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PubMed2004

Synthesis, antitumour and antimicrobial activities of new peptidyl derivatives containing the 1,3-benzodioxole system.

Two series of 5 and 6-substituted 1,3-benzodioxole peptidyl derivatives were synthesized and evaluated as antitumour and antimicrobial agents. The compounds that could be conveniently prepared in a few steps processes from natural safrole have been characterised by IR and 1H-NMR spectroscopy. In vivo antitumor activity tests showed that some of the compounds were able to inhibit carcinoma S-180 tumour growth in mice. The in vitro antimicrobial activity of all compounds revealed that they are able to promote the growth of some organisms, including Bacillus subtilis.

Animals↗
PubMed2006

Synthesis and antitumour evaluation of peptidyl-like derivatives containing the 1,3-benzodioxole system.

In the scope of a research program aiming at the synthesis and pharmacological evaluation of novel possible antitumour prototype compounds, we described in this paper the synthesis of peptidyl-like derivatives containing the 1,3-benzodioxole system. The proliferation inhibitors tested against tumour cell lines identified the derivatives tyrosine (4f) and lysine (4 g) as the most active among them, presenting IC(50) values in micromolar range and are more active than Safrole. For the study on the embryonic development, Safrole did not show any selectivity in this latter assay, which indicates that Safrole acts as a 'cell cycle-nonspecific' inhibitory agent. However, compound 4f presented a fair antimitotic effect, mainly on third cleavage and blastulae stages (38% and 1.7% of normal development, at 10 microg/mL), suggesting a time-dependent activity and a 'cell cycle-specific' agent action. Neither derivatives revealed hemolytic action in assay with mouse erythrocytes.

Animals↗
PubMed2005

Benzodioxole derivatives as negative effectors of plant proteases.

Previous work demonstrated that a commercial formulation of piperonyl butoxide (PBO) did inhibit the activity of some plant proteolytic enzymes. In this paper, the effect of pure PBO and nine pure PBO homologues (PBOH) appropriately synthesized toward bromelain and papain was studied in hydrocarbon solution using the bis(2-ethylhexyl)sodium sulfosuccinate (AOT) reverse micellar system. This study establishes that the majority of these compounds show, in vitro, interesting protease inhibition activities. The benzodioxole and dihydrobenzofuran structures, in particular, 5-[2-(2-butoxyethoxy)ethoxymethyl]-benzo[1,3]dioxole (EN 1-40) and 6-[2-(2-butoxyethoxy)ethoxymethyl]-5-propyl-2,3-dihydrobenzofuran (EN 16-5), respectively, appear to be responsible for protease inhibition. Measures of octanol/water partition coefficients on PBO and PBOH have demonstrated that water solubility plays a fundamental role in the expression of protease inhibition activity.

Bromelains↗
PubMed1986

Derivatives of 1-(1,3-benzodioxol-5-yl)-2-butanamine: representatives of a novel therapeutic class.

The alpha-ethyl phenethylamine derivative 1-(1,3-benzodioxol-5-yl)-2-butanamine was prepared. An asymmetric synthesis was used to prepare the enantiomers of this compound and the related alpha-methyl homologue (MDA). The racemates and enantiomers of both compounds were evaluated in the two-lever drug discrimination assay in rats trained to discriminate saline from 0.08 mg/kg of LSD tartrate. Stimulus generalization occurred with the racemate and the R-(-) enantiomer of the alpha-methyl homologue and the S-(+) enantiomer of the alpha-ethyl primary amine. No generalization occurred with the other enantiomers or with the N-methyl derivatives of either series. Human psychopharmacology studies revealed that the N-methyl derivative of the title compound was nonhallucinogenic and that it had a new, novel psychoactive effect. It is suggested that this compound is the prototype of a new pharmacologic class that may have value in facilitating psychotherapy and that this class be designated as entactogens.

Adult↗
PubMed1977

Synthesis and adrenergic beta-blocking activity of some 1,3-benzodioxole derivatives.

A series of 1,3-benzodioxole derivatives was synthesized. We found four compounds (2,3,10 and 11 in Table IV) to have about the same order of beta-blocking activity as that of sotalol. In addition, it is of interest that some of the compounds (2-4) were found to have hypotensive activites, although they were about one-tenth of that of hydralazine. Sotalol did not produce any change in blood pressure, and propranolol raised the blood pressure.

Adrenergic beta-Antagonists↗
PubMed2005

Large amplitude out-of-plane vibrations of 1,3-benzodioxole in the S0 and S1 states: an analysis of fluorescence and excitation spectra by ab initio calculations.

