In vivo pharmacokinetics and anti-anaphylactic activity of the novel mast cell inhibitor 4-(4'-hydroxylphenyl)-amino-6,7-dimethoxyquinazoline (WHI-P131).

WHI-P131 is a novel dimethoxyquinazoline compound that is a potent inhibitor of Janus kinase-3-(JAK3)-dependent mast cell responses. In the present study, the authors investigated the anti-anaphylactic activity and pharmacokinetics of WHI-P131 in mice. After intraperitoneal (i.

Mast cell modulation of immune responses to bacteria.

Mast cells are key elements of the immune system. These cells release a wide variety of pro-inflammatory mediators which are responsible for the pathophysiology of many allergic diseases. Recent studies, however, have shown that mast cells have the capacity to modulate the host's innate immune response to gram negative bacteria by their ability to phagocytose bacteria, process and present bacterial antigens to T cells and recruit phagocytic help through the release of physiological amounts of pro-inflammatory mediators.

Role of a JAK3-dependent biochemical signaling pathway in platelet activation and aggregation.

Here we provide experimental evidence that identifies JAK3 as one of the regulators of platelet function. Treatment of platelets with thrombin induced tyrosine phosphorylation of the JAK3 target substrates STAT1 and STAT3. Platelets from JAK3-deficient mice displayed a decrease in tyrosine phosphorylation of STAT1 and STAT3.

SPIKET and COBRA compounds as novel tubulin modulators with potent anticancer activity.

Agents that either promote or inhibit tubulin polymerization exhibit anticancer activity by disrupting normal mitotic spindle assembly and cell division as well as inducing apoptosis. Recently identified novel agents that target tubulin include synthetic spiroketal pyrans (SPIKET), targeting the spongistatin binding site of beta-tubulin, and COBRA compounds, targeting a unique binding cavity on alpha-tubulin. At nanomolar concentrations, the SPIKET compound SPIKET-P caused tubulin depolymerization in cell-free turbidity assays and exhibited potent cytotoxic activity against cancer cells as evidenced by destruction of microtubule organization, and prevention of mitotic spindle formation in human breast cancer cells.

Short-Term (13-week) toxicity study of 5-bromo-6-methoxy-5,6-dihydro-3'-azidothymidine-5'-(p-bromophenyl) methoxyalaninyl phosphate (WHI-07), a novel anti-HIV and contraceptive agent, in B6C3F1 mice.

The zidovudine derivative, WHI-07 (5-bromo-6-methoxy-5,6-dihydro-3'-azidothymidine-5'-(p-bromophenyl) methoxyalaninyl phosphate), is a dual-function spermicidal agent with potent anti-HIV activity. In this study, groups of 20 female B6C3F1 mice were exposed intravaginally to a gel microemulsion containing 0, 0.5, 1.

Induction of aerobic peroxidation of liposomal membranes by bis(cyclopentadienyl)-vanadium(IV) (acetylacetonate) complexes.

The ability of bis(cyclopentadienyl)-vanadium(IV) (acetylacetonate) (1) to initiate oxygen-dependent lipid peroxidation in zwitterionic liposomal membranes was examined in detail. A comparison of the rates of the lipid peroxidation reaction demonstrated that the electron-donating capacity of the substituted acetylacetonate ligand significantly influences the rate of reaction. An increase in the rate of lipid peroxidation correlated to a decrease in the V(IV)/V(V) redox potential.

Anti-HIV activity of aromatic and heterocyclic thiazolyl thiourea compounds.

Several thiazolyl thiourea derivatives were designed and synthesized as non-nucleoside inhibitors (NNRTI) of HIV-1 reverse transcriptase. Six lead compounds were identified that showed subnanomolar IC50 values for the inhibition of HIV replication, were minimally toxic to human peripheral blood mononuclear cells (PBMC) with CC50 values ranging from 28 to >100 microM, and showed remarkably high selectivity indices ranging from 28,000 to >100,000. The most promising compound was N-[1-(1-furoylmethyl)]-N'-[2-(thiazolyl)]thiourea (compound 6), which showed potency against two NNRTI-resistant HIV-1 isolates (A17 and A17 variant) at nanomolar to low micromolar concentrations, exhibited much greater potency against both wild-type as well as NNRTI-resistant HIV-1 than nevirapine, delavirdine, HI-443, and HI-244, was minimally toxic to PBMC, and had a selectivity index of > 100,000.

4-[3-Bromo-4-hydroxyphenyl)amino]-6,7-dimethoxyquinazolin-1-ium chloride methanol solvate and 4-[(3-hydroxyphenyl)amino]-6,7-dimethoxy-1-quinazolinium chloride.

The title compounds, C16H15BrN3(O3)(+).Cl(-).CH4O (WHI-P154) and C16H16N3(O3)(+).

Contraceptive efficacy and safety studies of a novel microemulsion-based lipophilic vaginal spermicide.

Objective: To investigate the in vivo contraceptive potency and safety of a novel microemulsion-based lipophilic vaginal spermicide.

