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L H Zalkow

Publications and source records attributed to L H Zalkow.

At least 19 recordsLinked to original sources
PubMed2001

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. Structure-activity relationships revealed that a phosphate surrogate such as a carboxyl or a xanthate group is required for inhibitory activity, and a hydrophobic alkyl chain, such as the cholesteryl side chain, contributes greatly to the potency. Without the cyano group, acid 26 and xanthate 27 were found to be more selective over Cdc25A (IC(50) = 5.1 microM and 1.1 microM, respectively) than toward CD45 (IC(50) > 100 microM, in each case), a receptor protein tyrosine phosphatase. Several of these inhibitors showed antiproliferative activities in the NCI 60-human tumor cell line screen. These steroidal derived Cdc25 inhibitors provide unique leads for the development of dual-specificity protein phosphatase inhibitors.

Antineoplastic Agents↗
PubMed2001

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 7.5 microM, respectively. The 20alpha epimer, 8a2 (IC(50)=0.64 microM), whose stereochemistry at C-20 coincides with that of cholesterol, was found 50 times more potent than the 20beta epimer, 8a1 (IC(50)=32.2 microM). In diaza-estrone derivatives, the 3-methoxy group on the aromatic A-ring of 23 exhibited moderate PI-PLC inhibitory activity (IC(50)=19.7 microM), while compound with a free hydroxyl group (21) was inactive. However, in diaza-pregnane derivatives, epimers with a 3-hydroxyl group (8a, IC(50)=7.4 microM) exhibited more potent PI-PLC inhibitory activity than their counterparts with 3-methoxyl group on the non-aromatic A-ring (26, IC(50)=17.4 microM). We have illustrated in our previous publication that 3-hydroxyl-6-aza steroids are potent PI-PLC inhibitors.(3) However, simultaneous presence of the 6-aza and 22,25-diaza moieties in one molecule as in 13, led to loss of activity. Epimeric mixture 8a showed selective growth inhibition effects in the NCI in vitro tumor cell screen with a mean GI(50) value (MG-MID) of 5.75 microM for 54 tumors.

Azacosterol↗
PubMed2000

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 = 1-2.1 microM). Compound 1 exhibited significant growth inhibition effects (IC50 = 1.3 microM in each case) against MCF-7 and HT-29 cancer cells in in vitro cell culture. Compound 1 also inhibited the in vitro adhesion and transmigration of HT-1080 fibrosarcoma cells at 2.5 and 5.0 microM, respectively. In vivo, compound 1, at 1 mg/kg/day, reduced the volume of MCF-7 tumors in xenograft models, without weight loss in mice. Structure activity relationships of this series of compounds revealed that a hydrophobic cholesteryl side chain, 3beta-hydroxy group and a C-6 nitrogen containing a hydrogen atom at position-6 are crucial for activity. N-Maleic amidoacid derivative 11 also exhibited weak inhibition (IC50 = 16.2 microM).

Animals↗
PubMed2000

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=2.2microM) reported by us recently (Peng, H.; Zalkow, L. H.; Abraham, R. T.; Powis, G. J. Med. Chem. 1998, 41, 4677). Structure-activity relationships of these compounds revealed that a hydrophobic cholesteryl side chain and a free carboxyl group are crucial for activity. The distance between these two pharmacophores is also important for the potency of these compounds. Several of the compounds showed selective growth inhibition effects in the NCI in vitro cancer cell line panel.

Acids↗
PubMed1997

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. Oryzalin inhibited colony formation of HT-29 colon carcinoma cells with an IC50 of 8 microM and inhibited the growth of a number of other cancer cell lines and primary human tumors in vitro with IC50 values in the range 3 to 22 microM. A number of oryzalin analogues were studied and an association was found between the ability to inhibit [Ca2+]i signalling and inhibition of the growth of HT-29 human colon cancer cells (P = 0.001) and of CCRF-CEM human leukemia cells (P = 0.016). Oryzalin at doses up to 600 mg/kg administered orally or subcutaneously daily to mice for 3 to 10 days beginning a day after tumor inoculation inhibited the growth of murine B16 melanoma by 63% but showed no appreciable activity when administered subcutaneously or intraperitoneally to mice beginning a number of days after tumor inoculation against a variety of human tumor xenografts. The peak plasma concentration of oryzalin following repeated subcutaneous administration of oryzalin at 600 mg/kg per day to mice was 37 microM and of its major metabolite N-depropyl oryzalin was 53 microM. CONCLUSION: It is unlikely that the absence of significant antitumor activity of oryzalin is a result of the inability to achieve adequate plasma concentrations.

