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PubMed2006

MDM2 inhibitors for cancer therapy.

The tumor suppressor p53 is a powerful antitumoral molecule frequently inactivated by mutations or deletions in cancer. However, half of all human tumors express wild-type p53, and its activation by antagonizing its negative regulator murine double minute 2 (MDM2) might offer a new therapeutic strategy. Proof-of-concept experiments have demonstrated the feasibility of this approach in vitro but the development of pharmacological inhibitors has been challenging. Recently, potent and selective small-molecule MDM2 inhibitors have been identified. Studies with these compounds have strengthened the concept that selective, non-genotoxic p53 activation is a viable alternative to current cytotoxic chemotherapy but clinical validation is still pending. Here, the new developments in the quest for pharmacological p53 activators are reviewed with an emphasis on small-molecule inhibitors of the p53-MDM2 interaction.

Benzodiazepines↗

PubMed1981

Novel tetracyclic spiropiperidines. 1. 3-Aryl-1,3-dihydrospiro[benzo[c]thiophene-1,4'-piperidines] as potential antidepressants.

A series of 3-aryl-1,3-dihydrospiro[benzo[c]thiophene-1,4'-piperidine] derivatives was synthesized and evaluated pharmacologically for potential psychotropic activity. Potent antidepressant-like activity was noted throughout the series, as assessed by tetrabenazine (TBZ) ptosis prevention in mice and potentiation of 5-hydroxytryptophan (5-HTP) induced behavioral effects in rats. A possible therapeutic advantage of the title compounds appears to be the overall low anticholinergic potential in comparison with the classic tricyclic antidepressants. Several congeners with nuclear halogen substitution also exhibited CNS stimulant properties, as evidenced by their ability to induce a dopamine agonist-like stereotypy and to increase the spontaneous motor activity in mice.

5-Hydroxytryptophan↗

PubMed2005

In-vivo effects of the 1,2,4-piperazine derivatives MM5 and MC1, putative 5-HT agonists, on dopamine and serotonin release in rat prefrontal cortex.

Two 1,2,4-substituted derivatives of piperazine were tested for their effect on dopamine and serotonin (5-HT) release in rat prefrontal cortex. Both compounds, 1-[4-(4-chinolin-2-yl-piperazin-1yl)-butyl]piperidin-2-on (MM5) and 1-[4-(2-methyl-4-chinolin-2-yl-piperazin-1-yl)-butyl]-8-azaspiro [4.5]decano-7,9-dion (MC1), produced hypothermia in mice and showed affinity for 5-HT1A receptors in-vitro. Like the selective 5-HT1A agonist 8-OH-DPAT (0.1 mg kg(-1)), MM5 given peripherally (30 mg kg(-1)) decreased the extracellular 5-HT level in rat prefrontal cortex, while MC1 suppressed 5-HT release at a higher dose (40 mg kg(-1)), but not at a lower one (30 mg kg(-1)). The effect of both compounds on 5-HT release was abolished by WAY 100635 (0.3 mg kg(-1)). MC1 (30 and 40 mg kg(-1)), but not MM5, raised cortical dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC) and extracellular homovanillic acid (HVA) levels. The effect of MC1 on dopamine release was reversed by neither WAY 100635 nor the non-selective 5-HT2 antagonist ritanserin (2 mg kg(-1)). However, ritanserin prevented the effect of the higher dose of MC1 on 5-HT release. The results of this study suggest that MM5 exhibits the profile of a 5-HT1A agonist devoid of dopaminergic activity. MC1 seems to possess moderate agonist activity at 5-HT1A and 5-HT2A receptors, while acting on 5-HT release in the rat prefrontal cortex. However, the facilitation of dopamine release by this compound does not seem to be related to its affinity for 5-HT1A and 5-HT2A receptors.

3,4-Dihydroxyphenylacetic Acid↗

PubMedDate not supplied

Solution-phase parallel synthesis of spirohydantoins.