We report the analytical expressions of the two-dimensional potential energy surfaces (PES) spanned by the puckering and flapping vibrations in the S0 and S1 states of 1,3-benzodioxole (BDO). Both PES are obtained from S0 and S1 energies computed on a grid of 2500 molecular geometries at the CASPT2 level. Both the S0 and S1 PES are anharmonic, and the planar geometry corresponds to a barrier that separates two minima at nonplanar geometries along the puckering/flapping deformations. Eigenvalues and eigenvectors of the mixed puckering/flapping modes are calculated by the Meyer flexible model. Improved vibronic levels, in better agreement with the observed spectra, are obtained by suitably optimized CASPT2 surfaces. To assign the lower-energy (0-500 cm(-1)) portion of emission and absorption spectra, we evaluate the band intensities by estimating the Franck-Condon factors between the puckering/flapping eigenvectors of the S0 and S1 states. From these calculations, we obtain a satisfactory assignment of the ground state IR spectra and of the fluorescence excitation spectrum. Both assignments are supported by the analysis of the vibrational structures of several single vibronic level (SVL) fluorescence spectra. The successful interpretation of these spectra shows that the S0 and S1 PES that we derive for BDO are substantially correct. The barrier heights in the two states are similar: 125.7 and 190.4 cm(-1) in S0 and in S1, respectively. In S0, the barrier is associated essentially with the puckering motion. In S1, it involves to a considerable extent also the flapping coordinate, whose vibrational frequency is much lower in S1 than in S0. This fact introduces a substantial Duschinsky effect in the S0-S1 transitions of BDO.

Journal Article↗
PubMed2003

Synthesis, chiroptical properties and absolute configuration of spiro[1,3-benzodioxole-methanocyclooct[b]indole].

The synthesis of chiral 1'H-spiro[1,3-benzodioxole-2,12'-[6',10']methanocyclooct[b]indole] 3, a fused polycyclic structure derived from bicyclo[3.3.1]nonane, was accomplished via the Fisher indolization reaction. Enantiomers of this structure were obtained by chiral HPLC enantiomer separation on a swollen microcrystalline triacetylcellulose column. Chiroptical properties of the resolved enantiomers containing indole and 1,2-methylenedioxybenzene chromophores were studied. Application of the sector rule to the 1,2-methylenedioxybenzene chromophore to establish the absolute configuration of this polycyclic structure did not lead to an unequivocal conclusion which is likely to be due to the transannular interaction of the chromophores. The enantiospecific synthesis from enantiomerically enriched (-)-(1R,5S)-bicyclo[3.3.1]nonane-2,9-dione 1 was performed to prove unequivocally the (+)-(6'R,10'S)-configuration of the title structure. This study demonstrates that semiempirical rules should be applied cautiously to the determination of the absolute configuration of molecules containing several chromophores.

Journal Article↗
PubMed2004

SSR240612 [(2R)-2-[((3R)-3-(1,3-benzodioxol-5-yl)-3-[[(6-methoxy-2-naphthyl)sulfonyl]amino]propanoyl)amino]-3-(4-[[2R,6S)-2,6-dimethylpiperidinyl]methyl]phenyl)-N-isopropyl-N-methylpropanamide hydrochloride], a new nonpeptide antagonist of the bradykinin B1 receptor: biochemical and pharmacological characterization.

The biochemical and pharmacological properties of a novel non-peptide antagonist of the bradykinin (BK) B(1) receptor, SSR240612 [(2R)-2-[((3R)-3-(1,3-benzodioxol-5-yl)-3-[[(6-methoxy-2-naphthyl)sulfonyl]amino]propanoyl)amino]-3-(4-[[2R,6S)-2,6-dimethylpiperidinyl]methyl]phenyl)-N-isopropyl-N-methylpropanamide hydrochloride] were evaluated. SSR240612 inhibited the binding of [(3)H]Lys(0)-des-Arg(9)-BK to the B(1) receptor in human fibroblast MRC5 and to recombinant human B(1) receptor expressed in human embryonic kidney cells with inhibition constants (K(i)) of 0.48 and 0.73 nM, respectively. The compound selectivity for B(1) versus B(2) receptors was in the range of 500- to 1000-fold. SSR240612 inhibited Lys(0)-desAr(9)-BK (10 nM)-induced inositol monophosphate formation in human fibroblast MRC5, with an IC(50) of 1.9 nM. It also antagonized des-Arg(9)-BK-induced contractions of isolated rabbit aorta and mesenteric plexus of rat ileum with a pA(2) of 8.9 and 9.4, respectively. Antagonistic properties of SSR240612 were also demonstrated in vivo. SSR240612 inhibited des-Arg(9)-BK-induced paw edema in mice (3 and 10 mg/kg p.o. and 0.3 and 1 mg/kg i.p.). Moreover, SSR240612 reduced capsaicin-induced ear edema in mice (0.3, 3 and 30 mg/kg p.o.) and tissue destruction and neutrophil accumulation in the rat intestine following splanchnic artery occlusion/reperfusion (0.3 mg/kg i.v.). The compound also inhibited thermal hyperalgesia induced by UV irradiation (1 and 3 mg/kg p.o.) and the late phase of nociceptive response to formalin in rats (10 and 30 mg/kg p.o.). Finally, SSR240612 (20 and 30 mg/kg p.o.) prevented neuropathic thermal pain induced by sciatic nerve constriction in the rat. In conclusion, SSR240612 is a new, potent, and orally active specific non-peptide bradykinin B(1) receptor antagonist.