Design: In vitro and in vivo spermicidal activity and safety of a submicron-particle-size, lipophilic gel-microemulsion (GM-4).

Setting: Center for Advanced Preclinical Sciences at the Parker Hughes Institute.

Pokeweed antiviral protein: a potential nonspermicidal prophylactic antiviral agent.

Objective: To investigate the effects of pokeweed antiviral protein (PAP), a 29-kDa anti-human immunodeficiency virus (HIV) protein purified from the leaves of Phytolacca americana, on human sperm function.

Design: Prospective, controlled study.

Setting: Reproductive biology department.

Intravaginal toxicity studies of a gel-microemulsion formulation of spermicidal vanadocenes in rabbits.

Bis-cyclopentadienyl complexes of vanadium(IV) or vanadocenes are rapid and potent inhibitors of human sperm motility with potential as a new class of contraceptive agents. We investigated the toxicity potential of intravaginally administered gel-microemulsion formulation of two representative vanadocenes, vanadocene acetylacetonato monotriflate (VDACAC) and vanadocene dithiocarbamate (VDDTC), in the rabbit model. New Zealand White rabbits in subgroups of three were exposed intravaginally to a gel-microemulsion with and without 0.

Anti-inflammatory activity of 2,4, 6-trihydroxy-alpha-p-methoxyphenyl-acetophenone (compound D-58).

Background: Active oxygen radicals as well as a variety of cytosolic protein tyrosine kinases play a role in the regulation of prostaglandin E(2) (PGE(2)), a key inflammatory mediator, released by skin cells in response to irradiation with ultraviolet B light (UVB). Identification of chemical compounds that can interrupt such events may provide a basis for the development of potent anti-inflammatory agents.

Objective: To investigate the effect of a novel genistein analog, 2,4, 6-trihydroxy-alpha-p-methoxyphenylacetophenone, with antioxidant property (compound D-58), on UVB-induced inflammatory responses.

Apoptosis-inducing oxovanadium(IV) complexes of 1,10-phenanthroline against human ovarian cancer.

In a systematic effort to identify a potent anticancer agent against human ovarian cancer, we synthesized 15 oxovanadium(IV) complexes, and examined their cytotoxic activity against human ovarian cancer cell lines PA-1, SKOV-3, ES-2 and OVCAR-3 using a MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyletetrazolium bromide]-based assay. The apoptosis-inducing ability of the oxovanadium compounds was evaluated by the two-color flow cytometric terminal deoxynucleotidyl transferase-based assay that labels 3'-hydroxyl ends of fragmented DNA (TUNEL) assay and confocal laser scanning microscopy. Notably, all eight oxovanadium complexes of 1,10 phenanthroline exhibited significant cytotoxicity and induced apoptosis within 24 h.

Piperidinylethyl, phenoxyethyl and fluoroethyl bromopyridyl thiourea compounds with potent anti-HIV activity.

Derivatives of piperidinylethyl, phenoxyethyl and fluoroethyl bromopyridyl thioureas were designed and synthesized as non-nucleoside reverse transcriptase inhibitors (NNRTIs) of HIV-1 reverse transcriptase (RT). The anti-HIV activity of these compounds was examined by determining their ability to inhibit the replication of the HIV-1 strain HTLV(IIIB) in human peripheral blood mononuclear cells. The unsubstituted parent pyridyl thiourea compound N-[2-(1-piperidine)ethyl]-N'-[2-(pyridyl)] thiourea (1) exhibited no anti-HIV activity, even at 100 microM.

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.

The compounds WHI-05 (5-bromo-6-methoxy-5, 6-dihydro-3'-azidothymidine-5'-[p-methoxyphenyl] 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 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.

Treatment of allergic asthma by targeting janus kinase 3-dependent leukotriene synthesis in mast cells with 4-(3', 5'-dibromo-4'-hydroxyphenyl)amino-6,7-dimethoxyquinazoline (WHI-P97).

4-(3',5'-Dibromo-4'-hydroxyphenyl)amino-6,7-dimethoxyquinazoline (WHI-P97) is a rationally designed potent inhibitor of Janus kinase (JAK)-3. Treatment of mast cells with WHI-P97 inhibited the translocation of 5-lipoxygenase (5-LO) from the nucleoplasm to the nuclear membrane and consequently 5-LO-dependent leukotriene (LT) synthesis after IgE receptor/FcepsilonRI crosslinking by >90% at low micromolar concentrations. WHI-P97 did not directly inhibit the enzymatic activity of 5-LO, but prevented its translocation to the nuclear membrane without affecting the requisite calcium signal.

Abnormalities of chromosome bands 13q12 to 13q14 in childhood acute lymphoblastic leukemia.

Purpose: Little is known about nonrandom deletions of chromosome bands 13q12 to 13q14 (13q12-14) in acute lymphoblastic leukemia (ALL). We determined the prognostic significance of cytogenetically identified breakpoints in 13q12-14 in children with newly diagnosed ALL treated on Children's Cancer Group protocols from 1988 to 1995.

