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Fatih M. Uckun - One of the best experts on this subject based on the ideXlab platform.
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2001. In vivo pharmacokinetics and metabolism of anti-human immunodeficiency virus agent d4T-5-[p-bromophenyl methoxyalaninyl Phosphate] (Sampidine) in mice. Drug Metab. Dispos
2020Co-Authors: Chunlin Chen, T K Venkatachalam, And Zhao-hai Zhu, Fatih M. UckunAbstract:This paper is available online at http://dmd.aspetjournals.org ABSTRACT: d4T-5-[p-Sampidine, bromophenyl methoxyalaninyl Phosphate] (HI-113), a novel Aryl Phosphate derivative of stavudine (d4T), exhibits substantially more potent anti-human immunodeficiency virus activity than d4T. The purpose of the present study was to investigate the in vivo pharmacokinetics and metabolism of this promising new anti-HIV agent in mice. Here, we report that HI-113 forms two active metabolites with favorable pharmacokinetics after systemic administration. Plasma HI-113 concentrations were measured by analytical high-performance liquid chromatography and the pharmacokinetic parameters were estimated using the WinNonlin program. After intravenous administration, the elimination half-life (t 1/2 ) of HI-113 was 3.6 min with a systemic clearance of 174.5 ml/min/kg. HI-113 was converted to the active metabolites alaninyl-d4T-monoPhosphate (ala-d4T-MP) and d4T. The T max values for ala-d4T-MP and d4T derived from intravenously administered HI-113 were 5.1 and 17.4 min, respectively. The elimination half-life for synthetic ala-d4T-MP was 38.9 min after intravenous administration. Ala-d4T-MP was metabolized to form d4T (T max ؍ 5.0 min). The elimination half-life of d4T derived from intravenously administered ala-d4T-MP (32.4 min) was similar to the elimination half-life of intravenously administered d4T (26.6 min). In contrast, the elimination half-life of d4T derived from HI-113 was substantially longer (116.2 min). Similarly, the elimination half-life of alad4T-MP derived from HI-113 (138.8 min) was markedly longer than the elimination half-life of ala-d4T-MP given intravenously (38.9 min). Following oral administration of HI-113, the elimination halflives of ala-d4T-MP (56.1 min) and d4T (102.6 min) were also prolonged
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© 2002 The British Society for Antimicrobial Chemotherapy Pre-clinical safety evaluation of novel nucleoside analogue-based dual-function microbicides (WHI-05 and WHI-07)
2015Co-Authors: Osmond J. D’cruz, Fatih M. UckunAbstract:methoxyalaninyl Phosphate] and WHI-07 [5-bromo-6-methoxy-5,6-dihydro-3′-azidothymidine-5′-(p-bromophenyl)-methoxyalaninyl Phosphate] are Aryl Phosphate derivatives of zidovudine (ZDV) with anti-HIV and contraceptive activity. WHI-05 and WHI-07 differ fundamentally from currently used surfactant microbicides that are cytotoxic to genital tract epithelial cells at spermicidal concentrations. These drugs were rationally designed to bypass the thymidine kinase dependency of ZDV activation in genital tract secretions, as well as to achieve spermi-cidal activity. WHI-05 and WHI-07 were formulated via a non-toxic gel-microemulsion for intra-vaginal use as potential anti-HIV spermicides. Pre-clinical safety studies of intravaginally administered WHI-05 and WHI-07 gel-microemulsions were performed in mice and rabbits to mimic closely the intravaginal application of a microbicidal preparation in women. In addition, systemic toxicity studies were performed in mice and non-human primates. The LD10 doses for WHI-05 and WHI-07 when administered intravenously or intraperitoneally were>500 mg/kg for mice. Female cynomolgus monkeys treated with 20 mg/kg WHI-05 and WHI-07 intravenously developed no grade 2–4 systemic toxicities. Repetitive intravaginal administration of 2 % WHI-05 and WHI-07 via a gel-microemulsion to achieve concentrations as high as 6.1 × 104 and 5.7 × 10
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Contraceptive Activity of a Spermicidal Aryl Phosphate Derivative of Bromo-Methoxy Zidovudine (Compound WHI-05) in Rabbits
Drug Research, 2011Co-Authors: Osmond J. D'cruz, Fatih M. UckunAbstract:WHI-05 (5-bromo-6-methoxy-5,6-dihydro-3’-azidothymidine-5’-(p-methoxyphenyl) methoxyalaninyl Phosphate, CAS 213982-93-5) is a highly promising antiviral and spermicidal agent with clinical potential as a vaginal contraceptive which can prevent the sexual transmission of AIDS. In this study, the contraceptive activity of WHI-05 in rabbits was evaluated. Exposure of semen to WHI-05 at the time of artificial insemination inhibited pregnancy and embryo implantation by 90 %. Intravaginal application of 2 % WHI-05 containing gel also inhibited the pregnancy rate by 90 %. WHI-05 had no side effects for the offspring of rabbits who became pregnant despite WHI-05.