Spirohydantoins are considered privileged structures, making them attractive for the preparation of compound libraries with the potential for diverse biological activity. However, very few modifications of this scaffold have been reported to date. The spirohydantoin template was elaborated into a library of 168 compounds through a two-step solution-phase parallel synthesis starting from various N-substituted piperidinones. The Strecker reaction was employed to generate alpha-amino nitriles from aniline and TMSCN (or KCN). Subsequent reaction of the anilido nitrogen with a diverse set of isocyanates, followed by refluxing under acidic conditions, afforded the title library in high yield and purity.

Combinatorial Chemistry Techniques↗

PubMed1983

Application of MDPF and fluorescamine XV chiroptical properties of MDPF condensation compounds with dipeptides in situ.

2-Methoxy-2,4-diphenyl-3(2H)-furanone (MDPF) reacts readily with the free amino group of a dipeptide to form a pyrrolinone-type chromophore with absorption maxima at 275-285 and 370-390 nm. A simple test tube procedure is described which allows in situ correlation of the absolute configuration of the NH2-terminal amino acid of a dipeptide with the chiroptical properties of its chromophoric derivative. In several cases, unexpected deviation of the chiroptical characteristics from previously established empirical rules is observed.

Circular Dichroism↗

PubMed2005

Inhibition of NF-kappaB activation and expression of inflammatory mediators by polyacetylene spiroketals from Plagius flosculosus.

Transcription factor NF-kappaB plays a key role for the inducible expression of genes mediating proinflammatory effects and is thus an important target for the development of antiinflammatory drugs. Here, we show that extracts from the plant Plagius flosculosus (L.) Alavi and Heyw. can inhibit the induction of NF-kappaB activity, and we describe the identification of three spiroketal compounds. Of those, only compound 1 could inhibit the phosphorylation and proteasomal degradation of IkappaB, thus preventing the nuclear import and DNA binding of NF-kappaB. Accordingly, compound 1, which is also found in the widely used medicinal herb chamomile, interfered with the LPS-induced production of IL-1, IL-6, TNF, and PGE2 in primary human monocytes.

Acetylene↗

PubMed2005

Biyouyanagin A, an anti-HIV agent from Hypericum chinense L. var. salicifolium.

[structure: see text] A structurally unique hydrophobic compound, biyouyanagin A, was isolated from the MeOH extract of the leaves of Hypericum chinense L. var. salicifolium. The structure of biyouyanagin A was elucidated on the basis of spectroscopic evidence. Biyouyanagin A showed a significant activity against HIV and inhibited cytokine production.

Anti-HIV Agents↗

PubMed1995

Synthesis and structure-activity studies of a series of 1-oxa-8-azaspiro[4.5]decanes as M1 muscarinic agonists.

2,8-Dimethyl-1-oxa-8-azaspiro[4,5]decan-3-one (17), designed by incorporating the tetrahydrofuran ring moiety of muscarone into an 8-azaspiro[4,5]decane skeleton, and related 1-oxa-8-azaspiro[4.5]decanes were synthesized and assessed as M1 muscarinic agonists for the symptomatic treatment of dementia of Alzheimer's type. The compounds were tested for central muscarinic M1 and M2 receptor affinity and in vivo muscarinic activities: namely, amelioration of scopolamine-induced impairment in rat passive avoidance tasks, and induction of hypothermia, tremor, and salivary secretion. Compound 17 exhibited potent muscarinic activities in vitro and in vivo with no selectivity. Systematic modifications of 17 were conducted, and a number of compounds, including the 2-ethyl analogue (18), 3-methylene analogue (29), 3-dithioketal analogues (26, 28), and 3-oxime analogue (37) were found to display preferential affinity for M1 receptors over M2 receptors and, in addition, to exhibit potent antiamnesic activity sufficiently separated from hypothermia-inducing activity, taken as an index of cholinergic side effects, compared with the reference compound RS86 (1). Structure-activity relationships are discussed in comparison with those for muscarone analogues. Of these compounds only two, 2-ethyl-8-methyl-1-oxa-8-azaspiro[4.5]decan-3-one (18) and 2,8-dimethyl-3-methylene-1-oxa-8-azaspiro[4.5]decane (29), stimulated phosphoinositide hydrolysis in rat hippocampal slices, indicating partial agonistic activity for M1 muscarinic receptors. The optical resolution of 18 and 29 was performed. Eudismic ratios of both compounds in binding affinity were low, but M1 agonist activity resided preferentially in the (-)-isomers. The absolute configuration of (-)-29 was determined by X-ray crystal structure analysis to be S, being the same as that of muscarone. Based on the in vivo selectivity, (-)-29 was selected for clinical studies.

