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P D Cook

Publications and source records attributed to P D Cook.

At least 55 records · Page 3Linked to original sources
PubMed1987

Synthesis and antitumor activity of fluorine-substituted 4-amino-2(1H)-pyridinones and their nucleosides. 3-Deazacytosines.

Novel fluorine-substituted deaza analogues of 5-azacytidine (AZC) and 5-aza-2'-deoxycytidine (dAZC) (3-deazacytosines) have been synthesized and tested for antitumor activity. Thus, 4-amino-3,5-difluoro-1-beta-D-ribofuranosyl-2(1H)-pyridinone (16), 4-amino-3-fluoro-1-beta-D-ribofuranosyl-2(1H)-pyridinone (17), 4-amino-5-fluoro-1-beta-D-ribofuranosyl-2(1H)-pyridinone (18), 4-amino-1-(2-deoxy-beta-D-erythro-pentofuranosyl)-3,5-difluoro-2 (1H)-pyridinone (25), 4-amino-1-(2-deoxy-beta-D-erythro-pentofuranosyl)-3-fluoro-2(1H)-pyridin one (26) 4-amino-1-(2-deoxy-alpha-D-erythro-pentofuranosyl)-3,5-difluoro-2(1H)-++ +pyridinon e (27), and 4-amino-1-(2-deoxy-alpha-D-erythro-pentofuranosyl)-3-fluoro-2 (1H)-pyridinone (28) were prepared by standard glycosylation procedures. Requisite heterocycle 4-amino-3,5-difluoro-2(1H)-pyridinone (6) was prepared in five steps from pentafluoropyridine (1). Other requisite fluoro heterocycles, 4-amino-3-fluoro-2(1H)-pyridinone (7) and 4-amino-5-fluoro-2(1H)-pyridinone (8), were obtained from a bis-defluorination of 4-amino-3,5,6-trifluoro-2(1H)-pyridinone (3) with hydrazine. Acetylation of 17 provided 4-amino-3-fluoro-1-(2,3,5-tri-O-acetyl-beta-D-ribofuranosyl)-2(1H)-pyrid inone (29). Structure proof of target nucleosides and heterocyclic compounds was provided by X-ray diffraction, 19F and 1H NMR, and UV. The ID50 values of fluorine-substituted 3-deazacytosines and 3-deazacytidines were greater than 1 X 10(-5) M in L1210 lymphoid leukemia cells in culture. Nucleoside 17 and its tri- and tetraacetates were the most active compounds with ID50 values of 1.07 X 10(-5), 1.23 X 10(-5), and 1.25 X 10(-5) M, respectively. The target nucleosides and intermediate heterocycles were inactive against P388 and L1210 lymphocytic leukemia in mice, except nucleoside 17 (NSC-378066) and its triacetate 29 (NSC-382021). Nucleoside 17 exhibited confirmed DN2 activity (% T/C 169-230) at five dose levels (25-300 mg/kg). Prodrug 29 exhibited similarly confirmed L1210 in vivo activity.

Animals↗
PubMed1986

Effect of selenazofurin on influenza A and B virus infections of mice.

The inhibitory effects of selenazofurin and ribavirin on influenza A and B virus infections in mice were compared. Both compounds, when administered intraperitoneally (i.p.), reduced lung consolidation and prolonged mean day of death, but ribavirin more effectively increased survivor number and lowered lung viral hemagglutinin (HA) titers. Lung HA titers often increased in selenazofurin-treated animals. To determine the most appropriate i.p. treatment schedule, influenza A virus-infected mice were treated once, twice or thrice daily for 7-9 days, or once only. Treatment once daily for 9 days beginning 4 h pre-virus exposure, for 3 days beginning 24 h post-virus exposure, or once only 48 h post-virus exposure was most effective. Body temperature, which usually declined during infection, increased to near-normal levels in animals treated with selenazofurin, especially in animals treated a single time or for 3 days with high dose levels. Selenazofurin was well tolerated at a dose of 50 mg/kg administered twice daily, and at 400 mg/kg administered once only. Rectal temperatures temporarily declined following every other day treatment with 400 mg/kg.

Animals↗
PubMed1986

Synthesis, antimalarial activity, and quantitative structure-activity relationships of tebuquine and a series of related 5-[(7-chloro-4-quinolinyl)amino]-3-[(alkylamino)methyl] [1,1'-biphenyl]-2-ols and N omega-oxides.

A series of 5-[(7-chloro-4-quinolinyl)amino]-3-[(alkylamino)methyl] [1,1'-biphenyl]-2-ols and N omega-oxides was prepared from the substituted 1-phenyl-2-propanones proceeding through the 5-nitro[1,1'-biphenyl]-2-ols, the corresponding amino, and acetamido derivatives to the N-[5-[(alkylamino)methyl]-6-hydroxy[1,1'-biphenyl]-3-yl]acetamides and final condensation with 4,7-dichloroquinoline or the N-oxide. In a quantitative structure-activity relationship study first run on 28 and later expanded to 40 substituted phenyl analogues and their N omega-oxides, increasing antimalarial potency vs. Plasmodium berghei in mice was found to be correlated with decreasing size (sigma MR) and electron donation (sigma sigma) of the phenyl ring substituents. A significant correlation with N omega-oxidation could not be demonstrated. Initial high activity against P. berghei infections in mice led to expanded studies that demonstrated in addition excellent activity against resistant strains of parasite, activity in primate models, and pharmacokinetic properties apparently allowing protection against infection for extended periods of time even after oral administration. Such properties encourage the clinical trial of a member of this class in man.