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antileukemic activity and cellular metabolism of the Aryl Phosphate derivative of bromo methoxy zidovudine compound whi 07
Drug Research, 2011Co-Authors: Fatih M. Uckun, Hungliang Tai, Osmond J DcruzAbstract:The novel Aryl Phosphate derivative of bromo-methoxy zidovudine (ZDV/AZT) (compound WHI-07, CAS 213982-96-8) was found to be a potent antileukemic agent against human leukemia, lymphoma, and multiple myeloma cell lines in MTT and clonogenic assays with low micromolar IC 50 values. In addition, WHI-07 was antimitotic, leading to cell fusion and developmental arrest in the Zebrafish model of rapid cell proliferation. WHI-07 was cytotoxic to drug-sensitive (NALM-6, MOLT-3, HL-60, P388) and multi-drug resistant (MDR) leukemia cell lines (HL-60/VCR, HL-60/ADR, P388/ ADR). Treatment of leukemia cells with WHI-07 showed rapid and dramatic depletion of all cellular nucleoside diPhosphate and triPhosphate (NDP/NTP) pools, which would contribute to the overall reduction of nucleic acid synthesis and cell death. WHI-07 was rapidly metabolized to alaninyl ZDV monoPhosphate (Ala-ZDV-MP), the levels of which inversely correlated with cytotoxic IC 50 values of WHI-07. Glutathione was found to mediate the in vitro and in vivo detoxification pathway of WHI-07 to 3’-azidothymidine-5’-p-bromophenylmethoxyalaninyl Phosphate and Ala-ZDV-MP, respectively. The proposed intracellular metabolic pathway for WHI-07 involves a thiol-mediated dehalogenation step followed by the paraoxon-sensitive carboxylesterase-mediated reaction leading to the formation of Ala-ZDV-MP as the major intracellular metabolite.
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zidampidine an Aryl Phosphate derivative of azt in vivo pharmacokinetics metabolism toxicity and anti viral efficacy against hemorrhagic fever caused by lassa virus
Bioorganic & Medicinal Chemistry, 2005Co-Authors: Fatih M. Uckun, T K Venkatachalam, D Erbeck, C L Chen, A S Petkevich, Alexei O VassilevAbstract:Abstract The pharmacokinetics, metabolism, and toxicity of Zidampidine, an Aryl Phosphate derivative of AZT, 3′-azidothymidine-5′-[ p -bromophenyl methoxyalaninyl Phosphate] were investigated in CD-1 mice. Following iv injection, Zidampidine was rapidly converted to its metabolites Ala-AZT-MP and AZT. Zidampidine was not toxic to mice at doses up to 250 mg/kg. We next examined the therapeutic effect of Zidampidine in CBA mice challenged with intracerebral injections of the Josiah strain of Lassa virus. Mice were treated either with vehicle or non-toxic doses of Zidampidine administered intraperitoneally 24 h prior, 1 h prior, and 24, 48, 72, and 96 h after virus inoculation. The probability of survival following the Lassa challenge was significantly improved for Zidampidine-treated mice (Kaplan Meier, Log-Rank p value
Osmond J Dcruz - One of the best experts on this subject based on the ideXlab platform.
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antileukemic activity and cellular metabolism of the Aryl Phosphate derivative of bromo methoxy zidovudine compound whi 07
Drug Research, 2011Co-Authors: Fatih M. Uckun, Hungliang Tai, Osmond J DcruzAbstract:The novel Aryl Phosphate derivative of bromo-methoxy zidovudine (ZDV/AZT) (compound WHI-07, CAS 213982-96-8) was found to be a potent antileukemic agent against human leukemia, lymphoma, and multiple myeloma cell lines in MTT and clonogenic assays with low micromolar IC 50 values. In addition, WHI-07 was antimitotic, leading to cell fusion and developmental arrest in the Zebrafish model of rapid cell proliferation. WHI-07 was cytotoxic to drug-sensitive (NALM-6, MOLT-3, HL-60, P388) and multi-drug resistant (MDR) leukemia cell lines (HL-60/VCR, HL-60/ADR, P388/ ADR). Treatment of leukemia cells with WHI-07 showed rapid and dramatic depletion of all cellular nucleoside diPhosphate and triPhosphate (NDP/NTP) pools, which would contribute to the overall reduction of nucleic acid synthesis and cell death. WHI-07 was rapidly metabolized to alaninyl ZDV monoPhosphate (Ala-ZDV-MP), the levels of which inversely correlated with cytotoxic IC 50 values of WHI-07. Glutathione was found to mediate the in vitro and in vivo detoxification pathway of WHI-07 to 3’-azidothymidine-5’-p-bromophenylmethoxyalaninyl Phosphate and Ala-ZDV-MP, respectively. The proposed intracellular metabolic pathway for WHI-07 involves a thiol-mediated dehalogenation step followed by the paraoxon-sensitive carboxylesterase-mediated reaction leading to the formation of Ala-ZDV-MP as the major intracellular metabolite.