3T3 Cells↗
PubMed1996

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. Cell-based and biochemical mechanism of action studies demonstrated that the compound inhibits the attachment of infectious virus and fusion of virus-infected cells to uninfected target cells by binding to the cationic V3 loop of the envelope glycoprotein. Resobene effectively inhibited the infection of cell populations which do and do not express cell surface CD4. Resobene prevented infection of the cervical epithelial cell line ME180, suggesting the compound may effectively act as a topical microbicide to prevent the sexual transmission of HIV.

HIV-1↗
PubMed1995

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. Some generalizations are presented on the structure-activity relationships which are based on the atomic multipole distribution in the azo compounds.

Antiviral Agents↗
PubMed1995

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. The compounds were only weak inhibitors of PtdIns-4-kinase. Some of the compounds inhibited protein kinase C, but c-Src protein tyrosine kinase was only weakly inhibited. In intact cells, PtdIns-3-kinase was only partly inhibited by concentrations of the halogenated quinones that inhibited cell growth. Some halogenated quinones showed in vivo antitumor activity without accompanying toxicity, while methyljuglone was without in vivo antitumor activity. Halogenated quinones may have multiple biochemical effects in the cell that could contribute to their cytotoxic and antitumor effects. Inhibition of PtdIns-3-kinase by the halogenated quinones may provide a lead for the development of more potent and specific inhibitors.

Breast Neoplasms↗
PubMed1994

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.

Antineoplastic Agents↗
PubMed1994

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. At higher concentrations, helenalin inhibited the [Ca2+]i responses. No change in resting [Ca2+]i was caused by helenalin even at high concentrations. Other helenalin analogues also increased the [Ca2+]i response. Helenalin did not inhibit protein kinase C (PKC) and PKC appeared to play a minor role in the effects of helenalin on [Ca2+]i responses in intact cells. Studies with saponin-permeabilized HT-29 human colon carcinosarcoma cells indicated that helenalin caused an increased accumulation of Ca2+ into nonmitochondrial stores and that the potentiating effect of helenalin on mitogen-stimulated [Ca2+]i responses was due in part to an increase in the inositol-(1,4,5)-trisphosphate-mediated release of Ca2+ from these stores.

3T3 Cells↗
PubMed1994

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, 6.7 and 16.1 microM, respectively. All three peptides inhibited colony formation of HT-29 human colon adenocarcinoma cells, with IC50 values of 7.2, 3.9 and 13.0 microM, respectively. The compounds also inhibited the growth of other human cancer cells in culture. One of the peptides, myroridin K, has previously been reported to have in vivo antitumour activity. It is possible that inhibition of PtdInsPLC is responsible for the cell growth inhibition and antitumour properties of the peptide compounds.

Animals↗
PubMed1992

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. In vitro tests showed considerable activity of these compounds against HIV-1.

Antiviral Agents↗
PubMed1992

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. Under the assay conditions used, the compounds were found to have IC50s (nM) ranging from 11.9 (m-nitro) to 1677 (p-maleimido); the parent compound, GBR-12783, had an IC50 of 12.0. Using a washout technique (repeated washing with 100 mM KCl) which completely removed the tightly bound, but reversible GBR-12783, both the m- and p-isothiocyanate compounds were found to irreversibly inhibit binding of [3H]methylphenidate to the stimulant recognition site. The m-maleimido derivative also irreversibly inhibited binding, albeit with lower efficacy than was observed with the isothiocyanate compounds. Neither the p-maleimido, nor the amino or nitro intermediates, were capable of irreversible inhibition.

Animals↗
PubMed1992

Novel anthraquinone inhibitors of human leukocyte elastase and cathepsin G.

A large series of variously substituted anthraquinones has been synthesized and assayed for inhibitory capacity against human leukocyte elastase (HLE) and cathepsin G (CatG), two serine proteinases implicated in diseases characterized by the abnormal degradation of connective tissue, such as pulmonary emphysema and rheumatoid arthritis. It was found that 2-alkyl-1,8-dihydroxyanthraquinone analogues are competitive inhibitors of HLE with IC50 values ranging from 4 to 10 microM, and also inhibit CatG with IC50 values ranging from 25 to 55 microM. Consequently, analogues containing the 2-alkyl-1-hydroxy-8-methoxyanthraquinone substitution pattern inhibit HLE to the same magnitude as for the compounds above, but show very little inhibition of CatG. Anthraquinones containing long, hydrophobic n-butyl carbonate moieties in the 1- and 8-positions in conjunction with a third hydrophobic substituent in the 2- or 3-position are highly selective for HLE, with Ki values in the range of 10(-7) M. All of the inhibitors described are completely reversible, with no evidence of acyl-enzyme formation detected.

Anthraquinones↗
PubMed1989

Synthesis of congeners and prodrugs. 3. Water-soluble prodrugs of taxol with potent antitumor activity.

