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At least 91 records · Page 5Linked to original sources
PubMed2004

Two pyrrolo[1,2-a]azepine type alkaloids from Stemona collinsae Craib: structure elucidations, relationship to asparagamine A, and a new biogenetic concept of their formation.

The alkaloids 1',2'-didehydrostemofoline (2) and 2'-hydroxystemofoline (3) from Stemona collinsae Craib (Stemonaceae) were studied by X-ray crystallography and NMR spectroscopy, and they are compared with the parent compound stemofoline (1). The X-ray analysis of the CH2Cl2 solvate of 2'-hydroxystemofoline (3) allowed the determination of the absolute configuration of this compound unequivocally, whereas optical rotation was used to infer the absolute configuration of 1',2'-didehydrostemofoline (2). Based on these results, it is shown that asparagamine A isolated from Asparagus racemosus Willd. (Asparagaceae) is identical to 1',2'-didehydrostemofoline obtained from S. collinsae Craib, and that the reported plant source of asparagamine A was most likely a Stemona species. In the context of the current investigations, a novel concept on the biosynthesis of Stemona alkaloids has been worked out and is presented here.

Alkaloids↗
PubMed1986

Evidence for a specific effect of BHT 920, an azepine derivative, on tyrosine hydroxylase in the dopaminergic system of the rat.

The effect of BHT 920, a putative presynaptic dopamine receptor agonist, on tyrosine hydroxylase was investigated in rats. The activity of the high affinity (BH4) form of striatal tyrosine hydroxylase was investigated dose-dependent manner in rats treated with BHT 920. This effect was pronounced in the dopaminergic system and was not observed to the same extent in the adrenal medulla. In vitro, BHT 920 had no effect upon striatal tyrosine hydroxylase activity. BHT 920 also did not affect either striatal adenylate cyclase activity or the extent of its stimulation by dopamine. The results concerning tyrosine hydroxylase were complemented by measurements of dopamine and DOPA in the striatal and the limbic system. The reduction in DOPA accumulation and in the high affinity form of tyrosine hydroxylase activity elicited by BHT 920 could be blocked by haloperidol, suggesting that BHT 920 may interact with the D2 dopamine receptor although a functional antagonism could not be ruled out. The present results suggest that BHT 920 may exert a specific effect upon tyrosine hydroxylase in dopaminergic nervous tissue which is not mediated by alpha 2-adrenoceptors.

Adenylyl Cyclases↗
PubMed2006

Tetrahydropyrrolo[3,2-c]azepin-4-ones as a new class of cytotoxic compounds.

Pyrroloazepinones 8a-j and 9a-j were designed by structural modification of lead compound 3. These compounds were tested on five tumor cell lines to determine the role of the azeto ring and the 2-methyl substituent in the cytotoxicity of compound 3. Our results show that compounds 8a-j (R1=CH3) have dramatically reduced cytotoxicity, resulting from the loss of the azeto moiety of lead compound 3. By contrast, azepinones 9a-j (R1=4-nitrophenyl) inhibited the proliferation of almost all cancer cell lines tested even though they lack the azeto ring. Preliminary SAR studies with these compounds revealed the importance of halogens at the para- or meta-position of the 1-phenyl moiety. Additionally, derivatives 9a (R2=H), 9e (R2=4-F), and 9g (R2=4-OMe) were selectively cytotoxic to U-251 cells. However, none of the pyrroloazepinones inhibited the enzymatic activity of CDK1/cyclin B, CDK5/p25, and GSK-3.

Antineoplastic Agents↗
PubMed2006

Tricyclic azepine derivatives: pyrimido[4,5-b]-1,4-benzoxazepines as a novel class of epidermal growth factor receptor kinase inhibitors.

A novel class of pyrimido[4,5-b]-1,4-benzoxazepines is described as inhibitors of epidermal growth factor receptor (EGFR) tyrosine kinase. Two compounds display potent EGFR inhibitory activity of less than 1 microM in cellular phosphorylation assays (IC(50) 0.47-0.69 microM) and are highly selective against a small kinase panel. Such compounds demonstrate anti-EGFR activity within a class that is different from any known EGFR inhibitor scaffolds. They also provide a basis for the design of kinase inhibitors with the desired selectivity profile.

Adenosine Triphosphate↗
PubMed2006

Novel tricyclic azepine derivatives: Biological evaluation of pyrimido[4,5-b]-1,4-benzoxazepines, thiazepines, and diazepines as inhibitors of the epidermal growth factor receptor tyrosine kinase.

Novel tricyclic derivatives containing an oxazepine, thiazepine, or diazepine ring were studied for their EGFR tyrosine kinase inhibitory activity. While the oxazepines were in general more potent than thiazepines, the diazepines displayed somewhat different structure-activity relationships. Moreover, the diazepines, in contrast to the oxazepines, showed appreciable inhibitory activity against the KDR tyrosine kinase. Furthermore, both oxazepines and diazepines demonstrated significant ability to inhibit autophosphorylation of EGFR in DiFi cells (generally, IC(50) values in the single-digit micromolar to submicromolar range).

Antineoplastic Agents↗
PubMed1995

Synthesis and evaluation of 6,7-dihydroxy-2,3,4,8,9,13b-hexahydro-1H- benzo[6,7]cyclohepta[1,2,3-ef][3]benzazepine, 6,7-dihydroxy- 1,2,3,4,8,12b-hexahydroanthr[10,4a,4-cd]azepine, and 10-(aminomethyl)-9,10- dihydro-1,2-dihydroxyanthracene as conformationally restricted analogs of beta-phenyldopamine.