Administration, Oral↗
PubMed1990

(+)-N-methyl-1-(1,3-benzodioxol-5-yl)-2-butanamine as a discriminative stimulus in studies of 3,4-methylenedioxy-methamphetamine-like behavioral activity.

The stimulus properties of 3,4-methylenedioxymethamphetamine (MDMA)-like compounds were studied in rats trained to discriminate saline from (+)-N-methyl-1-(1,3-benzodioxol-5-yl)-2-butanamine [(+)-MBDB] hydrochloride (7.18 mumol/kg; 1.75 mg/kg), the alpha-ethyl homolog of MDMA. In previous experiments with (+)-MBDB as a test drug, complete substitution was observed for MDMA but not for (+)-lysergic acid diethylamide or (+)-amphetamine. In the study reported here, the (+)-MBDB cue generalized to MDMA and the parent drug, 3,4-methylenedioxyamphetamine. All three drugs exhibited a similar stereoselectivity, the (+)-isomer having potency greater than the (-)-isomer. By contrast, the hallucinogens, (+)-lysergic acid diethylamide, 2,5-dimethoxy-4-methylamphetamine and mescaline and the psychostimulants (+)-amphetamine and (+)-methamphetamine did not substitute for (+)-MBDB. Cocaine produced partial substitution. The results support the hypothesis that the primary behavioral activity of MDMA-like compounds is unlike that of hallucinogens and stimulants and may represent the effects of a novel drug class, given the name entactogens. Although the mechanism of action for the discriminative stimulus properties of MDMA-like compounds is not known, there is evidence that presynaptic serotonergic, but not dopaminergic, mechanisms are critical. Finally, 5,6-methylenedioxy-2-aminoindan a non-neurotoxic 3,4-methylenedioxyamphetamine rigid analog that was previously found to substitute for MDMA but not for (+)-lysergic acid diethylamide was found in the study described here to substitute completely for (+)-MBDB. The N-methyl derivative 5,6-methylenedioxy-2-methylminoindan produced similar results. The demonstration of entactogen-like discriminative stimulus properties, for drugs devoid of neuronal degenerative toxicity potential, serves as evidence of the independent mechanisms for these effects in rats.

3,4-Methylenedioxyamphetamine↗
PubMed1987

Assessment of six benzyl-1,3-benzodioxole compounds for anti-juvenile hormone activity in Culex pipiens.

Fourth instar larvae of Culex pipiens were exposed to six benzyl-1,3-benzodioxole derivatives to assess the effectiveness of these compounds as anti-juvenile hormone agents. Mortality ranging from between 18 and 99% was observed in larvae and early pupae but the surviving adults showed no clearly defined anti-juvenile hormone effects. Adult effects included a reduction in number of eggs developed and the presence of degenerating eggs 4 days after the blood meal.

Animals↗
PubMed1985

Structure-function studies with derivatives of 6-benzyl-1,3-benzodioxole, a new class of synthetic compounds which inhibit tubulin polymerization and mitosis.

A new class of synthetic antineoplastic compounds, derivatives of 6-benzyl-1,3-benzodioxole, has significant antimitotic activity. These compounds inhibit microtubule assembly and are competitive inhibitors of the binding of colchicine to tubulin. Both their structure and their partial inhibition of tubulin-dependent GTP hydrolysis indicate that they are most comparable to podophyllotoxin of all known antimitotic drugs. Maximum activity required an intact dioxole ring, a methoxy or ethoxy substituent at position 5, and, on the benzyl moiety at position 6, a para-methoxy group. Additional methoxy groups on the benzyl substituent, to increase the apparent structural similarity to podophyllotoxin, resulted in major reduction of the antitubulin activity of these drugs.

