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Education, Medical↗
Biomedical subjects
M L Stein
Publications and source records attributed to M L Stein.
Synthesis and anti-human immunodeficiency virus type 1 integrase activity of hydroxybenzoic and hydroxycinnamic acid flavon-3-yl esters.
A series of new hydroxybenzoic and hydroxycinnamic acid flavon-3-yl esters were synthesized in order to obtain compounds targeting the human immunodeficiency virus (HIV) type 1 integrase (IN). The esters were tested for anti-IN and anti-reverse transcriptase (RT) activity in enzyme assays and for anti-HIV-1, anti-proliferative and anti-topoisomerase activity in cell-based assays. In enzyme assays, the two gallic acid flavon-3-yl esters showed a notable IN inhibition (IC50 values were 8.3 and 9.1 microM, respectively), while the two caffeic acid flavon-3-yl esters exhibited a modest activity (IC50 75 and 60 microM, respectively). Replacement of hydroxyl groups resulted in loss of potency. Caffeic acid 3',4'-dichloroflavon-3-yl ester also inhibited the RT activity whereas it was not active on human topoisomerases. It therefore represents an interesting example of a compound specifically targeting more than one step of the virus replication cycle.
Anti-HIV Agents↗
N-omega-carbethoxypentyl-4-quinolones: a new class of leukotriene biosynthesis inhibitors.
6-[(4-Quinolinyl)oxy]hexanoic acids and the corresponding esters were designed and synthesized as inhibitors of the production of arachidonic acid metabolites. The inhibitory activities were assayed in vitro by evaluation of serum leukotriene B4 and thromboxane B2 production. While all 6-[(4-quinolinyl)oxy]hexanoic acids and their esters proved to be inactive, the N-alkyl-4-quinolones, obtained as by-products in their synthesis, were found to be a new class of leukotriene biosynthesis inhibitors.
Enzyme Inhibitors↗
Effect of chloro-, cyano-, and amidino-substituted flavanoids on enterovirus infection in vitro.
Synthetic flavans, isoflavans and isoflavenes substituted with chloro, cyano and amidino groups were tested for their in vitro activity against poliovirus type 2, Coxsackie virus B4, echovirus type 6 and enterovirus 71. Plaque-reduction assays showed that substituted 3-(2H)-isoflavenes, carrying a double bond in the oxygenated ring, possess antiviral activity higher than that of the corresponding isoflavans. The most effective compounds were 4'-chloro-6-cyanoflavan and 6-chloro-4'-cyanoflavan. Studies on the mechanism of action of these two compounds suggested an effect on the early stages of viral replication.
Amidines↗
Sexual differences in the effect of the GABAergic system on LH secretion and in the hypothalamic ontogenesis of GABAA receptors in prepubertal rats.
The administration of aminooxyacetic acid (AOAA), which increases hypothalamic GABA concentrations, induced a significant increase in LH levels in female rats of 12, 16 and 18 days of age. This stimulatory effect of AOAA on serum LH levels was not observed at 21 and 25 days of age whereas a significant decrease in the LH concentrations by AOAA was found at 30 days of age. The neonatal androgenization of female rats abolished the effects of AOAA and no effects of AOAA were found in male rats at the different ages studied. The muscimol binding sites in medial basal and preoptic anterior hypothalamic areas showed a significant different sexual ontogenic pattern. Males rats castrated at birth showed a very similar ontogenic pattern of [3H]muscimol binding sites to female rats and significantly different to male control rats. It is concluded that there are sexual differences in the effect of GABAergic system on LHRH-LH secretion and in the development of hypothalamic GABAA receptors during sexual maturation. These differences are probably connected with the neonatal exposure to androgens that would induced changes in the composition and probably in the properties of GABAA receptor that in turn modified its effects on LHRH neurons.
Aging↗
Synthesis and binding properties to GABA receptors of 3-hydroxypyridinyl- and 3-hydroxypiperidinyl-analogues of baclofen.
The synthesis of 3-(3-hydroxy-2-pyridinyl)propanoic acid, 3-(3-hydroxy-2-pyridinyl)-4-aminobutanoic acid, their corresponding piperidine compounds, and of some cyclized derivatives is described. In in vitro assays none of the new compounds shows any noteworthy affinity for GABAA or GABAB receptors; only (R,S)-3-(3-hydroxy-2-pyridinyl)-4-aminobutanoic acid and its lactam inhibited in some degree [3H]GABA binding, at 10(-4) M concentration, with low specificity as regards the two receptors.
