Antitumor Agents 126. Novel 4β-Substituted Anilino Derivatives of 3′,4′ -O,O-Didemethylpodophyllotoxin as Potent Inhibitors of Human DNA Topoisomerase II

A series of derivatives of 3,4 0,0-didemethylpodophyllotoxin have been synthesized and evaluated for their inhibitor activity against neoplastic cell growth (KB) and against human DNA topoisomerase II as well as for their activity in causing cellular protein-linked DNA breakage. The results show that the compounds possessing a 4-anilino moiety either unsubstituted or substituted at the para (F, COOCH₃, COCH₃, CN, CH₂CN, NO₂) or meta (OH) positions or with an ethylenedioxy moiety showed the same or greater activity than etoposide in causing cellular protein-linked DNA breakage and in inhibiting DNA topoisomerase II. However, compared to the corresponding 4-0-demethyl analogues, the 3,4-O,O-didemethyl compounds have a similar potency in inhibition of DNA topoisomerase II but are less active in causing cellular protein-linked DNA breakage. Complete correlation between the three biological activities–cytotoxicity, inhibition of DNA topoisomerase II, and induction of protein-linked DNA breakage–was also not observed. This supports the possibility that the biological determinants of action among these compounds may be different.     

Mutagenicity of 4,4′-MethyIenedianiline Derivatives in the Salmonella histidine reversion assay

4,4-Methylenedianiline and its derivatives were assayed for mutagenicity in the Salmonella/microsomal mutagenicity assay developed by Ames. A specificity to revert strain TA98 suggests a mechanism of frameshift mutagenesis. Liver microsomal preparations (S-9) from rats induced with phenobarbital were most effective for metabolic activation. Alkyl substitution of 4,4-methylenedianiline did not alter its mutagenic activity; however, substitution of both positions ortho to the amino group eliminated mutagenic activity. Substitution with alkoxy-carbonyl groups eliminated mutagenic activity, whereas halogen substitution (chlorine, fluorine) enhanced the mutagenic activity. The results presented here show the use of structure-activity studies as predictive tools for the assessment of genotoxic properties of industrial chemicals.This research was supported by the Office of Health and Environmental Research, U.S. Department of Energy, under contract W-7405-eng-26 with the Union Carbide Corporation     

Evaluation of cardiotoxicity of a new anthracycline derivative: 4′ -deoxy-4′ -iodo-doxorubicin

Summary The present study in rats was performed to evaluate the cardiotoxic activity of 4 -deoxy-4 -iodo-doxorubicin (4-deoxy-4-I-DXR), a new anthracycline derivative with interesting antineoplastic properties and possible lower cardiotoxicity than doxorubicin (DXR). DXR produced ECG alterations consisting of a progressive and irreversible prolongation of SaT and QaT. In contrast, in 4-deoxy-4-I-DXR-treated rats the increase in SaT and QaT duration was significantly lower than that observed in DXR-treated rats and slightly increased over controls.DXR produced significant histologic changes in myocardium consisting of myocyte vacuolization and myofibrillar loss. No significant modifications were observed in mitochondria. In contrast, no significant cardiac lesions were observed in 4-deoxy-4-I-DXR-treated rats. These results suggest that this new anthracycline derivative has a significantly lower degree of cardiotoxic activity than DXR.     

Metabolism of 6,7-dimethoxy 4-(4′-chlorobenzyl)isoquinoline. II. Role of liver catechol O-methyltransferase and glutathione

1. On i.v. administration to rats of ¹⁴C-6,7-dimethoxy 4-(4′-chlorobenzyl)isoquinoline (PV2) 23% dose of ¹⁴C was excreted in urine and 72% in faeces. The pattern of metabolites showed ten ¹⁴C-PV2 derivatives and unchanged PV2. Seven metabolites have been characterized by comparison with authentic compounds e.g. the ketone of PV2, the N-oxide PV2, the demethylated metabolites 6-hydroxy-PV2, 7-hydroxy-PV2 and 6,7-dihydroxy PV2, the benzyl ring-hydroxylated metabolites, 3′-hydroxy-PV2 and 6,7,3′-trihydroxy-PV2. Unchanged PV2 and its metabolites are excreted both free and conjugated.