Alkanes↗

PubMed1998

Specific receptors for synthetic GH secretagogues in the human brain and pituitary gland.

In vitro studies have been performed to demonstrate and characterize specific binding sites for synthetic GH secretagogues (sGHS) on membranes from pituitary gland and different human brain regions. A binding assay for sGHS was established using a peptidyl sGHS (Tyr-Ala-hexarelin) which had been radioiodinated to high specific activity at the Tyr residue. Specific binding sites for 125I-labelled Tyr-Ala-hexarelin were detected mainly in membranes isolated from pituitary gland and hypothalamus, but they were also present in other brain areas such as choroid plexus, cerebral cortex, hippocampus and medulla oblongata with no sex-related differences. In contrast, negligible binding was found in the thalamus, striatum, substantia nigra, cerebellum and corpus callosum. The binding of 125I-labelled Tyr-Ala-hexarelin to membrane-binding sites is a saturable and reversible process, depending on incubation time and pH of the buffer. Scatchard analysis of the binding revealed a finite number of binding sites in the hypothalamus and pituitary gland with a dissociation constant (Kd) of (1.5 +/- 0.3) x 10(-9) and (2.1 +/- 0.4) x 10(-9) mol/l respectively. Receptor activity is sensitive to trypsin and phospholipase C digestion, suggesting that protein and phospholipids are essential for the binding of 125I-labelled Tyr-Ala-hexarelin. The binding of 125I-labelled Tyr-Ala-hexarelin to pituitary and hypothalamic membranes was displaced in a dose-dependent manner by different unlabelled synthetic peptidyl (Tyr-Ala-hexarelin, GHRP2, hexarelin, GHRP6) and non-peptidyl (MK 0677) sGHS. An inhibition of the specific binding was also observed when binding was performed in the presence of [D-Arg1-D-Phe5-D-Trp7,9-Leu11]-substance P, a substance P antagonist that has been found to inhibit GH release in response to sGHS. In contrast, no competition was observed in the presence of other neuropeptides (GHRH, somatostatin, galanin or Met-enkephalin) which have a known influence on GH release. In conclusion, the present data demonstrate that sGHS have specific receptors in human brain and pituitary gland and reinforce the hypothesis that these compounds could be the synthetic counterpart of an endogenous GH secretagogue involved in the neuroendocrine control of GH secretion and possibly in other central activities.

Adult↗

PubMed1975

Antitumor agents. 16. Steroidal alpha-methylene-gamma-lactones.

Several novel steroidal alpha-methylene-gamma-lactones and related derivatives have been synthesized as potential steroid alkylating antitumor agents. The synthesis of these compounds involved the convenient Reformatsky-type reaction between ethyl-alpha-(bromomethyl)acrylate and the proper steroidal ketones. In vitro assay for the cytotoxicity of these compounds against the growth of tissue culture cells originating from human epidermoid carcinoma of the larynx (H.Ep.-2) has shown significant activity. Cytotoxicity was improved at least sixfold with the introduction of lipophilic steroidal character. Preliminary in vivo tumor assay also indicated that these compounds were active against Walker 256 carcinosarcoma in rats and were inactive against both L1210 lymphoid leukemia and Ehrlich ascites carcinoma in mice. However, the simple alpha-methylene-beta,beta-dicarbethoxy-gamma-butyrolactone significantly inhibited Ehrlich ascites tumor growth.