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antiretroviral spermicide whi 07 prevents vaginal and rectal transmission of feline immunodeficiency virus in domestic cats
Antimicrobial Agents and Chemotherapy, 2004Co-Authors: Osmond J Dcruz, Barbara Waurzyniak, Fatih M. UckunAbstract:WHI-07 [5-bromo-6-methoxy-5,6-dihydro-3′-azidothymidine-5′-(p-bromophenyl)-methoxy alaninyl Phosphate] is a novel dual-function Aryl Phosphate derivative of zidovudine with potent anti-human immunodeficiency virus (HIV) and spermicidal activities. WHI-07 was active against the feline immunodeficiency virus (FIV). This study evaluated whether topical application of WHI-07 as a single agent and in combination with an organometallic vanadium complex, vanadocene dithiocarbamate (VDDTC), via a nontoxic gel microemulsion can block vaginal as well as rectal transmission of feline AIDS (FAIDS) by chronically FIV-infected feline T cells in the natural host model. Genital transmission of FIV was monitored in recipient cats by the appearance of viral antibodies to FIV Gag proteins and by virus isolation of blood leukocytes as measured by FIV reverse transcriptase activity and FIV-specific PCR. Microbicidal activity was considered effective when the treated cats did not show evidence of FIV infection for up to 18 weeks postchallenge. An aggregate analysis of 46 specific-pathogen-free cats revealed that a single dose of the infected cell inoculum efficiently transmitted FIV infection when delivered into the vagina (100%) or rectum (66%). Pretreatment of the vagina or rectum with 2% WHI-07 alone or in combination with 0.25% VDDTC significantly (P = 0.004) protected cats from genital transmission by the highly infectious inoculum (7 million FIVBangston-infected feline T cells). Collectively, using the vaginal and rectal transmucosal model for FAIDS, our studies demonstrated that WHI-07 either alone or in combination with a vanadocene has clinical potential for the development of a dual-function anti-HIV microbicide for sexually active women.
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contraceptive activity of a spermicidal Aryl Phosphate derivative of bromo methoxy zidovudine compound whi 07 in rabbits
Fertility and Sterility, 2003Co-Authors: Osmond J Dcruz, Fatih M. UckunAbstract:Abstract Objective To determine the vaginal contraceptive activity of WHI-07 in the rabbit model. Design Prospective, controlled study. Setting Center for advanced preclinical sciences. Animal(s) Subgroups of 15, 16, or 24 New Zealand White does and 24 bucks per experiment. Intervention(s) Ex vivo (Experiment 1) and in vivo (Experiments 2 and 3) treatment of semen with WHI-07 or Nonoxynol-9 (N-9). In Experiment I, ovulated does in subgroups of 15 were artificially inseminated with semen mixed with WHI-07 or vehicle. In Experiment 2, ovulated does in subgroups of 24 were artificially inseminated within 2 min after intravaginal administration of 2% WHI-07 gel-microemulsion or 2% N-9 gel and allowed to complete term pregnancy. In Experiment 3, ovulated does in subgroups of 16 were artificially inseminated at 15, 30, or 60 minutes. Main outcome measure(s) The numbers of implanted embryos on postinsemination day 8 or the proportion of does that became pregnant and delivered newborn rabbits; the litter size, weight, growth, and viability of pups until lactation day 5. Result(s) Exposure of semen to WHI-07 at the time of artificial insemination completely inhibited pregnancy rates (WHI-07–pretreated, 0%, vs. control, 60%) and embryo implantation (WHI-07-pretreated, 0/175 vs. control, 68/170). Intravaginal administration of a 2% WHI-07 gel-microemulsion or 2% N-9 gel before artificial insemination significantly inhibited pregnancy rates (81% and 85% inhibition, respectively) when compared with control. Furthermore, the 2% WHI-07 gel-microemulsion provided ⪢90% inhibition of fertility even when insemination was delayed until 60 minutes after intravaginal application. Rabbits that delivered litters despite intravaginal application of 2% WHI-07 gel-microemulsion had healthy offsprings with no perinatal or postnatal repercussions. Conclusion(s) WHI-07 is a potent contraceptive agent in vivo. Intravaginal use of WHI-07 gel-microemulsion has clinical potential as a safe prophylactic contraceptive, in addition to its microbicide activity to curb the sexual transmission of HIV.