2. Enzymic O-methylation of 6,7-dihydroxy-PV2 by liver catechol-O-methyl transferase (COMT) in vitro produced 6-hydroxy, 7-methoxy-PV2. After blockade of COMT by pyrogallol in vivo, the excretion of 6,7-dihydroxy-PV2 was increased and the excretion of 6-hydroxy, 7-methoxy-PV2 decreased.

3. Hydroxylation of the benzyl ring of PV2 and its metabolites indicates the formation of an intermediate epoxide followed by glutathione conjugation. After glutathione depletion in vivo by diethyl maleate (DEM) liver covalent binding of ¹⁴C-PV2 metabolites was increased and biliary excretion of benzyl ring-hydroxylated PV2 metabolites decreased. Replacement of glutathione depletion by a cysteine derivative restored liver covalent binding and the excretion of PV2 metabolites to levels similar to those observed in control rats, indicating that glutathione conjugation may be an important metabolic pathway for the detoxication of PV2 and its metabolites in vivo.     

Synthesis of 4′-Ethynyl-2′-deoxy-4′-thioribonucleosides and Discovery of a Highly Potent and Less Toxic NRTI

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Isolation of (−)-4′-demethyl traxillagenin from Thujopsis dolabrata Sieb. et Zucc. var. hondai Makino

(−)-4′-Demethyl traxillagenin was isolated from the sawdust of Thujopsis dolabrata Sieb. et Zucc. var. hondai Makino (Cupressaceae). This is the first example of its isolation from this plant.     

Photocleavage of DNA by 4′-bromoacetophenone analogs

4'-Bromoacetophenone analogs, which are able to generate monophenyl radicals capable of hydrogen atom abstraction, were investigated as possible photoinducible DNA cleaving agents. The potential of 4'-bromoacetophenone as a possible new DNA cleaver is explored. Pyrrolecarboxatmid conjugated 4'-bromoacetophenones, in particular, DNA cleaving activity and sequence-selectivity on the contiguous AT base pair sites.     

A pharmaco-scintigraphy study of riboflavin 5′-phosphate sodium capsules (1 vs. 4)

The comparative in-vivo disintegration, gastric emptying and bioavailability of 41 mg radiolabeled riboflavin 5′-phosphate sodium capsules administered as a single hard gelatin capsule or as four capsules was evaluated in human subjects. A total of 41 mg of riboflavin 5′-phosphate sodium and 7 MBq of technetium sulfur colloid were incorporated in a single gelatin capsule or the same dose was administered in four capsules. A randomized crossover design was conducted in eight subjects under fasting conditions. Capsule disintegration and gastric emptying was measured by γ scintigraphy and the relative amount of riboflavin excreted in the urine was measured by HPLC. The in-vivo disintegration time and gastric emptying of the four capsules was significantly faster than for the one capsule. The bioavailability of the four capsule regimen was 16.5 versus 11.2% for the one capsule. The amount of riboflavin excreted in the urine in the 0–2 h interval was significantly greater for the four versus one capsule. The in-vivo performance of one 41 mg riboflavin 5′-phosphate sodium capsule is significantly different than the equivalent dose administered in four capsules. Further studies are needed to understand the underlying mechanism for the difference between the regimens.     

Human pharmacokinetics of esorubicin (4′ -deoxydoxorubicin)

Summary The pharmacokinetics of esorubicin, a new anthracycline antibiotic, was investigated in conjunction with a phase I clinical trial. The drug was administered to 12 patients as an intravenous bolus at a dose of 20 to 40mg/m². All patients had normal renal and hepatic functions and no third space fluid accumulation. Plasma and urine samples were assayed by HPLC. The peak plasma concentration of esorubicin was 0.74 ± 0.57 M (mean ± SE). Esorubicin disappeared from plasma according to a tri-exponential pattern with a terminal half-life of 20.4 ± 7.3 hr. The area under the plasma concentration versus time curve was 0.64 ± 0.31 Mxhr. Total body plasma clearance was 45.5 ± 26.8 liter/min/m² and the apparent volume of the central compartment, 41.0 ± 24.8 L. A single metabolite, 4-deoxydoxorubicinol, was detected in plasma. This metabolite was observed in 5 patients only and its mean peak concentration was 0.029 ± 0.017 M. The area under the plasma versus concentration time curve for 4-deoxydoxorubicinol was 0.02 ± 0.014 Mxhr. The urinary excretion of total fluorescence within 5 days of therapy was 7.3 ± 1.3% of the administered dose. Esorubicin represented more than 80% of the excreted anthracyclines. As in plasma, 4 -deoxydoxorubicinol was the only metabolite detectable in urine. No correlation between the various pharmacokinetic parameters and drug-induced toxicity was observed in this small group of patients.This work was presented in part at the 4th NCI EORTC Symposium on New Drugs in Cancer Therapy (Brussels, Belgium, December 14–17, 1983) and at the 20th Annual Meeting of the American Society of Clinical Oncology (Toronto, Canada, May 6–8, 1984).     

