Synthesis and biological activity of the structural analogues of (-)-cabenegrin A-I.

A series of phenylbutene and butanol derivatives (6a-j, 12, 13, 15, 17, 24b,c, 26, 27a,b) were prepared from the readily available resorcinol derivatives 2a-f and 7-hydroxy-chroman (18). The products were tested for inhibitory activity on the LPS-induced TNF-alpha production in the plasma in comparison with that of cabenegrin A-I (1a).

Synthesis of vinca alkaloids and related compounds, Part XCVI. Nitration study of vinblastine-type bisindole alkaloids.

The bisindole alkaloids vinblastine, vincristine, and N-formyl-leurosine were nitrated and subsequently converted to amino derivatives. In the case of compounds 5e and 5b cytotoxic activity has been found for non-small cell lung cancer and breast cancer in the concentration range tested (10(-5)-10(-9) M). 5b also showed potency in the screen for colon cancer and leukemia.

Role of sodium channel inhibition in neuroprotection: effect of vinpocetine.

Vinpocetine (ethyl apovincaminate) discovered during the late 1960s has successfully been used in the treatment of central nervous system disorders of cerebrovascular origin for decades. The increase in the regional cerebral blood flow in response to vinpocetine administration is well established and strengthened by new diagnostical techniques (transcranial Doppler, near infrared spectroscopy, positron emission tomography). The latest in vitro studies have revealed the effect of the compound on Ca(2+)/calmodulin dependent cyclic guanosine monophosphate-phosphodiesterase 1, voltage-operated Ca(2+) channels, glutamate receptors and voltage dependent Na(+)-channels; the latest being especially relevant to the neuroprotective action of vinpocetine. The good brain penetration profile and heterogenous brain distribution pattern (mainly in the thalamus, basal ganglia and visual cortex) of labelled vinpocetin were demonstrated by positron emission tomography in primates and man. Multicentric, randomized, placebo-controlled clinical studies proved the efficacy of orally administered vinpocetin in patients with organic psychosyndrome. Recently positron emission tomography studies have proved that vinpocetine is able to redistribute regional cerebral blood flow and enhance glucose supply of brain tissue in ischemic post-stroke patients.

[New antitumor derivatives of vinblastine]. / Uj, antitumor hatású vinblasztin származékok.

The alkaloids of Catharanthus roseus vincristine 1 and vinblastine 2 are widely used in the chemotherapy of cancer. Their nitro-derivatives have also antitumour activity [2]. The dinitro-derivatives 4, 6-9 were prepared for pharmacological investigation. Some new hydroxymethyl derivatives 12-14, 17-18, 23-24 of the antitumour indole-indoline alkaloids vinblastine 2 and leurosine 5 were synthetised in two different ways a) by the selective reduction of 2, 5 or deacetoxy-vinblastine 16, b) by the ferric chloride mediated coupling reaction of catharanthine 19 and the corresponding vindoline derivatives 21, 22. Synthetising 24 a new bisvindoline 25 was the main product. 13 and 14 showed cytotoxic activity for small cell lung cancer LXFS 650.

Analysis and implications of transition-band signals in high-resolution NMR.

The problem of signals generated in and received from regions outside the active coil area is discussed in the context of using standard measurement techniques. Some of the conceptual and practical consequences of the existence of such transition-band signals are highlighted. Examples include radiation damping, pulse-width calibration, lineshape and radiofrequency homogeneity tests, improper saturation, and exchange- and relaxation-rate determinations. One interesting implication is that apparent sample-to-sample variations in the calibrated 90 degrees pulse width values are a function not only of probe tuning and bulk susceptibility effects, but also of the linewidths involved. A semi-quantitative treatment of the phenomenon is also given.

Inhibition of gamma-aminobutyric acid uptake by bicuculline analogues.

Enantiomers of norbicuculline, (+)[1S,9R] and (-)[1R,9S]erythro-1-[1'-(4',5'-methylenedioxyphthalidyl)]-6,7-meth ylenedioxy-1,2,3,4-tetrahydroisoquinoline and of the N-methyl derivatives {(+)[1S,9R] and (-)[1R,9S]bicuculline} were found to inhibit the progress of the gamma-aminobutyric acid transporter-mediated uptake of 40 microM [14C]gamma-aminobutyric acid into native plasma membrane vesicles from the rat cerebral cortex at 30 degrees C. The values for the dissociation constants of the reversible inhibition, relative to (+)[1S,9R]bicuculline, in order of increasing inhibition, were: (-)[1R,9S]bicuculline, 3.3; (+)[1S,9R]-bicuculline, 1.0; (-)[1R,9S]norbicuculline, 0.4 approximately (+)[1S,9R]norbicuculline; guvacine, 0.02. The norbicucullines have higher potencies than (+)[1S,9R]bicuculline for the gamma-aminobutyric acid transporter, in contrast to the relative potencies of these inhibitors for the inhibition of function and gamma-aminobutyric acid binding of the gamma-aminobutyric acid type A receptor.

