxicity reduced greatly with the addition of free folic acid.

CONCLUSIONFolate conjugated PGA did not significantly compromise PGA catalytic activity and enabled binding prodrug-activating enzyme PGA to folate receptor expressing cells, and increased the sensitivity of the cells to doxorubicin followed by administration of its prodrug substrate.

Antibiotics, Antineoplastic ; pharmacology ; Carrier Proteins ; metabolism ; Cell Line, Tumor ; Doxorubicin ; analogs & derivatives ; pharmacology ; Drug Delivery Systems ; Female ; Folate Receptors, GPI-Anchored ; Folic Acid ; chemistry ; pharmacology ; HeLa Cells ; Humans ; Inhibitory Concentration 50 ; Ovarian Neoplasms ; pathology ; Penicillin Amidase ; chemistry ; pharmacology ; Prodrugs ; pharmacology ; Receptors, Cell Surface ; metabolism