Patients And Methods: Breakpoints in 13q12-14 were identified in 36 (2%) of the 1,946 cases with accepted cytogenetic data.

An inhibitor of Janus kinase 3:4-(4-hydroxyphenylamino)-6, 7-dimethoxyquinazolin-1-ium chloride methanol solvate.

The crystal structure of the title compound, C(16)H(16)N(3)O(3)(+). Cl(-).CH(4)O (WHI-P131, an inhibitor of Janus kinase 3), contains four hydrogen bonds.

Three leflunomide metabolite analogs.

The title compounds, 1-cyano-2-hydroxy-N-[4-(methylsulfonyl)phenyl]but-2-enamide, C(12)H(12)N(2)O(4)S, PHI492, 1-cyano-2-hydroxy-N-[3-(methylsulfonyl)phenyl]but-2-enamide, C(12)H(12)N(2)O(4)S, PHI493, and N-[3-bromo-4-(trifluoromethoxy)phenyl]-1-cyano-2-hydroxybut-2-e namide , C(12)H(8)BrF(3)N(2)O(3), PHI495, are potent inhibitors of Bruton's tyrosine kinase (BTK). The molecular structures of these compounds are similar and they display similar hydrogen-bonding networks and crystal packing. Examination of the crystal-packing interaction in the three compounds reveals an alternating direction of adjacent molecules in the crystalline lattice due to intermolecular cyano-amide hydrogen bonding.

Stereochemistry of halopyridyl and thiazolyl thiourea compounds is a major determinant of their potency as nonnucleoside inhibitors of HIV-1 reverse transcriptase.

Chiral derivatives of two cyclohexylethyl halopyridyl thiourea compounds (HI-509 and HI-510), two alpha-methyl benzyl halopyridyl compounds (HI-511 and HI-512), and a cyclohexyl ethyl thiazolyl thiourea compound (HI-513) were synthesized as nonnucleoside inhibitors (NNI) of human immunodeficiency virus (HIV) reverse transcriptase (RT). The R stereoisomers of all five compounds inhibited the recombinant RT in vitro with 100-fold lower IC50 values. HI-509R, HI-510R, HI-511R, HI-512R and HI-513R were active anti-HIV agents and inhibited HIV-1 replication in human peripheral blood mononuclear cells at nanomolar concentrations, whereas their enantiomers were inactive.

Highly sensitive liquid chromatography-electrospray mass spectrometry (LC-MS) method for the determination of etoposide levels in human serum and plasma.

Etoposide is one of the most commonly used antineoplastic agents. A highly sensitive liquid chromatography-electrospray mass spectrometry (LC-MS) method was developed for the determination of etoposide in human serum and plasma. Etoposide was extracted with chloroform and extracts were reconstituted in acetonitrile followed by the evaporation of chloroform with nitrogen gas.

X-ray crystallographic analysis of pokeweed antiviral protein-II after reductive methylation of lysine residues.

Pokeweed antiviral protein II (PAP-II) is a naturally occurring protein isolated from early summer leaves of the pokeweed plant (Phytolacca americana). PAP-II belongs to a family of ribosome-inactivating proteins which catalytically deadenylate ribosomal and viral RNA. The chemical modification of PAP-II by reductive methylation of its lysine residues significantly improved the crystal quality for X-ray diffraction studies.

Residual bone marrow leukemic progenitor cell burden after induction chemotherapy in pediatric patients with acute lymphoblastic leukemia.

We used highly sensitive multiparameter flow cytometry and blast colony assays to quantify the leukemic progenitor cell (LPC) burden of postinduction chemotherapy bone marrows from newly diagnosed and relapsed pediatric patients with acute lymphoblastic leukemia (ALL). Of 890 newly diagnosed patients, 243 (27%) had detectable LPC in the postinduction bone marrow samples with an average (mean +/- SE) LPC content of 22+/-9 LPC/10(6) mononuclear cell (MNC; range, 0-7199/10(6) MNC; median, 0/10(6) MNC). By comparison, 24 of 50 (48%) patients with relapsed ALL had detectable LPC in their postinduction bone marrow specimens (P = 0.

Evaluation of subchronic (13-week) and reproductive toxicity potential of intravaginal gel-microemulsion formulation of a dual-function phenyl phosphate derivative of bromo-methoxy zidovudine (compound whi-07) in B(6)C(3)F(1) mice.

Heterosexual transmission of human immunodeficiency virus (HIV) accounts for 90% of all new infections worldwide and significantly contributes to new acquired immunodeficiency syndrome (AIDS) cases in the USA. In a systematic effort to develop a microbicidal contraceptive capable of preventing HIV transmission as well as providing fertility control, we previously identified novel phenyl phosphate derivatives of 3'-azido-3'-deoxythymidine (zidovudine) that exhibit potent anti-HIV and spermicidal activities. This study reports the preclinical studies of our lead compound WHI-07, 5-bromo-6-methoxy-5,6-dihydro-3'-azidothymidine-5'-(p-bromophenyl) methoxyalaninyl phosphate, for use as a dual-function topical microbicide.