Aminobutyrates↗
Synthesis of some guanylhydrazones and imidazolinylhydrazones as thromboxane-synthase and platelet aggregation inhibitors.
The imidazolinylhydrazones of (3-pyridinyloxy)-acetaldehyde and of 6-[3-(2-formyl-pyridinyl)oxy]hexanoic acid were synthesized as cyclic analogues of the corresponding guanylhydrazones which were found to be selective inhibitors of human thromboxane-synthase. The benzene isosters were also prepared in order to define the importance of the ring nitrogen for the activity. Moreover, the guanyl- and imidazolinyl-hydrazones of two 6-[(3-pyridinyl)oxy]hexanoic acids showing in the 2 position an alkyl chain with an alpha, beta-unsaturated ketonic function were prepared. Imidazolinylhydrazones 7 and 18 are selective inhibitors of thromboxane-synthase, while the two guanylhydrazones 14 and 15 which do not affect prostanoid biosynthesis seemed to be antagonists at the thromboxane receptor.
Dinoprostone↗
Constituents of Eriobotrya japonica. A study of their antiviral properties.
The CHCl3 extract of Eriobotrya japonica from an Italian source was shown to contain four new triterpene esters, namely, 23-trans-p-coumaroyltormentic acid [1], 23-cis-p-coumaroyltormentic acid [2], 3-O-trans-caffeoyltormentic acid [3], and 3-O-trans-p-coumaroylrotundic acid [4], in addition to three common ursolic acid derivatives 5, 6, and 7. An investigation of the antiviral properties of compounds 1-7 revealed that only 3 significantly reduced rhinovirus infection. The compounds were ineffective towards human immunodeficiency virus type 1 (HIV-1) and Sindbis virus replication.
Antiviral Agents↗
Mechanism of action of the antirhinovirus flavanoid 4',6-dicyanoflavan.
4',6-Dicyanoflavan (DCF), a new antirhinovirus compound, was shown to inhibit an early event of rhinovirus type 1B replication in HeLa cells. When DCF was present from the beginning of infection or was added no later than the first hour of infection, the compound completely prevented viral RNA and protein synthesis and the virus-induced shutoff of host translation. DCF had no adverse effect either on virus binding to the cell membrane or on virus penetration into cells, whereas it delayed the uncoating kinetics of neutral redencapsidated rhinovirus. DCF also prevented mild acid or thermal inactivation of virus infectivity, although it reversibly interacted with virions. These results suggest that the stabilizing effect of DCF on virion capsid conformation is responsible for uncoating inhibition.
Antiviral Agents↗
Deletion of two growth-factor repeats from the low-density-lipoprotein receptor accelerates its degradation.
The region of the low-density-lipoprotein (LDL) receptor showing sequence similarity to the epidermal-growth-factor (EGF) precursor is required for LDL binding and the acid-induced dissociation of ligand and receptor. We describe here a naturally occurring mutant LDL receptor, found in a patient with homozygous familial hypercholesterolaemia, which lacks the first two growth-factor-like repeats of the EGF-precursor-like ('homology') domain. The mutation in the receptor gene is a 2.5 kb deletion including exons 7 and 8. The molecular mass of the mutant receptor (145 kDa) was approx. 15 kDa smaller than the normal LDL receptor. The mutant receptors were derived from precursors (105 kDa) that apparently underwent normal processing. Fibroblasts from the patient had high-affinity binding sites for the the apolipoprotein E-containing ligand, beta VLDL, but did not bind LDL. In the presence of beta VLDL, receptors were rapidly degraded. The mutant receptors also displayed an abnormally rapid turnover, about four times faster than that of normal receptors, in the absence of ligand; this accelerated degradation accounted for the low level of expression of mutant receptors in up-regulated cells. These data support a role for the growth-factor-like repeats in the binding of LDL (but not beta VLDL) and in receptor recycling, and indicate that a normal rate of turnover of unoccupied receptors is dependent on the integrity of these segments of the protein.
Adolescent↗
Iron dextran in the treatment of iron-deficiency anaemia of pregnancy. Haematological response and incidence of side-effects.
Sixty pregnant patients with a haemoglobin (Hb) less than 8 g/dl and proven iron-deficiency anaemia were randomly allocated to two treatment groups. Group A received the usual recommended dose of iron dextran (Imferon; Fisons) and group B received two-thirds of the recommended dose. A further 30 patients received oral iron (group C). There was no difference in Hb value between the three groups 4 weeks after treatment or 3 months after delivery. At 6 months after delivery, a higher mean Hb value was found in the patients in group A than those in groups B and C. Significantly higher serum ferritin levels were found in group A and this difference was still present 6 months postnatally. There was no significant difference in the incidence of delayed reactions between the two groups who received iron dextran.
