Synthesis of 3-[(N-carboalkoxy)ethylamino]-indazole-dione derivatives and their biological activities on human liver carbonyl reductase.

A series of indazole-dione derivatives were synthesized by the 1,3-dipolar cycloaddition reaction of appropriate substituted benzoquinones or naphthoquinones and N-carboalkoxyamino diazopropane derivatives. These compounds were evaluated for their effects on human carbonyl reductase. Several of the analogs were found to serve as substrates for carbonyl reductase with a wide range of catalytic efficiencies, while four analogs display inhibitory activities with IC(50) values ranging from 3-5 microM.

Synthesis and MEK1 inhibitory activities of imido-substituted 2-chloro-1,4-naphthoquinones.

Mitogen activated protein kinases are of interest as research tools and as therapeutic target for certain physiological disorders. In this study, we found 2-chloro-3-(N-succinimidyl)-1,4-naphthoquinone 6 to be a selective inhibitor of MEK1 with an IC(50) of 0.38 microM.

Novel pyrrolo-quinoline derivatives as potent inhibitors for PI3-kinase related kinases.

Several pyrrolo-quinoline gamma-lactones were found as novel inhibitors for two members of the PI3-kinase related kinase (PIKK) family, Ataxia-Telangiectasia-mutated (ATM) protein and the mammalian Target of Rapamycin (mTOR). Preliminary structure-activity relationship studies indicated that an electrophilic exocyclic double bond conjugated to the carbonyl group of the gamma-lactone ring was crucial for the PIKK inhibitory potency. One of the best ATM inhibitors in this series, DK8G557, showed IC(50) values of 0.

Structure-activity relationship of aza-steroids as PI-PLC inhibitors.

A number of aza-steroids were synthesized as potent phosphatidylinositol phospholipase C (PI-PLC) inhibitors. The epimeric mixtures 22,25-diazacholesterol (8a) and 3beta-hydroxy-22,25-diazacholestane (8b) were among the most active of these inhibitors, with IC(50) values of 7.4 and 7.

Syntheses and biological activities of a novel group of steroidal derived inhibitors for human Cdc25A protein phosphatase.

Silica gel supported pyrolysis of an azido-homo-oxa steroid led to rearrangement, presumably by a mechanism similar to that of solution phase Schmidt fragmentation, to produce a group of novel inhibitors for the oncogenic cell cycle regulator Cdc25A phosphatase. Cyano-containing acid 17, one of the best inhibitors in this group, inhibited the activity of Cdc25A protein phosphatase reversibly and noncompetitively with an IC(50) value of 2.2 microM.

3Beta-hydroxy-6-aza-cholestane and related analogues as phosphatidylinositol specific phospholipase C (PI-PLC) inhibitors with antitumor activity.

6-Aza steroid analogues were synthesized as PI-PLC inhibitors. The most active compound, 3beta-hydroxy-6-aza-cholestane (1) showed potent PI-PLC inhibition (IC50 = 1.8 microM), similar to that of the commercially available steroid analogue U73122 (IC50 = 1-2.

Steroidal derived acids as inhibitors of human Cdc25A protein phosphatase.

A group of steroidal derived acids were synthesized and found to be human Cdc25A inhibitors. Their potency ranged from 1.1 to > 100 microM; the best ones compare very favorably with that of the novel cyano-containing 5,6-seco-cholesteryl acid 1 (IC50=2.

Human immunodeficiency virus type 1 cDNA integration: new aromatic hydroxylated inhibitors and studies of the inhibition mechanism.

Integration of the human immunodeficiency virus type 1 (HIV-1) cDNA is a required step for viral replication. Integrase, the virus-encoded enzyme important for integration, has not yet been exploited as a target for clinically useful inhibitors. Here we report on the identification of new polyhydroxylated aromatic inhibitors of integrase including ellagic acid, purpurogallin, 4,8, 12-trioxatricornan, and hypericin, the last of which is known to inhibit viral replication.

Azodicarbonamide inhibits HIV-1 replication by targeting the nucleocapsid protein.