Taxol has shown good in vivo antitumor activity in a number of test systems. The formulation of taxol for antitumor testing has been difficult. Esterification at either C-2' or C-7 resulted in loss of in vitro tubulin assembly activity but not cytotoxicity. These observations suggested that esters at C-2' and/or C-7, which would tend to promote water solubility, might serve as useful prodrugs of taxol. The reaction of taxol with either succinic anhydride or glutaric anhydride in pyridine solution at room temperature gave the crystalline mono 2'-adducts 1b and 1f, respectively. Salts of these acids (1b, 1f, 1i) were formed by the addition of 1 equiv of the corresponding base, followed by evaporation and/or freeze-drying of the solvent(s). The salts had improved antitumor activity as compared to the free acids. The triethanolamine and N-methylglucamine salts showed greatly improved aqueous solubility and were more active than the sodium salts. The glutarate series was preferred because of the higher activity and the higher yields obtained. 2'-Glutaryltaxol (1f) was coupled with 3-(dimethylamino)-1-propylamine, using CDI, to form in excellent yield the amino amide 1o. The hydrochloride salt (1p) showed good solubility and was extremely potent and active. At 10 mg/kg, in the B16 screen, 1p gave a T/C of 352 with 5 out of 10 cures. In the MX-1 breast xenograft assay, this prodrug gave values of -100 at doses of 40 and 20 mg/kg, with all live animals being tumor free.

Alkaloids↗
PubMed1988

Anonamine, C19H27NO7, neosenkirkine, C19H27NO6, and hydroxysenkirkine, C19H27NO7.CH3OH. Macrocyclic secopyrrolizidine alkaloids from Senecio anonymus Wood.

lambda(Mo K alpha) = 0.71069 A, T = 298 K. Anonamine (I) (12,21-dihydroxy-4-methyl-4,8-secosenecionan-8,11,16-trione): C19H27NO7, Mr = 381.2, monoclinic, C2, a = 24.247 (7), b = 8.766 (2), c = 9.072 (1) A, beta = 99.21 (2) degrees, U = 1903.3 (8) A3, Z = 4, Dm = 1.32 (1), D chi = 1.330 g cm-3, mu(Mo K alpha) = 1.09 cm-1, F(000) = 816. Neosenkirkine (II) (12-hydroxy-4-methyl-4,8-secosenecionan-8,11,16-trione): C19H27NO6, Mr = 365.2, monoclinic, C2, a = 24.45 (1), b = 8.781 (2), c = 9.029 (2) A, beta = 98.99 (3) degrees, U = 1915 (1) A3, Z = 4, Dm = 1.27 (1), D chi = 1.267 g cm-3, mu(Mo K alpha) = 1.01 cm-1, F(000) = 784. Hydroxysenkirkine (III) [12,18-dihydroxy-4-methyl-4,8-secosenecionan-8, 11,16-trione-methanol (1/1)]: C19H27NO7.CH3OH, Mr = 413.2, orthorhombic, P2(1)2(1)2(1), a = 9.052 (3), b = 13.150 (4), c = 17.404 (8) A, U = 2071 (1) A3, Z = 4, Dm = 1.33 (1), D chi = 1.325 g cm-3, mu(Mo K alpha) = 1.10 cm-1, F(000) = 888. Full-matrix least squares refinement converged at R values of 0.042, 0.043 and 0.051 for 3163, 2894 and 2896 reflections for (I), (II), (III), respectively. All three crystals exhibit hydrogen bonds, including intramolecular O11...HO12 and intermolecular O8...HO12. In addition, intermolecular hydrogen bonds appear in (I) between O21...HO21' and in (III) between O8...HOCH3. The observed N...C8 distances across the eight-membered otonecine rings were 2.200, 2.245 and 1.712 A in (I), (II) and (III) respectively.

Molecular Structure↗
PubMed1988

Semisynthetic pyrrolizidine alkaloid N-oxide antitumor agents. Esters of heliotridine.

The C-9 and C-7 monoesters and C-7, C-9 diesters of heliotridine with (S)-(+) and (R)-(-)-2-hydroxy-2-phenylbutyric acid were prepared, converted into their N-oxides, and compared with the corresponding C-9 monoesters of retronecine in the in vivo P388 lymphocytic leukemia screen. Relative in vitro cytotoxicities of some of the free bases and their corresponding N-oxides were also measured against the A204 rhabdomyosarcoma cell line by using the soft agar colony forming assay. Stereochemistry at C-7 of the necine and at C-2' of the necine acid appears to have a significant effect on the antitumor activity in this system. In the heliotridine series, the configuration of the necic acid has a pronounced effect on the site selectivity (C-7 vs C-9) in esterification with carbodiimidazole. An explanation for this site selectivity is offered.

Animals↗