Synthesis of vinca alkaloids and related compounds. Part 84. Sulfonamide derivatives of some vinca alkaloids with cardiovascular activity.

(+)-Vincamine (1) and (+)-vinpocetine (2) were chlorosulfonylated and the resulting sulfonyl chloride isomers (3-6) were transformed into sulfonamides (7-10). The ester group of sulfonamides was modified by selective hydrolysis and transesterification. Apovincaminol derivatives (14-16) were also prepared by reduction. In addition to the known cerebrovascular effects of the unsubstituted compounds (1,2) sulfonamides also show a significant peripheral vasodilator effect.

Chemistry of indoles carrying a basic function, Part 3. Synthesis of spiro[cyclopropane-1,3'[3H]indol]-2'(1'H)-ones with antihypoxic effects.

Hydroxyindolones (1-6, 15-16) were transformed into isatinylidenes (7, 9-13, 17-19) by dehydration with 4-toluenesulfonic acid. The dimer-type compounds (14, 20) were also isolated in a few cases. The obtained isatinylidenes were transformed into 3-spiro-cyclopropane-oxindoles (21-32) with dimethyloxosulfonium methylide. Compound 22 shows protective effects against hypobaric hypoxia and triethyltin induced brain edema.

Estimation of impurity profiles of drugs and related materials Part 15. Identification of minor impurities in cimetidine.

Besides several known impurities in cimetidine, two additional compounds at levels below 0.1% were detected by ion-pair reversed-phase high-performance liquid chromatography (HPLC). The impurities were isolated from crude cimetidine using normal-phase preparative HPLC. 1H and 13C NMR and mass spectrometric investigations revealed the structures of the impurities to be 2,5-bis[(N'-cyano-N"-methyl)guanidinoethylthiomethyl]-4-methylimid azole (VII) and 1,8-bis[(N'-cyano-N"-methyl)guanidino]-3,6-dithiaoctane (VIII). These structures were verified by synthesis of the impurities and comparison of the spectra and chromatographic (HPLC and TLC) retention data of the isolated and synthesized materials.

Synthesis, anti-GABA activity and preferred conformation of bicuculline and norbicuculline enantiomers.

Synthesis of erythro-(±)-[1SR,9RS]-norbicuculline and threo-(±)-[1SR,9SR]-noradlumidine from piperonal was performed using Bischler-Napieralski cyclization as a key step. Resolution gave rise to (+)-[1S,9R]-norbicuculline ([1S,9R] norBIC) and (-)-[1R,9S]-norbicuculline ([1R,9S] norBIC) in >99.5% enantiomeric purity. Bicuculline enantiomers were readily obtained by methylation of the latter products. [1S,9R]BIC was about 70 times more potent than [1R,9S] BIC as an inhbitor of GABA(A) receptor binding and was about 100 and 900 times more potent than [1S,9R] norBIC at pH 7.1 and 5.0 respectively. Similarly, [1S,9R] norBIC was much less potent than [1S,9R] BIC as an inhibitor of GABA-specific (36)Cl(-) ion flux. The observed increase of about two orders of magnitude in the in vitro biological activity caused by N2-CH(3) substitution in [1S,9R] norBIC was attributed to different conformations for erythro- and nor-erythro-bicucullines indicated by (1)H nuclear Overhauser enhancements of [1S,9R] BIC and [1S,9R] norBIC.

Inhibitors of lipid peroxidation among new pyrimido[1',6':1,2]pyrido[3,4-b]indoles.

A series of potent inhibitors of NADPH- and Fe(2+)-dependent lipid peroxidation has been found among new pyrimido[1'6':1,2]pyrido[3,4-b]indole derivatives. According to preliminary structure-activity relationship analysis the saturated pyrimidine moiety was responsible for this effect. Some members of this family were effective in a bilateral carotid occlusion model in mice, and some derivatives showed protective effect in a mouse head injury model.

Structural elucidation of two novel ergot alkaloid impurities in alpha-ergokryptine and bromokryptine.

Two novel natural derivatives (2 and 3) of the ergot alkaloid alpha-ergokryptine (1), as well as their synthetically brominated analogues (5 and 6) were isolated and identified by NMR and MS methods. Compounds 2 and 5 contain what appears to be a so far unknown natural amino acid building block. Complete 1H and 13C NMR assignments are given for compounds 1-6.

Vasodilator and angioprotective activity of 1-ethyl-1-hydroxyalkyl-octahydroindolo[2,3a]quinolizine derivates.