Nucleocapsid p7 (NCp7) proteins of human immunodeficiency virus type 1 (HIV-1) contain two zinc binding domains of the sequence Cys-(X)2-Cys-(X)4-His-(X)4-Cys (CCHC). The spacing pattern and metal-chelating residues (3 Cys, 1 His) of these nucleocapside CCHC zinc fingers are highly conserved among retroviruses. These CCHC domains are required during both the early and late phases of retroviral replication, making them attractive targets for antiviral agents.

Inhibition of intracellular Ca2+ signalling, cytotoxicity and antitumor activity of the herbicide oryzalin and its analogues.

Purpose: Studies were conducted on oryzalin (3,5-dinitro-N,N-di(n-propyl)sulfanilamide), a widely used dinitroaniline sulfonamide herbicide, which was identified from plant extracts as an inhibitor of mitogen- and growth factor-mediated intracellular free Ca2+ ([Ca2+]i) signalling in mammalian cells.

Methods And Results: Oryzalin inhibited vasopressin, bradykinin and platelet-derived growth factor [Ca2+]i signalling in Swiss 3T3 fibroblasts with IC50 values of 14, 16 and 18 microM, respectively. 45Ca2+ uptake into nonmitochondrial stores of saponin-permeabilized Swiss 3T3 cells was inhibited by oryzalin with an IC50 of 34 microM.

Inhibition of human immunodeficiency virus replication by the sulfonated stilbene dye resobene.

The anti-HIV sulfonated dye, resobene, was found to be a potent inhibitor of the attachment of HIV to target cells, the fusion of envelope- and CD4-expressing cells, and the cell-to-cell transmission of virus. Resobene inhibited the infection of phenotypically distinct, established human cell lines and fresh human peripheral blood lymphocytes and macrophages by laboratory-derived isolates of human immunodeficiency virus type 1 (HIV-1) and type 2 (HIV-2), and a panel of biologically diverse primary clinical isolates, including syncytium-inducing and non-syncytium-inducing viruses and strains representative of the various virus clades found worldwide. The compound was also active against all drug-resistant virus isolates tested.

Antiviral activity of a derivative of the photosensitive compound Hypericin.

Eight synthetic compounds related to the photosensitive antiviral quinonic plant compound hypericin were screened for light-mediated antiviral activity. The compound 2,5,9,12-tetra(carboxyethylthiomethyl) hypericin was found to have activity against membrane-enveloped Sindbis virus and murine cytomegalovirus but not against the non-enveloped poliovirus. The activity of this compound was investigated in more detail.

Inhibition of glycosylphosphatidylinositol (GPI) phospholipase D by suramin-like compounds.

A number of proteins are found attached to the plasma membrane of mammalian cells by a glycosylphosphatidylinositol (GPI) anchor that can be cleaved by GPI specific phospholipase D (GPI-PLD). There are no known specific inhibitors of GPI-PLD. We examined some inhibitors of phosphatidylinositol specific phospholipase C (PI-PLC) for their ability to inhibit human serum and human bone marrow cell GPI-PLD.

Novel quinone antiproliferative inhibitors of phosphatidylinositol-3-kinase.

The inhibition of phosphatidylinositol-3-kinase (PtdIns-3-kinase), protein kinase C and c-Src protein tyrosine kinase by a series of halogenated naphthoquinones and quinoline quinones related to the plant-derived naphthoquinones juglone and methyljuglone, which inhibit protein kinase C, has been investigated. Some of the compounds inhibited PtdIns-3-kinase at micromolar concentrations and below. PtdIns-3-kinase inhibition was time dependent and could be prevented by endogenous thiol.

Molecular similarity from atomic electrostatic multipole comparisons. Application to anti-HIV drugs.

A procedure is presented for the rapid calculation of the similarity between a pair of molecules based on atomic electrostatic multipole comparison. The multipoles are derived from semiempirical SCF wave functions, and the results obtained compare favorably with ab initio results. The method is illustrated by correlating the similarity and anti-HIV-1 activity of a series of azo compounds.

Advances with phospholipid signalling as a target for anticancer drug development.