Androstanes↗

PubMed2002

Stereoselective synthesis of structurally simplified cephalostatin analogues by multiple Heck reactions and their biological evaluation.

The stereoselective synthesis of structurally simplified heptacyclic cephalostatin analogues 2, 3, 18-21, 31, 32 and 33 by multiple Heck reactions is described. The key step of the synthesis is a selective Heck reaction of hydrindene 7 with 12 and 25, respectively at the vinyl bromide moiety followed by the introduction of a second molecule of 7 and a twofold intramolecular Heck reaction. The obtained bissteroidal heptacyclic compounds 2 and 3, in which the central octahydrophenazine moiety of 1 is replaced by a benzene ring, contain an unusual cis-annulation of the two newly generated rings. The cytotoxicity of some of the derivatives was determined on human lung cancer cell line A 549 in HTFCA tests (Human tumor colony forming ability). They show a rather high activity with an ED(50) in the micro molar range.

Humans↗

PubMed2002

Conformationally restrained analogues of sympathomimetic catecholamines. Synthesis and adrenergic activity of 5,6- and 6,7-dihydroxy-3,4-dihydrospiro[naphthalen-1(2H)-2',5'-morpholines].

The 5,6- (10a) and 6,7-dihydroxy-3,4-dihydrospiro[naphthalen-1(2H)-)-2',5'-morpholine](11a) and their N-isopropyl derivatives (10b and 11b) (DDSNMs), which can be viewed as the result of the combination of the structure of the 2-(3,4-dihydroxyphenyl)morpholine 5a or 5b (DPMs) with the structure of the corresponding 1-(aminomethyl)-5,6-dihydroxy- (8a or 8b) or 1-(aminomethyl)-6,7-dihydroxy-1,2,3,4-tetrahydro-1-naphthalen-ol (9a or 9b) (1-AMDTNs) were synthesised. The new compounds DDSNMs 10a,b and 11a,b were assayed for their alpha- and beta-adrenergic properties by means of binding experiments and functional tests and the results were compared with those obtained for catecholamines 1a, b and the previously described morpholine (5) and tetrahydronaphthalene (8, 9) derivatives. The affinity and activity indices thus obtained indicate in general a low ability of the new compounds 10 and 11 to interact with the alpha- and beta-adrenoceptors, which, in all cases, was lower than that of the corresponding morpholine (5) and tetrahydronaphthalene (8, 9) analogues.

Adrenergic Agonists↗

PubMed1999

Studies on inducers of nerve growth factor: synthesis of the cyathin core.

[formula: see text] Compounds that induce the synthesis of nerve growth factor (NGF) are of interest as alternatives to the administration of the native peptide. We have initiated a program to study the NGF synthesis stimulating activity of the erinacine and scabronine diterpenes. Herein, we report an approach to the core cyathin system by sequential application of an oxidative coupling and [4 + 3] cycloaddition.

Anti-Bacterial Agents↗

PubMed1993

Differential cardiovascular effects of 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT), flesinoxan, 5-methyl-urapidil and MDL 75,608A in conscious spontaneously hypertensive rats.