The present study was designed to define the geometry of the hydrophobic accessory region for binding of dopamine D1 receptor ligands and to assess the relative importance of ethylamine side chain conformation for receptor affinity. Three compounds, 6,7-dihydroxy-2,3,4,8,9,13b-hexahydro-1H-benzo[6,7]cyclohepta[1,2, 3-ef][3]benzazepine, 4, 6,7-dihydroxy-1,2,3,4,8,12b-hexahydroanthr[10,4a,4-cd]aze pin e, 5, and 10-(aminomethyl)-9,10-dihydro-1,2-dihydroxyanthracene, 6, were synthesized as conformationally restricted analogs of beta-phenyldopamine. Molecular modeling studies were performed to compare these three compounds with the high-affinity D1 agonists dihydrexidine (DHX), 2, and SKF 38393, 3. The beta-phenyl moieties in the target compounds are constrained by means of either an ethyl (4) or methylene (5 and 6) bridge. The compounds adopt minimum-energy conformations in which the beta-phenyl group is approximately -22 degrees (4), -12 degrees (5), and -30 degrees (6) from coplanarity with the catechol ring. These compounds also embody either a freely rotating (6) or a rigidified gauche (4 and 5) rotameric conformation of the dopamine ethylamine side chain, the latter nearly perfectly superimposible on the benzazepine portion of SKF 38393. Radioligand competition experiments showed that compounds 4, 5, and 6 have only micromolar affinity for both the D1 and D2 dopamine receptor subtypes. The low affinity of 4-6, relative to 2 and 3, may be due to improper orientation of the beta-phenyl moiety and provides important information about the three-dimensional orientation of the hydrophobic accessory binding domain of the dopamine D1 receptor. In addition, the negligible affinity of 6, as compared to 2 and 3, indicates that the rotameric positioning of the ethylamine side chain may not be a primary determinant of receptor affinity.

Animals↗
PubMed2004

Synthesis and structure-activity relationships of 5,6,7,8-tetrahydro-4H-thieno[3,2-b]azepine derivatives: novel arginine vasopressin antagonists.

A variety of novel heterocyclic compounds having thienoazepine, pyrroloazepine, furoazepine, and thienodiazepine skeletons were synthesized, most of which exhibited potent antagonism of [(3)H]-AVP specific binding in assays using rat liver (V1), rat kidney (V2), human platelet plasma membranes, and recombinant human CHO cells (V2), as well as antagonizing AVP-induced hypertension in rats (V1, intravenous) and showing a diuretic effect in rats (V2, oral). By detailed studies of the structure-activity relationships of these compounds, the thienoazepine derivative 1 was found to be a very potent combined V1 and V2 antagonist. After further pharmacological and toxicological evaluation as well as physical properties, the hydrochloride 2 (JTV-605) of compound 1 was selected for clinical studies as a potent AVP antagonist with a long duration of action.

Animals↗
PubMed2000

An asymmetric aminohydroxylation approach to the azepine core of (-)-balanol.

[reaction: see text]An efficient formal synthesis of the potent protein kinase C inhibitor (-)-balanol that relies on a modified asymmetric aminohydroxylation of the alpha,beta-unsaturated aryl ester (1) is reported. The aryl ester functionality and the dihydroquinyl alkaloid ligand system (DHQ)2-AQN are used to control the regio- and enantioselectivity of the process.

Amination↗
PubMed2001

Effects of S-ethyl hexahydro-1H-azepine-1-carbothioate (molinate) on di-n-butyl dichlorovinyl phosphate (DBDCVP) neuropathy.

Certain esterase inhibitors protect from organophosphate-induced delayed polyneuropathy (OPIDP) when given before a neuropathic organophosphate by inhibiting neuropathy target esterase (NTE). In contrast, they can exaggerate OPIDP when given afterwards and this effect (promotion) is associated with inhibition of another esterase (M200). In vitro sensitivities of hen, rat, and human NTE and M200 to the active metabolites of molinate, sulfone, and sulfoxide, were similar. NTE and M200 were irreversibly inhibited (> 78%) in brain and peripheral nerve of hens and rats given molinate (100-180 mg/kg, sc). No clinical or morphological signs of neuropathy developed in these animals. Hens and rats were protected from di-n-butyl dichlorovinyl phosphate neuropathy (DBDCVP, 1 and 5 mg/kg, sc, respectively) by molinate (180 or 100 mg/kg, sc, 24 h earlier, respectively) whereas 45 mg/kg, sc molinate causing about 34% NTE inhibition offered partial protection to hens. Hens treated with DBDCVP (0.4 mg/kg, sc) developed a mild OPIDP; molinate (180 mg/kg, 24 h later) increased the severity of clinical effects and of histopathology in spinal cord and in peripheral nerves. Lower doses of molinate (45 mg/kg, sc), causing about 47% M200 inhibition, did not promote OPIDP whereas the effect of 90 mg/kg, sc (corresponding to about 50-60% inhibition) was mild and not statistically significant. OPIDP induced by DBDCVP (5 mg/kg, sc) in rats was promoted by molinate (100 mg/kg, sc). In conclusion, protection from DBDCVP neuropathy by molinate is correlated with inhibition of NTE whereas promotion of DBDCVP neuropathy is associated with > 50% M200 inhibition.

Animals↗