Animals↗
PubMed1996

Novel benzodioxan derivative, 5-[3-[((2S)-1,4-benzodioxan-2-ylmethyl) amino]propoxy]-1,3-benzodioxole HCl (MKC-242), with anxiolytic-like and antidepressant-like effects in animal models.

Behavioral effects of MKC-242 (5-{3-[((2>)-1,4-benzodioxan-2-ylmethyl)amino] propoxy}-1,3-benzodioxole CHl), a novel and selective serotonin 1A receptor agonist, were investigated in rats and mice and compared against those of diazepam, buspirone and tandospirone. MKC-242 (0.0625-0.25 mg/kg, p.o.) significantly increased punished drinking in water-deprived rats. The reference compounds also increased punished drinking at doses of 10 to 40 mg/kg, p.o. The increase by MKC-242 was blocked by N-tert-butyl-3-(4-(2-methoxypenyl)piperazin-1-yl) -2-phenylpropanamide, a serotonin 1A receptor antagonist. MKC-242 (0.1-0.5 mg/kg, p.o.) also increased social interaction under high light and unfamiliar conditions in rats. It had weak benzodiazepine-like side effects in mice. MKC-242 (1, 3 mg/kg, p.o.) attenuated the reduction of locomotion caused by restraint stress in rats, the same effects were observed on both buspirone (100 mg/kg, p.o.) and tandospirone (100 mg/kg, p.o.). In the forced swimming test in rats, MKC-242 (0.3-3 mg/kg, i.p.), 8-hydroxy-2-(di-n-propylamino) tetralin (1, 3 mg/kg, i.p.) and amitriptyline (30 mg/kg, i.p.) reduced immobility, although diazepam, buspirone and tandospirone did not. The reduction by MKC-242 and 8-OH-DPAT was antagonized by N-tert-butyl-3-(4-(2-methoxyphenyl)piperazin-1-yl) -2-phenylpropanamide. Moreover, the reduction was also blocked by 1-(2--pyrimidinyl)piperazine (1-PP), a common metabolite of buspirone and tandospirone. These findings suggest that MKC-242 possesses potent anxiolytic and antidepressant properties that are mediated via an activation of serotonin 1A receptors.

Animals↗
PubMed1996

Neuroendocrine pharmacology of three serotonin releasers: 1-(1,3-benzodioxol-5-yl)-2-(methylamino)butane (MBDB), 5-methoxy-6-methyl-2-aminoindan (MMAi) and p-methylthioamphetamine (MTA).

Serotonin (5-hydroxytryptamine, 5-HT)-releasing drugs are important experimental tools to examine the role of serotonergic nerve terminals in the secretion of hormones. The drugs 1-(1,3-benzodioxol-5-yl)-2-(methylamino)butane (MBDB), 5-methoxy-6-methyl-2-aminoindan (MMAI) and p-methylthioamphetamine (MTA) have been suggested to be 5-HT releasers. The present study characterized MBDB, MMAI and MTA by using their effects on the secretion of the hormones adrenal corticotrophin (ACTH), corticosterone, prolactin, oxytocin and renin. The time course of the effect of MBDB, MMAI and MTA (5 mg/kg, i.p.) showed that the peak effect on plasma ACTH occurred 10 min after the injection, whereas the prolactin response did not reach a maximum until 30 min after injection. MBDB increased plasma renin concentration within 10 min, whereas the effect of MTA was significant only at 30 min after injection. All three 5-HT releasers decreased HR (within 5 min) and blood pressure (at 15 min after injection). MBDB, MMAI and MTA increased plasma ACTH, corticosterone, prolactin and renin levels in a dose-dependent manner, whereas no changes were observed in plasma vasopressin concentrations. MTA and MMAI, but not MBDB, significantly increased plasma oxytocin concentrations in a dose-dependent manner. Pretreatment of rats with fluoxetine blocked the ACTH response to MBDB and MMAI, but not to MTA. The prolactin response to all three 5-HT releasers was blocked by fluoxetine. The oxytocin response to MTA and MMAI was inhibited by fluoxetine. The renin responses to all three 5-HT releasers were not significantly inhibited by fluoxetine. The results suggest that MBDB, MMAI and MTA can increase the secretion of several hormones, at least in part, through stimulation of serotonergic neurotransmission. However, these three 5-HT releasers seem to have effects on other (and as yet uncharacterized) mechanisms that can stimulate the secretion of some hormones.

3,4-Methylenedioxyamphetamine↗