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lack of adverse effects on fertility of female cd 1 mice exposed to repetitive intravaginal gel microemulsion formulation of a dual function anti hiv agent Aryl Phosphate derivative of bromo methoxy zidovudine compound whi 07
Journal of Applied Toxicology, 2001Co-Authors: Osmond J Dcruz, Fatih M. UckunAbstract:5-bromo-6-methoxy-5,6-dihydro-3(')-azidothymidine-5(')-(p-bromophenyl) methoxyalaninyl Phosphate (WHI-07), a novel bromo-methoxy-substituted Aryl Phosphate derivative of zidovudine (ZDV), is a potent dual-function contraceptive agent with anti-HIV activity. Its potential for reproductive toxicity was assessed in a series of experiments using CD-1 mice under the conditions of its intended use as an intravaginal microbicide. Female CD-1 mice were exposed intravaginally to a gel-microemulsion formulation containing 0%, 0.5%, 1.0% or 2.0% WHI-07 for up to 13 weeks. On a molar basis, these concentrations represent 1400-5700 times its in vitro spermicidal IC(50) and 1.4-5.7(x10(6)) times its in vitro anti-HIV IC(50). We examined the effects of intravaginally administered WHI-07 on: ovulation efficiency; in vivo fertilization and early embryonic, fetal development; and reproductive outcome, including neonatal survival and pup development. Compound WHI-07 was administered intravaginally during superovulation, organogenesis and prior to mating for 5 and 10 consecutive days and for 13 weeks, respectively. Mice were evaluated for ovulation efficiency and fertilization rate and cleavage 14 and 40 h after human chorionic gonadotropin (hCG) injection, respectively. Pregnant mice were administered 2% WHI-07 intravaginally during gestation days (GD) 6-15 and measures of teratogenicity were evaluated on GD 17. For short-term toxicity study, mice were given intravaginal treatment of gel-microemulsion containing 0%, 0.5%, 1.0% and 2.0% WHI-07 for 13 weeks and then mated with untreated males to evaluate potential reproductive and developmental effects. Repeated intravaginal exposure of mice to 2% WHI-07 had no adverse effects on ovulation response, mean number of eggs recovered or the percentage of eggs fertilized or cleaved. No evidence of reproductive toxicity, fetal toxicity or teratogenicity was found following repetitive intravaginal application of 2% WHI-07 during the period of organogenesis. Furthermore, repeated intravaginal exposure of mice to 0.5-2.0% WHI-07 for 13 weeks had no adverse effect on the subsequent reproductive capability, perinatal outcome or growth and development of the offspring. Compound WHI-07 shows unique clinical potential as a safe, dual-function vaginal contraceptive for curbing mucosal and perinatal HIV transmission.
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thymidine kinase independent intracellular delivery of bioactive nucleotides by Aryl Phosphate derivatives of bromo methoxy zidovudine compounds whi 05 and whi 07 in normal human female genital tract epithelial cells and sperm
Biology of Reproduction, 2001Co-Authors: Osmond J Dcruz, T K Venkatachalam, Fatih M. UckunAbstract:The compounds WHI-05 (5-bromo-6-methoxy-5,6-dihydro39-azidothymidine-59-[p-methoxyphenyl] methoxyalaninyl Phosphate) and WHI-07 (5-bromo-6-methoxy-5,6-dihydro-39-azidothymidine-59-[p-bromophenyl] methoxyalaninyl Phosphate) are Aryl Phosphate derivatives of zidovudine (ZDV) with dual-function anti-human immunodeficiency virus and contraceptive activity. These drugs were rationally designed to bypass the thymidine kinase (TK) dependency of ZDV activation as well as to achieve spermicidal activity. We investigated the TK activity and intracellular metabolism of WHI-05 and WHI-07 in normal human vaginal and cervical epithelial cells as well as sperm. The time- and concentration-dependent intracellular formation of ZDV metabolites following addition of WHI-05 and WHI-07 to normal human vaginal, ectocervical, and endocervical epithelial cells as well as motile sperm was studied by analytical HPLC. Thymidine kinase activity in these cells was determined by the flow cytometric method based on intracellular phosphorylation of the fluorescent nucleoside, 5-amino-2-deoxyuridine-dansyl chloride and by the ability of cell-free extracts to convert [ 3 H]thymidine to thymidine monoPhosphate in comparison to NALM-6, a pre-B leukemia cell line. TK activity of genital tract epithelial cells and sperm was found to be relatively low or lacking. Addition of WHI-05 and WHI-07 to vaginal and cervical epithelial cells resulted in their concentration- and time-dependent conversion to alaninyl ZDV monoPhosphate (Ala-ZDV-MP) and 59-ZDV monoPhosphate as the major metabolites. Studies using motile human sperm also demonstrated the conversion of WHI-05 and WHI-07 to Ala-ZDV-MP. These results demonstrate that human female genital tract epithelial cells and sperm efficiently convert WHI-05 and WHI-07 to bioactive ZDV metabolites despite their TK deficiency. female reproductive tract, gamete biology kinases, sperm, vagina
T K Venkatachalam - One of the best experts on this subject based on the ideXlab platform.