Hypolipidemic activity of d-pantothenic acid 4′-phosphate salts

Translated from Khimikofarmatsevticheskii Zhurnal, Vol. 24, No. 8, pp. 31–34, August, 1990.     

Phase I trial of 4′-deoxydoxorubicin given weekly

Summary Twenty-six patients with various solid tumors entered a Phase I trial with 4 -Deoxydoxorubicin (Esorubicin, IMI-58), a new doxorubicin analogue. The drug was administered weekly i.v. for 3–4 weeks. Leukopenia proved to be dose limiting. The maximum tolerated dose (MTD) was reached at 20 mg/m² weekly for 3 weeks. For Phase II trials, a weekly dose of 15 and 17.5 mg/m² can be proposed for poor and good risk patients respectively. Non-hematologic toxicity was minimal. Phase II trials with this new anthracycline are warranted.     

Tricin 4′-O-(erythro-β-guaiacylglyceryl) ether and tricin 4′-O-(threo-β-guaiacylglyceryl) ether isolated from Njavara (Oryza sativa L. var. Njavara), induce apoptosis in multiple tumor cells by mitochondrial pathway

Njavara is an important medicinal rice variety of Kerala, India widely used in Ayurveda for the treatment of rheumatoid arthritis, paralysis, neurodegenerative diseases and in rejuvenation therapy. The study evaluated, for the first time, antitumor effects of the two rare flavonolignans, tricin 4′-O-(erythro-β-guaiacylglyceryl) ether (compound 1) and tricin 4′-O-(threo-β-guaiacylglyceryl) ether (compound 2), isolated from ‘Njavara’ black. Both the compounds induced apoptosis in three cancer cell lines colon adenocarcinoma cell line HCT 116, ovarian cancer cell line SKOV3 and breast cancer cell line MCF-7. Chromatin condensation in the three cancer cell lines by Hoechst staining showed >50 % of apoptosis by compounds 1 and 2 at concentration 40 and 30 μg/ml, respectively after 48 h. Further studies substantiated that both the compounds targeted cancer cells through mitochondrial membrane potential loss and subsequent chromatin condensation. Both compounds significantly increased the Annexin V binding thus confirming compounds 1 and 2 to be potential apoptotic agents.     

Derivatives of aryl-4-guanidinomethylbenzoate and N-aryl-4-guanidinomethylbenzamide as new antibacterial agents： synthesis and bioactivity

AIM: The aim of the present study was to design, synthesize, and evaluate novel antibacterial agents, derivatives of aryl-4-guanidinomethylbenzoate and N-aryl-4-guanidinomethylbenzamide. METHODS: A total of 44 derivatives of aryl-4-guanidin-omethylbenzoate (series A) and N-aryl-4-guanidinomethylbenzamide (series B) were synthesized and their antibacterial activities were assessed in vitro against a variety of Gram-positive and Gram-negative bacteria by an agar dilution method. RESULTS: Twelve compounds showed potent bactericidal effects against a panel of Gram-positive germs, including methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE), vancomycin-intermediate Staphylococcus aureus (VISA), and methicillin-resistant coagulase-negative staphylococci (MRCNS), with minimum inhibitory concentrations (MIC) ranging between 0.5 and 8 microg/mL, which were comparable to the MIC values of several marketed antibiotics. They exhibited weak or no activity on the Gram-negative bacteria tested. In addition, these compounds displayed high inhibitory activities towards oligopeptidase B of bacterial origin. CONCLUSION: In comparison with the previously reported MIC values of several known antibiotics, the derivatives of aryl-4-guanidinomethylbenzoate and N-aryl-4-guanidinomethylbenzamide showed comparable in vitro bactericidal activities against VRE and VISA as linezolid. Their growth inhibitory effects on MRSA were similar to vancomycin, but were less potent than linezolid and vancomycin against MRCNS. This class of compounds may have the potential to be developed into narrow spectrum antibacterial agents against certain drug-resistant strains of bacteria.     