Aminoquinolines↗
PubMed1986

Synthesis of 8-amino-3-deazaguanine via imidazole precursors. Antitumor activity and inhibition of purine nucleoside phosphorylase.

8-Amino-3-deazaguanine (15), an analogue of both 3-deazaguanine (1) and 8-aminoguanine (6), an antitumor agent and a purine nucleoside phosphorylase (PNP) inhibitor, respectively, was synthesized from the ammonolysis of an imidazole precursor, methyl 2-(benzoylamino)-5-(cyanomethyl)-1H-imidazole-4-carboxylate (13). The requisite imidazole, methyl 2-(benzoylamino)-4-(methoxycarbonyl)-1H-imidazole-5-acetate (11), was prepared from the monoheterocyclic rearrangement of dimethyl 3-[(5-phenyl-1,2,4-oxadiazol-3-yl)amino]-2-pentenedioate (10) by NaH/DMF. Ammonolysis and subsequent dehydration of 11 provided the penultimate imidazole intermediate 13. Its deprotected (NaOMe/100 degrees C) product, methyl 2-amino-5-(cyanomethyl)-1H-imidazole-4-carboxylate (14), was also converted to 15. 8-Amino-3-deazaguanine, as its methanesulfonic acid (mesylate 7), exhibited an inhibition constant (IC50) of 9.9 microM against isolated mammalian PNP. It was a very weak inhibitor of T and B cell growth and did not enhance 2'-deoxyguanosine toxicity in the same cells. 8-Amino-3-deazaguanine mesylate was not significantly active in L1210 cells in vitro or L1210 leukemic mice. Thus, the amino group introduced in the 8-position of 3-deazaguanine enhances its PNP activity but diminishes its antitumor activity.

Animals↗
PubMed1985

Biochemical and antitumor activity of tiazofurin and its selenium analog (2-beta-D-ribofuranosyl-4-selenazolecarboxamide).

2-beta-D-Ribofuranosyl-4-selenazolecarboxamide (selenazofurin, CI-935), the selenium analog of tiazofurin (CI-909), was 3- to 10-fold more cytotoxic to murine or human tumor cells in vitro than tiazofurin and was also more active against P388 mouse leukemia in vivo. In vitro cytotoxicity could be reversed by guanosine or guanine but not by other purine nucleosides or bases. Three human tumor cell lines selected for selenazofurin or tiazofurin resistance showed cross resistance between selenazofurin and tiazofurin. Treatment with tiazofurin, selenazofurin, or mycophenolic acid decreased guanylate pools and caused an accumulation of IMP in WIL2 human lymphoma cells. The decrease in guanylate pools was accompanied by inhibition of RNA and DNA synthesis. The NAD analogs of tiazofurin and selenazofurin were inhibitors of L1210 IMP dehydrogenase (IMP:NAD oxidoreductase, EC 1.2.1.14), and both showed uncompetitive inhibition with respect to NAD having Kii values of 5.7 X 10(-8)M and 3.3 X 10(-8)M respectively.

Animals↗
PubMed1985

Activity of selenazofurin against influenza A and B viruses in vitro.

Activity of the new antiviral compound selenazofurin was compared with the known active compounds ribavirin and amantadine against influenza A and B viruses. In experiments with Madin Darby canine kidney cells, selenazofurin inhibited the cytopathic effect and yield of influenza A/NWS/33 virus, with 50% effective dose ranges of 0.7 to 1.4 micrograms/ml (virus rating [VR], 1.3 to 1.4). The 50% effective dose range for ribavirin was 1.2 to 1.6 micrograms/ml (VR, 1.0 to 1.3), and for amantadine it was 9 micrograms/ml (VR, 0.9). Selenazofurin and ribavirin were similarly inhibitory to influenza B/Lee/40 virus, whereas amantadine was inactive. Selenazofurin appeared somewhat cytotoxic in these studies at concentrations as low as 1 micrograms/ml.

Amantadine↗
PubMed1984

Synthesis and antiviral/antitumor activities of certain 3-deazaguanine nucleosides and nucleotides.