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2001. In vivo pharmacokinetics and metabolism of anti-human immunodeficiency virus agent d4T-5-[p-bromophenyl methoxyalaninyl Phosphate] (Sampidine) in mice. Drug Metab. Dispos
2020Co-Authors: Chunlin Chen, T K Venkatachalam, And Zhao-hai Zhu, Fatih M. UckunAbstract:This paper is available online at http://dmd.aspetjournals.org ABSTRACT: d4T-5-[p-Sampidine, bromophenyl methoxyalaninyl Phosphate] (HI-113), a novel Aryl Phosphate derivative of stavudine (d4T), exhibits substantially more potent anti-human immunodeficiency virus activity than d4T. The purpose of the present study was to investigate the in vivo pharmacokinetics and metabolism of this promising new anti-HIV agent in mice. Here, we report that HI-113 forms two active metabolites with favorable pharmacokinetics after systemic administration. Plasma HI-113 concentrations were measured by analytical high-performance liquid chromatography and the pharmacokinetic parameters were estimated using the WinNonlin program. After intravenous administration, the elimination half-life (t 1/2 ) of HI-113 was 3.6 min with a systemic clearance of 174.5 ml/min/kg. HI-113 was converted to the active metabolites alaninyl-d4T-monoPhosphate (ala-d4T-MP) and d4T. The T max values for ala-d4T-MP and d4T derived from intravenously administered HI-113 were 5.1 and 17.4 min, respectively. The elimination half-life for synthetic ala-d4T-MP was 38.9 min after intravenous administration. Ala-d4T-MP was metabolized to form d4T (T max ؍ 5.0 min). The elimination half-life of d4T derived from intravenously administered ala-d4T-MP (32.4 min) was similar to the elimination half-life of intravenously administered d4T (26.6 min). In contrast, the elimination half-life of d4T derived from HI-113 was substantially longer (116.2 min). Similarly, the elimination half-life of alad4T-MP derived from HI-113 (138.8 min) was markedly longer than the elimination half-life of ala-d4T-MP given intravenously (38.9 min). Following oral administration of HI-113, the elimination halflives of ala-d4T-MP (56.1 min) and d4T (102.6 min) were also prolonged
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zidampidine an Aryl Phosphate derivative of azt in vivo pharmacokinetics metabolism toxicity and anti viral efficacy against hemorrhagic fever caused by lassa virus
Bioorganic & Medicinal Chemistry, 2005Co-Authors: Fatih M. Uckun, T K Venkatachalam, D Erbeck, C L Chen, A S Petkevich, Alexei O VassilevAbstract:Abstract The pharmacokinetics, metabolism, and toxicity of Zidampidine, an Aryl Phosphate derivative of AZT, 3′-azidothymidine-5′-[ p -bromophenyl methoxyalaninyl Phosphate] were investigated in CD-1 mice. Following iv injection, Zidampidine was rapidly converted to its metabolites Ala-AZT-MP and AZT. Zidampidine was not toxic to mice at doses up to 250 mg/kg. We next examined the therapeutic effect of Zidampidine in CBA mice challenged with intracerebral injections of the Josiah strain of Lassa virus. Mice were treated either with vehicle or non-toxic doses of Zidampidine administered intraperitoneally 24 h prior, 1 h prior, and 24, 48, 72, and 96 h after virus inoculation. The probability of survival following the Lassa challenge was significantly improved for Zidampidine-treated mice (Kaplan Meier, Log-Rank p value
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stampidine is a potent inhibitor of zidovudine and nucleoside analog reverse transcriptase inhibitor resistant primary clinical human immunodeficiency virus type 1 isolates with thymidine analog mutations
Antimicrobial Agents and Chemotherapy, 2002Co-Authors: Sharon Pendergrass, T K Venkatachalam, Sanjive Qazi, Douglas D RichmanAbstract:We report the antiretroviral activity of stavudine-5'-(p-bromophenyl methoxyalaninyl Phosphate) (stampidine [STAMP]), a novel Aryl Phosphate derivative of stavudine, against primary clinical human immunodeficiency virus type 1 (HIV-1) isolates. STAMP inhibited each one of nine clinical HIV-1 isolates of non-B envelope subtype and 20 genotypically and phenotypically nucleoside analog reverse transcriptase inhibitor-resistant HIV-1 isolates at subnanomolar to low-nanomolar concentrations.