Synthesis and Pharmacological Properties of 1-Aryl-4-(3′4′,5′-trimethoxybenzoyl)piperazines

A series of 1-aryl-4-(3′,4′,5′-trimethoxybenzoyl)piperazines (IIa - IIg) having structures containing 3,4,5-trimethoxybenzoyl fragments were synthesized and characterized. Compounds IIa and IIc - IIg demonstrated weak anxiolytic properties and moderately decreased the spontaneous motor activity in rats. Compound IIb exhibited anxiolytic activity comparable with that of buspirone but, in contrast to this reference drug, increased the motor activity of test animals. __________ Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 39, No. 5, pp. 12 – 14, May, 2005.     

Formation of 4′-carboxyl acid metabolite of imrecoxib by rat liver microsomes

AIM: Imrecoxib is a novel and moderately selective COX-2 inhibitor. The aim of the present in vitro investigation was to study the formation of the major metabolite 4'-carboxylic acid imrecoxib (M2) and identify the enzyme(s) involved in the reaction. METHODS: The formation of M2 was studied in rat liver cytosol in the absence or presence of liver microsome. The formed metabolite was identified and quantified by LC/MS(n). In addition, to characterize the cytochrome P450 (CYP) isozymes involved in M2 formation, the effects of typical CYP inhibitors (such as ketoconazle, quinine, alpha-naphthoflavone, methylpyrazole, and cimetidine) on the formation rate of M2 were investigated. RESULTS: The formation of M2 from 4-hydroxymethyl imrecoxib (M4) was completely dependent on rat liver microsomes and NADPH. Enzyme kinetic studies demonstrated that the formation rate of M2 conformed to monophasic Michaelis-Menten kinetics. Additional experiments showed that the formation of M2 was induced significantly by dexamethasone and lowered by ketoconazole strongly and concentration-dependently. By comparison, other CYP inhibitors, such as alpha-naphthoflavone, cimetidine, quinine, and methylpyrazole had no inhibitory effects on this metabolic pathway. CONCLUSION: These biotransformation studies of imrecoxib in rat liver at the subcellular level showed that the formation of M2 occurs in rat liver microsomes and is NADPH-dependent. The reaction was mainly catalyzed by CYP 3A in untreated rats and in dexamethasone-induced rats. Other CYP, such as CYP 1A, 2C, 2D, and 2E, seem unlikely to participate in this metabolic pathway.     

Rapid Synthesis of Boc-2′,6′-dimethyl-l-tyrosine and Derivatives and Incorporation into Opioid Peptidomimetics

l-tyrosine has found widespread use in the development of synthetic opioid ligands. Opioids featuring this residue at the N-terminus often display superior potency at one or more of the opioid receptor types, but the availability of the compound is hampered by its cost and difficult synthesis. We report here a short, three-step synthesis of Boc-2′,6′-dimethyl-l-tyrosine (3a) utilizing a microwave-assisted Negishi coupling for the key carbon–carbon bond forming step, and employ this chemistry for the expedient synthesis of other unnatural tyrosine derivatives. Three of these derivatives (3c, 3d, 3f) have not previously been examined as Tyr¹ replacements in opioid ligands. We describe the incorporation of these tyrosine derivatives in a series of opioid peptidomimetics employing our previously reported tetrahydroquinoline (THQ) scaffold, and the binding and relative efficacy of each of the analogues at the three opioid receptor subtypes: mu (MOR), delta (DOR), and kappa (KOR).     

Comparative in vitro activity of 4′-deoxy-4′-iododoxorubicin and other anthracyclines in the human tumor clonogenic assay

A new halogenated anthracycline analog 4-deoxy-4-iododoxorubicin (IODO) was compared with doxorubicin (DOX) and deoxydoxorubicin (DEOX) in the human tumor clonogenic assay (HTCA) using human tumor cell lines. For all cell lines tested, IODO had lower ID₅₀ value and thus greater in vitro potency and cytotoxicity than DOX. DEOX had lower average ID₅₀ values than either IODO or DOX in all cell lines except HEC1A, where DEOX was equal to IODO. Analysis of variance likewise confirmed significantly greater activity for IODO versus DOX in most cell lines tested. Previous in vivo studies demonstrate oral activity in a variety of tumors as well as less cardiotoxicity. Thus, the results of in vitro and in vivo studies suggest that IODO is an active compound of potential clinical interest.     