The effects of intravenous (i.v.) administration of four agonists at central 5-HT1A receptors were investigated and compared. Acute iv injection of 0.1 mg/kg of 8-OH-DPAT induced a decrease in blood pressure both in spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY). The maximal hypotensive effect was observed 15 and 10 min after injection, respectively, but the effect was greater and longer-lasting in the SHR. 8-OH-DPAT significantly decreased heart rate in WKY and, to a lesser extent, in SHR. The i.v. injection of 1 mg/kg of flesinoxan caused a similar fall in blood pressure and heart rate in SHR and WKY. The i.v. administration of 1 mg/kg of 5-methyl-urapidil or MDL 75,608A caused a fall in blood pressure which was significantly more pronounced in SHR than in WKY. 5-methyl-urapidil induced a significant tachycardia in WKY, but had little effect on heart rate in SHR. MDL 75,608A caused a short-lasting tachycardia in SHR and WKY. In conscious SHR, the intracerebroventricular (icv) injection of 10 micrograms of 8-OH-DPAT or 100 micrograms of either flesinoxan or MDL 75,608A caused a decrease in blood pressure and heart rate. The icv injection of 100 micrograms of 5-methyl-urapidil caused only a decrease in blood pressure. Chronic pre-treatment with these compounds, by daily i.v. injection, did not significantly influence the hypotensive or bradycardic effects in an acute experiment. The involvement of alpha 1-adrenoceptors in the effects of these compounds was studied by administering phenylephrine (1 microgram/i.v.) at 5-min intervals before and after the i.v. injection of the experimental compounds. The injection of phenylephrine reproducibly increased blood pressure by 35-40 mm Hg after saline pre-treatment, and these responses were not affected by the i.v. injection of 0.1 mg/kg of either 8-OH-DPAT or 1 mg/kg of flesinoxan. In contrast, the phenylephrine-induced pressor responses were markedly diminished at 5 min after treatment with 1 mg/kg of either 5-methyl-urapidil or MDL 75,608A, but slowly recovered thereafter. These results show that the 5-HT1A receptor agonists 8-OH-DPAT, flesinoxan, 5-methyl-urapidil and MDL 75,608A show antihypertensive properties in conscious SHR after iv or icv injection. However, the mechanism of action of the compounds differs: 8-OH-DPAT and flesinoxan may act predominantly as 5-HT1A receptor agonists, where as 5-methyl-urapidil and MDL 75,608A also seem to have an effect on peripheral alpha 1-adrenoceptors.

8-Hydroxy-2-(di-n-propylamino)tetralin↗

PubMed1992

Selective reversible and irreversible ligands for the kappa opioid receptor.

(+-)-(5 beta,7 alpha,8 beta)-3,4-Dichloro-N-methyl-N-[3-methylene-2- oxo-8-(1-pyrrolidinyl)-1-oxaspiro[4,5]dec-7-yl]benzeneacetamide (14) and its (5 alpha,7 alpha,8 beta) diastereomer 15 have been synthesized from 1,4-cyclohexanedione monoethylene ketal (1) in 10 steps. Compound 14, which we have designated SMBU-1, was found to bind with moderate affinity (Ki = 109 nM) and good selectivity (mu/kappa = 29) to the kappa opioid receptor, while 15 was only 1/10 as potent as a kappa ligand. Preincubation of brain membranes with 14 resulted in wash-resistant inhibition of kappa-receptor binding (69 +/- 6% of control at 10(-6) M). The ketone precursor trans-N-methyl-N-[5-oxo-2-(1- pyrrolidinyl)cyclohexyl]benzeneacetamide (12) showed a higher kappa-affinity (Ki = 78 nM) and a much higher kappa-selectivity (mu/kappa = 166) than 14. Compound 10, the ethylene ketal precursor of 12, exhibited a similar receptor binding profile to 14, with increased kappa-selectivity (mu/kappa = 55), while ketal 11, being a regioisomer of 10 and an oxygen isostere of the kappa-selective analgesic spiradoline (U-62,066), demonstrated the highest kappa-affinity (Ki = 1.5 nM) and kappa-selectivity (mu/kappa = 468) observed in this series.

Benzeneacetamides↗

PubMed1992

Stimulation by risperidone of rat prolactin secretion in vivo and in cultured pituitary cells in vitro.