A new procedure for the preparation of the antiviral and antitumor agent 3-deazaguanine (1) and its metabolite 3-deazaguanosine (2) has been developed by reacting methyl 5(4)-(cyanomethyl) imidazole-4(5)-carboxylate (4) and 5-(cyanomethyl)-1- (2,3,5-tri-O-benzoyl-beta-D-ribofuranosyl)imidazole-4-carboxylate (6), respectively, with hydrazine. The 3-deazaguanosine 3',5'-cyclic phosphate (13) was prepared from 5-(cyanomethyl)-1-beta-D-ribofuranosyl-imidazole-4-carboxamide 5'-phosphate. Glycosylation of the trimethylsilyl 4 with 1-O-methyl-2-deoxy-3,5-di-O-p-toluoyl-D-ribofuranose in the presence of trimethylsilyl trifluoromethanesulfonate gave the corresponding N-1 and N-3 glycosyl derivatives with alpha-configuration (18 and 20) as the major products, along with minor amounts of the beta-anomers (19 and 21). However, glycosylation of the sodium salt of 4 with 1-chloro-2-deoxy-3,5-di-O-p-toluoyl-alpha-D-erythro-pentofurano se (17) gave exclusively the beta-anomers (19 and 21) in good yield. Base-catalyzed ring closure of these imidazole nucleosides gave 2'-deoxy-3-deazaguanosine (29), the alpha-anomer 28, and the corresponding N-3 positional isomers 27 and 26. The site of glycosylation and the anomeric configuration of these nucleosides have been assigned on the basis of 1' NMR and UV spectral characteristics and by single-crystal X-ray analysis for 27-29. In a preliminary screening, several of these compounds have demonstrated significant broad-spectrum antiviral activity against certain DNA and RNA viruses in vitro, as well as moderate activity against L1210 and P388 leukemia in cell culture.

Animals↗
PubMed1982

Evaluation of the anti-herpesvirus drug combinations: virazole plus arabinofuranosylhypoxanthine and virazole plus arabinofuranosyladenine.

Combinations of Virazole plus arabinofuranosylhypoxanthine (ara-Hx) and Virazole plus arabinofuranosyladenine (ara-A) were investigated in KB or BHK cells infected with types 1 or 2 herpes viruses. Combinations of Virazole and ara-Hx exhibited significant synergy as evaluated graphically (isobolograms) or by fractional inhibitory concentration (FIC) indices. Optimal ratios for the combination were 1:1 to 1:10 for Virazole to ara-Hx. At these ratios, FIC indices in the range of 0.5-0.2 were commonly observed. Combinations of Virazole and ara-A were antagonistic when observed in the presence of pentostatin, an adenosine deaminase inhibitor. In the absence of pentostatin, the minimum inhibitory concentration (MIC) of ara-A and degree of synergy with Virazole were variable.

Animals↗
PubMed1979

Inhospital family practice--a one year summary.

A review of 914 medical records of patients hospitalized at the Polyclinic Medical Center of Harrisburg by members of the Department of Family Practice is presented. The age distribution of these patients was essentially bimodal, with peak numbers in the less than one year and greater than 65 years age groups. Physicians and physician groups which perform obstetrics rendered hospital care to a larger number of infants than those not performing obstetrics. The family physicians gave hospital care for a large number of different conditions. The family physicians frequently consulted other medical specialists, especially cardiologists and general surgeons. The consultation rate varied considerably among the physicians studied.

Adolescent↗
PubMedDate not supplied

Monitoring solution-phase combinatorial library synthesis by capillary electrophoresis.

Capillary electrophoresis has been applied to monitor model reactions in solution-phase combinatorial chemistry. In particular, the simultaneous alkylation reactions of secondary amines with a series of benzyl halides has been investigated. Reactant and product concentrations were monitored using capillary electrophoresis in a non-aqueous buffer system. The simplified sample preparation was a key feature making this an attractive method of analysis. The results demonstrate that capillary electrophoresis is a useful tool for monitoring reactions to determine initial rates, rate constants, and extinction correlation coefficients for quantitative analysis in combinatorial chemistry, and is a broadly applicable technique for the analysis of a variety of organic and bioorganic transformations.

Acetamides↗
PubMedDate not supplied

Synthesis and electrochemistry of anthraquinone-oligodeoxynucleotide conjugates.

Electroactive oligodeoxynucleotides (ODNs) with specific base sequences have a potential application as electrical sensors for DNA molecules. To this end, a phosphoramidite that bears a 9, 10-anthraquinone (AQ) group tethered to the 2'-O of the uridine via a hexylamino linker, 2'-O-[6-[2-oxo(9, 10-anthraquinon-2-yl)amino]hexyl]-5'-O-(4,4'-dimethoxytrityl)uridi ne 3'-[2-(cyanoethyl)bis(1-methylethyl)phosphoramidite] (3), has been synthesized and used to prepare three ODNs with tethered AQs using standard phosphoramidite chemistry. The synthetic methodology thus allows the synthesis of ODNs with electroactive tags attached to given locations in the base sequence. Cyclic voltammetric behavior of these AQ-ODN conjugates was examined in aqueous buffer solutions at a hanging mercury drop electrode. At slow sweep rates, nearly reversible two-electron waves characteristic of an adsorbed anthraquinone/hydroquinone redox couple was observed for all of the AQ-ODN conjugates. Approximate Langmuirian isotherms were found for the AQ-ODNs with molecular footprints, calculated from the saturation coverages, that scaled with molecular size. The cyclic voltammetric response of the duplexes formed from the AQ-ODNs and their complementary ODN was complicated by the competitive adsorption of the individual ODNs and possibly the duplex species as well.

Adsorption↗