Cyclodextrins as Mucosal Absorption Promoters of Insulin. II. Effects of β-Cyclodextrin Derivatives on α-Chymotryptic Degradation and Enteral Absorption of Insulin in Rats

The relative effectiveness of two -cyclodextrin derivatives, i.e., dimethyl--cyclodextrin (DMCD) and hydroxypropyl--cyclodextrin (HPCD), in enhancing enteral absorption of insulin was evaluated in the lower jejunal/upper ileal segments of the rat by means of an in situ closed loop method. The incorporation of 10% (w/v) DMCD to a 0.5 mg/ml porcine-zinc insulin solution dramatically increased insulin bioavailability from a negligible value (~0.06%) to 5.63%, when administered enterally at a dose of 20 U/kg. However, addition of 10% (w/v) HPCD did not improve enteral insulin uptake significantly with a bioavailability of only 0.07%. Similarly, the pharmacodynamic relative efficacy values obtained after the enteral administration of 20 U/kg insulin, 20 U/kg insulin with 10% HPCD, and 20 U/kg insulin with 10% DMCD were 0.24%, 0.26%, and 1.75%, respectively. Biodegradation studies of 0.5 mg/ml insulin hexamers by 0.5 µM -chymotrypsin revealed no inhibitory effect on the enzymatic activity by the two cyclodextrins. On the contrary, the apparent first-order rate constant increased significantly in the presence of 10% DMCD, suggesting insulin oligomer dissociation by DMCD. Histopathological examination of the rat intestine was performed to detect tissue damage following enteral administration of the -cyclodextrin derivatives. Light microscopic inspection indicated no observable tissue damage, thereby arguing direct membrane fluidization as the primary mechanism for enhanced insulin uptake. This study indicates the feasibility of using cyclodextrins as mucosal absorption promoters of proteins and peptide drugs.     

Role of Brain Tissue Localized Purine Metabolizing Enzymes in the Central Nervous System Delivery of Anti-HIV Agents 2′-β-Fluoro-2,3′-Dideoxyinosine and 2′-β-Fluoro-2′,3′-Dideoxyadenosine in Rats

Purpose. This study examines the central nervous system (CNS) delivery of 2--fluoro-2,3-dideoxyadenosine (F-ddA) and 2--fluoro-2,3-dideoxyinosine (F-ddl), acid stable analogues of dideoxyadenosine (ddA) and dideoxyinosine (ddI) having reduced susceptibility to purine salvage pathway enzymes important in the metabolism of ddA and ddI, adenosine deaminase (ADA) and purine nucleoside phosphorylase (PNP), respectively. Their CNS delivery compared to that for ddI provides insight into the role of brain tissue ADA and PNP in these processes. Methods. Brain and cerebrospinal fluid (CSF) concentration-time profiles were obtained for F-ddI during and after intravenous infusions of F-ddl, and for both F-ddA and F-ddI after F-ddA infusions in normal rats or rats pre-treated with the ADA inhibitor 2-deoxycoformycin (DCF). Rate constants for CNS entry, efflux and metabolism were estimated by computer fits using plasma concentration-time profiles as the driving force functions. Results. The CNS delivery of F-ddI did not differ significantly from that for ddI. F-ddA, which is more lipophilic than F-ddI, provided higher brain ( 8×) and CSF ( 11×) concentrations of total dideoxynucleoside (F-ddA and F-ddI) compared to F-ddI. Deamination by brain tissue ADA to form F-ddI reduced CNS levels of intact F-ddA but provided higher brain parenchyma (5×) and CSF/plasma (3×) ratios of F-ddI relative to F-ddI controls. Thus, F-ddA functions in part as a CNS-activated prodrug of F-ddI. DCF pre-treatment inhibited brain tissue ADA, abolishing the prodrug effect, and enhancing F-ddA concentrations in both brain parenchyma (5×) and CSF (6×). Conclusions. PNP metabolism does not appear to play a role in the low CNS delivery of ddI. On the other hand, deamination of F-ddA by brain tissue ADA is an important process, such that F-ddA functions in part as a CNS-activated prodrug of F-ddI. Enhanced CNS uptake of intact F-ddA can be achieved with ADA inhibition.