The blood flow enhancing activity of the homologue series of "trans" racemic 1-ethyl-1-hydroxyalkyl-1,2,3,4,6,7,12,12b-octahydroindolo[2, 3a]quinolizine (1) was studied in anesthetized dogs. It was found that the femoral vasodilator activity is the strongest for 1b, and decreases if the carbon chain is shortened (1a) or lengthened (1c). Also, a breakdown of vasodilation was observed with the racemic "cis" derivative (2). After resolution of 1b the optically active compound 3 retained the dilator capacity while 4 isomer lost it. Hence 3 (RHG-2981, vintoperol, CAS 106498-99-1) was selected for detailed pharmacological study. Dose-response studies performed in anesthetized dogs showed that vintoperol 0.03 mg/kg (i.v.) was more potent as peripheral vasodilator than buflomedil or pentoxifylline at doses ranging from 1 to 15 mg/kg. Similar results were observed during a 4-week cross-over test of maximal running distance of femoral ligated mice. The running performance, as measured by the rotating drum, showed a linear increase in the untreated control group (UCG) as a consequence of every day testing (= intensive endurance training). After bilateral femoral occlusion the maximal running distance of the mice fell off, and despite daily training it stagnated. If 0.3 or 1 mg/kg/d vintoperol or 10 mg/kg/d pentoxifylline was administered orally 4 days after the bilateral femoral occlusion, the maximal running distance increased. In the case of 1.0 mg/kg of vintoperol applied daily, the rate of enhancement approached, or even overtook, that of the UCG. 0.3 mg/kg/d of vintoperol showed less activity, however, this result is still about twice better than the effect of 10 mg/kg/d pentoxifylline.

Synthesis of vinca alkaloids and related compounds, XLIV: Synthesis of trifluoro-apovincaminic acid ester.

Via the intermediate iminium salt 8 the 21,21,21-trifluoro-apovincaminic acid ethyl ester (2), a derivative of CAVINTONR (1) was synthesized. The pharmacological effect of 2 changed dramatically compared with the parent compound.

Berbanes: a new class of selective alpha 2-adrenoceptor antagonists.

The alpha-adrenoceptor blocking properties of some berbanes have been studied and compared with those of idazoxan, yohimbine, phentolamine, and prazosin. Their effects on presynaptic alpha 2-adrenoceptors were studied on chemical neurotransmission of isolated rat vas deferens and longitudinal muscle strip of guinea pig ileum; xylazine or norepinephrine was employed as agonist. The alpha 1-adrenoceptor blocking activities of the berbanes were tested on isolated rat vas deferens and rabbit pulmonary artery by using phenylephrine or norepinephrine as agonist. The antagonistic activity of the berbanes and the reference compounds on alpha 2- and alpha 1-adrenoceptors was characterized by the apparent pA2 values. Of the compounds studied, [8aS*-(8a alpha,12a alpha,13a alpha)]-11 alpha-hydroxy-5,6,8a,9,10,11,12a,13,13,a-decahydro-8H-benzo[g]-1,3 -benzodioxolo[5,6-a]quinoli zine, 6d, proved to be the most selective antagonist at the presynaptic alpha 2-adrenoceptors (alpha 1:alpha 2 ratio = 1659). Since blockade of alpha 2-adrenoceptors located on noradrenergic axon terminals leads to an increase of norepinephrine release, this compound could have potential as an antidepressant agent.

Octahydroindolo[2,3-a]quinolizines and 3,4-dihydro-beta-carbolines as new inhibitors of human platelet aggregation.

Octahydroindolo[2,3-a]quinolizines and 3,4-dihydro-beta-carbolines proved to be powerful inhibitors of human platelet aggregation. They exhibited IC50 values two magnitudes lower than those of the commonly used cyclo-oxygenase inhibitors and no influence upon the routine parameters of blood coagulation was observed in vitro. Some of the compounds increased the vascular production of prostacyclin.

Investigations on the chemistry of berbanes. 10. Synthesis of raunescinone analogues with hypotensive and antihypertensive activity.

The pharmacologically active (methylenedioxy)- and diethoxyepialloberbane keto esters I have been synthesized with use of the readily available keto esters 2 as starting material. By choice of the appropriate reaction sequence both antipodes of keto ester 2a can be employed to provide any enantiomer of the desired raunescinone analogue 1a. Hypotensive, antihypertensive, and central depressant effects of 1a are described. The principle effect observed for 1a was a potent hypotensive and antihypertensive effect of long duration without depression of the central nervous system.

Pharmacodynamic investigation of (+/-)-salutaridine.

The alkaloid 5,6,8,14-tetradehydro-4-hydroxy-3, 6-dimethoxy-17-methyl-morphinan-7-one[+/-)-salutaridine) was found to possess 3H-gamma-aminobutyric acid (3H-GABA) displacing activity (IC50 less than 1 mumol/l) in rat brain synaptic membranes. The enhancement of specific 3H-diazepam binding by increasing concentration of (+/-)-salutaridine follows a maximum curve indicating (+/-)-salutaridine to be a partial agonist at the GABA/benzodiazepine receptor complex.