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thymidine kinase independent intracellular delivery of bioactive nucleotides by Aryl Phosphate derivatives of bromo methoxy zidovudine compounds whi 05 and whi 07 in normal human female genital tract epithelial cells and sperm
Biology of Reproduction, 2001Co-Authors: Osmond J Dcruz, T K Venkatachalam, Fatih M. UckunAbstract:The compounds WHI-05 (5-bromo-6-methoxy-5,6-dihydro39-azidothymidine-59-[p-methoxyphenyl] methoxyalaninyl Phosphate) and WHI-07 (5-bromo-6-methoxy-5,6-dihydro-39-azidothymidine-59-[p-bromophenyl] methoxyalaninyl Phosphate) are Aryl Phosphate derivatives of zidovudine (ZDV) with dual-function anti-human immunodeficiency virus and contraceptive activity. These drugs were rationally designed to bypass the thymidine kinase (TK) dependency of ZDV activation as well as to achieve spermicidal activity. We investigated the TK activity and intracellular metabolism of WHI-05 and WHI-07 in normal human vaginal and cervical epithelial cells as well as sperm. The time- and concentration-dependent intracellular formation of ZDV metabolites following addition of WHI-05 and WHI-07 to normal human vaginal, ectocervical, and endocervical epithelial cells as well as motile sperm was studied by analytical HPLC. Thymidine kinase activity in these cells was determined by the flow cytometric method based on intracellular phosphorylation of the fluorescent nucleoside, 5-amino-2-deoxyuridine-dansyl chloride and by the ability of cell-free extracts to convert [ 3 H]thymidine to thymidine monoPhosphate in comparison to NALM-6, a pre-B leukemia cell line. TK activity of genital tract epithelial cells and sperm was found to be relatively low or lacking. Addition of WHI-05 and WHI-07 to vaginal and cervical epithelial cells resulted in their concentration- and time-dependent conversion to alaninyl ZDV monoPhosphate (Ala-ZDV-MP) and 59-ZDV monoPhosphate as the major metabolites. Studies using motile human sperm also demonstrated the conversion of WHI-05 and WHI-07 to Ala-ZDV-MP. These results demonstrate that human female genital tract epithelial cells and sperm efficiently convert WHI-05 and WHI-07 to bioactive ZDV metabolites despite their TK deficiency. female reproductive tract, gamete biology kinases, sperm, vagina
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enhancing effects of a mono bromo substitution at the para position of the phenyl moiety on the metabolism and anti hiv activity of d4t phenyl methoxyalaninyl Phosphate derivatives
Bioorganic & Medicinal Chemistry Letters, 1998Co-Authors: T K Venkatachalam, Shyitai Jan, Hungliang Tai, Rakesh Vig, Chunlin Chen, Fatih M. UckunAbstract:Abstract d4T-5′-[p-Bromophenyl methoxyalaninyl Phosphate] (d4T-pBPMAP), a novel phenyl Phosphate derivative of 2′,3′-didehydro-2′,3′-dideoxythymidine (d4T) that has an enhanced ability to undergo hydrolysis due to the electron withdrawing properties of its single bromo substituent at the para-position of the phenyl moiety, was found to yield substantially more of the key metabolite alaninyl d4T monoPhosphate (A-d4T-MP) than the unsubstituted d4T-5′-phenyl methoxyalaninyl Phosphate or para-methoxy substituted d4T-5′-phenyl methoxyalaninyl Phosphate. d4T-pBPMAP was tested for its anti-HIV-1 activity in peripheral blood mononuclear cells (PBMNC) and thymidine kinase (TK)-deficient CEM T-cells. d4T-pBPMAP was 12.6-fold more potent than the parent compound d4T in inhibiting p24 production (IC50 values: 44 nM vs 556 nM) and 41.3-fold more potent than d4T in inhibiting the reverse transcriptase (RT) activity (IC50 values: 57 nM vs 2355 nM) in HIV-1-infected TK-deficient CEM cells. Similarly, d4T-pBPMAP was more potent than the unsubstituted or para-methoxy substituted phenyl methoxyalaninyl Phosphate derivatives of d4T. d4T-pBPMAP did not exhibit any detectable cytotoxicity to PBMNC or CEM cells at concentrations as high as 10,000 nM. Notably, d4T-pBPMAP was capable of inhibiting the replication of a zidovudine (ZDV/AZT)-resistant HIV-1 strain as well as HIV-2 in PBMNC at nanomolar concentrations. To our knowledge, this is the first demonstration that the potency of the d4T-Aryl-Phosphate derivatives can be substantially enhanced by introducing a single para-bromo substituent in the Aryl moiety.
Stan R Brown - One of the best experts on this subject based on the ideXlab platform.