Anemia, Hypochromic↗
Structure and in vitro antiviral activity of triterpenoid saponins from Calendula arvensis.
A reinvestigation of the aerial parts of Calendula arvensis afforded, in addition to the oleanolic acid glycosides 1-4 (4), the new glycoside 5 whose structure was elucidated by spectral and chemical studies and determined as 3-O-(beta-D-galactopyranosyl-(1----3) [beta-D-glucopyranosyl-(1----4)]-beta-D-glucopyranosyl) oleanolic acid (28----1)-beta-D-glucopyranosyl ester. Furthermore, some antiviral tests were performed on glycosides 1-5 and on 5a, the hydrolysis product of 5, towards vesicular stomatitis virus (VSV) and rhinovirus (HRV) infection in cell cultures. An inhibitory effect against VSV multiplication was observed for all the compounds tested while HRV replication was significantly affected only by compound 3.
Animals↗
Antiviral activity of constituents of Tamus communis.
The antiviral activity of the phenanthrene derivatives 1-6, of the spyrostane triglycosides dioscin (7) and gracillin (8), of the furostanol tetraglycosides methylprotodioscin (9), its (25S) epimer methylprotoneodioscin (10), and methylprotogracillin 11, have been tested towards two RNA viruses: vesicular stomatitis virus and human rhinovirus type 1B. All these products were extracted from the rizomes of Tamus communis L; compound 11 was isolated also from Asparagus cochinchinesis, together with pseudoprotodioscin (12), a 20 (22)-unsaturated furostanoside, which was also investigated for antiviral activity. The results were of some interest mainly for the phenanthrene derivatives.
Animals↗
In vitro effect of synthetic flavanoids on astrovirus infection.
In this study we investigated the activity of halogeno-, cyano- and amidino-isoflavenes, isoflavans and flavans on the multiplication of human astroviruses. These are naked small round viruses which have been recognized as causative agents of human gastroenteritis, and whose capsid proteins are similar to those of picornaviruses. Although all drugs tested caused a dose-dependent reduction of viral antigen synthesis as monitored by immunofluorescence, the chloro derivatives were the most effective.
Animals↗
Activities and mechanisms of action of halogen-substituted flavanoids against poliovirus type 2 infection in vitro.
The effects of some halogen-substituted flavanoids (dichloroflavan, halogenated isoflavans, and isoflavenes) on poliovirus type 2 infection was examined. Only two isoflavenes exhibited a significant inhibitory activity on the virus-induced cytopathic effect and plaque formation. In a single cycle of viral replication, both compounds reduced the viral yield by approximately 90%. The presence of the isoflavenes from the beginning of infection or during the adsorption period only prevented the shutoff of host translation and viral RNA and protein synthesis, suggesting that the drugs blocked an early step of viral replication. Indeed, both isoflavenes were not virucidal, did not protect virus infectivity from heat inactivation, and had no measurable effect on the binding of virus to cells, viral penetration, and uncoating of the viral RNA. In contrast, both compounds significantly reduced the infectivity of free viral RNA. The possibility that compounds interfere with poliovirus replication at a very early stage of translation of the input RNA is discussed.
Flavonoids↗
Dimethyl cathate: synthesis and pharmacological investigation.
Dimethyl cathate was synthesized through a reaction sequence starting from 3,4-pyridinedicarboxylic acid anhydride, and hydrolyzed to the not yet described cathic acid. Pharmacological screening procedures only showed a protection against the convulsive effect of pentylenetetrazol.
Analgesics↗
Effect of isoflavans and isoflavenes on rhinovirus 1B and its replication in HeLa cells.
The effect of newly synthesized halogenated isoflavans and isoflavenes on human rhinovirus 1B (HRV 1B) infection of HeLa cells has been examined. Both series of drugs inhibited virus plaque formation in cell cultures, isoflavans being more effective than isoflavenes. Cells pretreated with compounds before challenge with HRV 1B became resistant to the virus-induced cytopathic effect. The antiviral state induced by the most active compounds persisted for at least 10 h and did not appear to be mediated by interferon production. Experiments whereby the compounds were added at varying times indicated that the isoflavans and isoflavenes interfere with early events of virus replication without affecting virus binding to the cell membrane. In addition to their effects on virus multiplication, the isoflavans were also found to have a direct action on the virus. The inhibitory effect on virus infectivity required extraction with chloroform for reversal. Isoflavans also protected the virions against mild acid or heat inactivation.
Cell Survival↗