Risperidone, a new antipsychotic agent which antagonizes both 5-hydroxytryptamine-2 (5-HT2) and dopamine-2 (D2) receptors, was evaluated for its effects on prolactin release. One hr after either p.o. or i.p. dosing, risperidone was 3 to 5 times more potent than the classical D2 receptor antagonist haloperidol in stimulating rat prolactin levels in vivo. This result was unexpected because haloperidol is a more potent D2 receptor antagonist than risperidone in vitro. Mechanisms which might explain these observations were investigated. Compared to haloperidol, risperidone was 0.34 (95% confidence interval: 0.23, 0.48) times as potent in reversing the suppression by dopamine of rat anterior pituitary cell prolactin release in vitro, which is consistent with the compounds' striatal D2 receptor binding potencies in vitro. Administration of ketanserin, a 5-HT2 receptor antagonist, along with haloperidol did not modify haloperidol's activity on either in vitro pituitary cell prolactin release (up to 1000 nM ketanserin) or in vivo prolactin concentrations (5 mg/kg ketanserin, i.p.). In vitro incubation of haloperidol and risperidone with a liver homogenate supernatant (S-9) led to extensive (greater than 86%) metabolism of each compound. S-9 treatment abolished haloperidol's effects on pituitary cell prolactin release. Risperidone's ability to increase prolactin release was unchanged after S-9 treatment, and 9-hydroxy-risperidone, identified as a major metabolite in the S-9 conditioned media, was equipotent to risperidone in modulating prolactin release in vitro.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1981

Synthesis and antihypertensive activity of a series of 8-substituted 1-oxa-3,8-diazaspiro[4.5]decan-2-ones.

Forty-three new 1-oxa-3,8-diazaspiro[4,5]decan-2-ones optionally substituted with 2-(3-indolyl)ethyl, 3-(2-methoxyphenoxy)-2-hydroxypropyl, or 2-(1,4-benzodioxan 2-yl)-2-hydroxyethyl at the 8 position were prepared for screening as antihypertensive agents in the spontaneous hypertensive rat. For the 8-[2-(3-indolyl)ethyl] compounds the most active were those substituted in the 4 position, where activity was at maximum with the 4-ethyl compound (1). The 8-[3-(2-methoxyphenoxy)-2-hydroxypropyl] compounds were less active than their 1,4-benzodioxane counterparts, which were tested as mixtures of erythro and threo diastereoisomers. Both the 4-ethyl-8-[2-(1,4-benzodioxan-2-yl)-2-hydroxyethyl]-substituted 38 and (S)-3-methyl-8-[3-(2-methoxyphenoxy)-2-hydroxypropyl]-substituted 42 were designed as mixed alpha- and beta-adrenergic receptor blockers. Bother compounds lowered blood pressure, but they gave no evidence of working as beta-adrenergic blockers. Examination of 8-[2-(3-indolyl)ethyl]-1-oxa-3,8-diazaspiro[4.5]-decan-2-one (8) and 3 methyl-8-[2-(1,4-benzodioxan-2-yl)-2-hydroxyethyl]-1-oxa-3,8-diazaspiro[4,5]decan-2-one (29) in the dog showed them to be alpha-adrenergic blockers. Compound 29 was primarily an alpha 2-adrenoceptor antagonist, while 8 was more skewed toward alpha 1-adrenoceptor antagonism. Tilt-response studies for evaluating the potential for producing orthostatic hypotension showed that both 8 and 29 had little potential for avoiding orthostatic hypotension at therapeutically effective doses.

Animals↗

PubMed1995

Succinimide derivatives. II. Synthesis and antipsychotic activity of N-[4-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]butyl]-1,2-cis- cyclohexanedicarboximide (SM-9018) and related compounds.

Cyclic imides bearing omega-(4-benzisothiazol-3-yl-1-piperazinyl)alkyl moieties were synthesized and tested for antipsychotic activity. The in vitro binding affinities of these compounds were examined for dopamine 2 (D2) and serotonin 2 (5-HT2) receptor sites. Structure-activity relationships within these series are discussed. One of these compounds, N-[4-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]butyl]-1,2-cis- cyclohexamedicarboximide (SM-9018), was found to be more potent and more selective in vivo than tiospirone in its antipsychotic activity. SM-9018 (17) is currently undergoing clinical evaluation as a selective antipsychotic agent.

Animals↗