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leaving group assistance in the la3 catalyzed cleavage of dimethyl o methoxycarbonyl Aryl Phosphate triesters in methanol
Journal of the American Chemical Society, 2009Co-Authors: David R Edwards, Alexei A Neverov, Tony C Liu, Graham E Garrett, Stan R BrownAbstract:The catalytic methanolysis of a series of dimethyl Aryl Phosphate triesters where the Aryl groups contain an o-methoxycarbonyl (o-CO2Me) substituent (4a-i) was studied at 25 degrees C in methanol containing La3+ at various concentrations and (s)(s)pH. Determination of the second-order rate constant for La3+(2)-catalyzed cleavage of substrate 4a (dimethyl (o-methoxycarbonyl)phenyl Phosphate) as a function of (s)(s)pH was assessed in terms of a speciation diagram that showed that the process was catalyzed by La3+(2)(-OCH3)x dimers, where x = 1-5, that exhibit only a 5-fold difference in activity between all the species. The second-order catalytic rate constants (k2(La)) for the catalyzed methanolysis of 4a-i at (s)(s)pH 8.7 fit a Bronsted relationship of log k2(La) = (-0.82 +/- 0.11)(s)(s)pKa(lg) + (11.61 +/- 1.48), where the gradient is shallower than that determined for a series of dimethyl Aryl Phosphates that do not contain the o-CO2Me substituent, log k2(La) = (-1.25 +/- 0.06)(s)(s)pKa(lg) + (16.23 +/- 0.75). Two main observations are that (1) the o-CO2Me group preferentially accelerates the cleavage of the Phosphate triesters with poor leaving groups relative to those with good leaving groups and (2) it provides an increase in cleavage rate relative to those of comparable substrates that do not have that functional group, e.g., k2(La)(dimethyl o-(methoxycarbonyl)phenyl Phosphate)/k2(La)(dimethyl phenyl Phosphate) = 60. Activation parameters for the La3+(2)-catalyzed methanolysis of 4a and dimethyl 4-nitrophenyl Phosphate show respective DeltaH(double dagger) (DeltaS(double dagger)) values of 3.3 kcal/mol (-47 cal/mol x K) and 0.7 kcal/mol (-46.5 cal/mol x K). The data are analyzed in terms of a concerted reaction where the catalytic complex (La3+(2)(-OCH3)(x-1)) binds to the three components of a rather loose transition state composed of a nucleophile CH3O-, a nucleofuge -OAr, and a central (RO)2P(2+)-O(-) in a way that provides leaving group assistance to the departing Aryloxy group.
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dissociative solvolytic cleavage of methyl ortho carboxymethyl Aryl Phosphate diesters mediated by yb3 in methanol gives a 1012 fold rate acceleration attributable to leaving group assistance
Journal of the American Chemical Society, 2009Co-Authors: David R Edwards, Alexei A Neverov, Stan R BrownAbstract:The Yb3+-catalyzed cleavage of a series of eight methyl Aryl Phosphates (2a−h) where the Aryl groups all contain an ortho-methoxycarbonyl group was studied in acidic methanol from 1.34 ≤ sspH ≤ 3.34 at 25 °C. All substrates show saturation binding of the metal ion that is analyzed to provide a conditional binding constant (Kb) for a 1:1 substrate/Yb3+ complex and catalytic rate constant (kcat) that varies between about 2 × 10−3 and 50 × 10−3 s−1 over the range of substrates. Detailed analysis indicates that at very low concentration of Yb3+, 3 equiv of substrate are bound, and with increasing [Yb3+], the binding changes to a 1:1 complex which decomposes by a pathway independent of sspH over the range investigated. Control studies show that substrates without the o-methoxycarbonyl group still bind to the Yb3+ with approximately the same strength as do the o-methoxycarbonyl containing substrates but have no observable reaction when bound. A Jaffe plot of the kcat vs substituent σ-values indicates that, duri...
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a simple dnase model system comprising a dinuclear zn ii complex in methanol accelerates the cleavage of a series of methyl Aryl Phosphate diesters by 1011 1013
Journal of the American Chemical Society, 2008Co-Authors: Alexei A Neverov, David R Edwards, Tony C Liu, Shannon E Bunn, Christopher J White, Stephanie A Melnychuk, Stan R BrownAbstract:The di-Zn(II) complex of 1,3-bis[N1,N1′-(1,5,9-triazacyclododecyl)]propane with an associated methoxide (3:Zn(II)2:−OCH3) was prepared and its catalysis of the methanolysis of a series of fourteen methyl Aryl Phosphate diesters (6) was studied at sspH 9.8 in methanol at 25.0 ± 0.1 °C. Plots of kobs vs [3:Zn(II)2:−OCH3]free for all members of 6 show saturation behavior from which KM and kcatmax were determined. The second order rate constants for the catalyzed reactions (kcatmax/KM) for each substrate are larger than the corresponding methoxide catalyzed reaction (k2–OMe) by 1.4 × 108 to 3 × 109-fold. The values of kcatmax for all members of 6 are between 4 × 1011 and 3 × 1013 times larger than the solution reaction at sspH 9.8, with the largest accelerations being given for substrates where the departing Aryloxy unit contains ortho-NO2 or C(═O)OCH3 groups. Based on the linear Bronsted plots of kcatmax vs sspKaof the phenol, βlg values of −0.57 and −0.34 are determined respectively for the catalyzed methan...