The phosphatidylinositol-3-kinases (PtdIns-3-kinase) are a family of enzymes involved in the control of cell replication. One member of the family, the mammalian p110/p85 PtdIns-3-kinase, is a potential target for anticancer drug development because of its role as a component of growth factor and oncogene activated signalling pathways. There are a number of inhibitors of this PtdIns-3-kinase, the most potent being wortmannin (IC50 4 nM).

A multiwell assay for inhibitors of phosphatidylinositol-3-kinase and the identification of natural product inhibitors.

A convenient and reliable multisample assay for the screening of inhibitors of the growth factor signalling enzyme phosphatidylinositol-3-kinase (PtdIns-3-K) has been developed. Four natural product inhibitors of Ptdlns-3-K have been identified with IC50 values for hypericin 0.18 microM, emodin 3.

A multisample assay for inhibitors of phosphatidylinositol phospholipase C: identification of naturally occurring peptide inhibitors with antiproliferative activity.

A convenient and reliable multisample assay for the screening of inhibitors of the growth factor signalling enzyme phosphatidylinositol specific phospholipase C (PtdInsPLC) has been developed. Three naturally occurring peptide inhibitors of PtdInsPLC have been identified, myroridin K, streptothricin B and edeine, with IC50 values of 8.3, 6.

Wortmannin, a potent and selective inhibitor of phosphatidylinositol-3-kinase.

Phosphatidylinositol-3-kinase is an important enzyme for intracellular signaling. The microbial product wortmannin and some of its analogues have been shown to be potent inhibitors of phosphatidylinositol-3-kinase. The 50% inhibitory concentration for inhibition by wortmannin is 2 to 4 nM.

Synthesis of 2-methyl-(Z)-4-(phenylimino)naphth[2,3-d]oxazol-9-one , a monoimine quinone with selective cytotoxicity toward cancer cells.

A regio and stereospecific synthesis of 2-methyl-(Z)-4-(phenylimino)naphth[2,3-d]oxazol-9-one (1) was achieved by using titanium tetrachloride in methylene chloride in the preparation of the imine. The regiochemistry was assigned by single-crystal X-ray analysis. In vitro tests showed that this diastereomer is selectively active for some solid cancer tumors.

Increased intracellular Ca2+ signaling caused by the antitumor agent helenalin and its analogues.

The antitumor sesquiterpene lactone helenalin, which is found in species of the plant genus Helenium, caused a marked potentiation of the increases in intracellular free Ca2+ concentration ([Ca2+]i) produced by mitogens such as vasopressin, bradykinin, and platelet-derived growth factor in Swiss mouse 3T3 fibroblasts. Removing external Ca2+ partly attenuated the increased [Ca2+]i responses caused by helenalin. The increased [Ca2+]i responses occurred at concentrations of helenalin that inhibited cell proliferation.

Quinobene, a new potent anti-HIV agent.

A simple synthesis of the sulfonated azo dye Quinobene (3) and its derivatives, as well as the results of their evaluation in anti-HIV screening have been described. Thus, reacting the diazonium salt of 4,4'-diaminostilbene-2,2'-disulfonic acid with 8-hydroxyquinoline-5-sulfonic acid yielded the readily isolable title compound. The lithium and tetramethylammonium salts of Quinobene and its complexes with Cu(II), Zn(II), Mg(II) were also prepared.

Synthesis and pharmacology of irreversible affinity labels as potential cocaine antagonists: aryl 1,4-dialkylpiperazines related to GBR-12783.

As part of a program aimed at designing irreversible antagonists of the stimulant and reinforcing properties of cocaine, derivatives of GBR-12783 containing electrophilic substituents were synthesized. GBR-12783, a potent and selective inhibitor of both stimulant binding and dopamine transport, was modified to incorporate either isothiocyanate or maleimido groups at the meta- or para-positions in one phenyl ring of the geminal diphenyl portion of the molecule. The effect of these compounds, as well as their respective amino- or nitro-substituted precursors, on stimulant binding to rat striatal tissue was studied using the [3H]methylphenidate radioreceptor assay.