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the dinuclear zn ii complex catalyzed cyclization of a series of 2 hydroxypropyl Aryl Phosphate rna models progressive change in mechanism from rate limiting p o bond cleavage to substrate binding
Journal of the American Chemical Society, 2007Co-Authors: Shannon E Bunn, Tony C Liu, And Alexei A Neverov, Stan R BrownAbstract:A methoxide-bridged dinuclear Zn(II) complex of 1,3-[N,N‘-bis(1,5,9-triazacyclododecane)]propane (1-Zn(II)2:(-OCH3)) was prepared, and its catalysis of the cyclization of a series of 2-hydroxypropyl Aryl Phosphates (4a−g) was investigated in methanol at pH 9.8, T = 25 °C by stopped-flow spectrophotometry. An X-ray diffraction structure of the hydroxide analogue of 1-Zn(II)2:(-OCH3), namely 1-Zn(II)2:(-OH), reveals that each of the Zn(II) ions is coordinated by the three N's of the triazacyclododecane units and a bridging hydroxide. The cyclizations of substrates 4a−g reveal a progressive change in the observed kinetics from Michaelis−Menten saturation kinetics for the poorer substrates (4-OCH3 (4g); 4-H (4f); 3-OCH3 (4e); 4-Cl (4d); 3-NO2, (4c)) to second-order kinetics (linear in 1-Zn(II)2:(-OCH3)) for the better substrates (4-NO2,3-CH3 (4b); 4-NO2, (4a)). The data are analyzed in terms of a multistep process whereby a first formed complex rearranges to a reactive complex with a doubly activated phosphat...
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mechanistic studies of la3 and zn2 catalyzed methanolysis of Aryl Phosphate and phosphorothioate triesters development of artificial phosphotriesterase systems
Organic and Biomolecular Chemistry, 2005Co-Authors: Tony Liu, Alexei A Neverov, Josephine S W Tsang, Stan R BrownAbstract:The methanolyses of a series of O,O-diethyl O-Aryl Phosphates (2,5) and O,O-diethyl S-Aryl phosphorothioates (6) promoted by methoxide and two metal ion systems, (La3+)2(−OCH3)2 and 4:Zn2+:−OCH3 (4 = 1,5,9-triazacyclododecane) has been studied in methanol at 25 °C. Bronsted plots of the logk2 values vs.sspKa for the phenol leaving groups give βlg values of −0.70, −1.43 and −1.12 for the methanolysis of the Phosphates and −0.63, −0.87 and −0.74 for the methanolysis of the phosphorothioates promoted by the methoxide, La3+ and Zn2+ systems respectively. The kinetic data for the metal-catalyzed reactions are analyzed in terms of a common mechanism where there is extensive cleavage of the P–XAr bond in the rate-limiting transition state. The relevance of these findings to the mechanism of action of the phosphotriesterase enzyme is discussed.
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characterization of protein tyrosine phosphatase 1b inhibition by chlorogenic acid and cichoric acid
Biochemistry, 2017Co-Authors: J M Lipchock, Heidi P Hendrickson, Bonnie Douglas, Kelly E Bird, Patrick S Ginther, Ivan RivaltaAbstract:Protein tyrosine phosphatase 1B (PTP1B) is a known regulator of the insulin and leptin signaling pathways and is an active target for the design of inhibitors for the treatment of type II diabetes and obesity. Recently, cichoric acid (CHA) and chlorogenic acid (CGA) were predicted by docking methods to be allosteric inhibitors that bind distal to the active site. However, using a combination of steady-state inhibition kinetics, solution nuclear magnetic resonance experiments, and molecular dynamics simulations, we show that CHA is a competitive inhibitor that binds in the active site of PTP1B. CGA, while a noncompetitive inhibitor, binds in the second Aryl Phosphate binding site, rather than the predicted benzfuran binding pocket. The molecular dynamics simulations of the apo enzyme and cysteine–phosphoryl intermediate states with and without bound CGA suggest CGA binding inhibits PTP1B by altering hydrogen bonding patterns at the active site. This study provides a mechanistic understanding of the alloste...
