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PubMedDate not supplied

RS-102221: a novel high affinity and selective, 5-HT2C receptor antagonist.

The 5-HT2C receptor is one of three closely related receptor subtypes in the 5-HT2 receptor family. 5-HT2A and 5-HT2B selective antagonists have been described. However, no 5-HT2C selective antagonists have yet been disclosed. As part of an effort to further explore the function of 5-HT2C receptors, we have developed a selective 5-HT2C receptor antagonist, RS-102221 (a benzenesulfonamide of 8-[5-(5-amino-2,4-dimethoxyphenyl) 5-oxopentyl]-1,3,8-triazaspiro[4.5]decane-2,4-dione). This compound exhibited nanomolar affinity for human (pKi = 8.4) and rat (pKi = 8.5) 5-HT2C receptors. The compound also demonstrated nearly 100-fold selectivity for the 5-HT2C receptor as compared to the 5-HT2A and 5-HT2B receptors. RS-102221 acted as an antagonist in a cell-based microphysiometry functional assay (pA2 = 8.1) and had no detectable intrinsic efficacy. Consistent with its action as a 5-HT2C receptor antagonist, daily dosing with RS-102221 (2 mg/kg intraperitoneal) increased food-intake and weight-gain in rats. Surprisingly, RS-102221 failed to reverse the hypolocomotion induced by the 5-HT2 receptor agonist 1-(3-chlorophenyl)piperazine (m-CPP). It is concluded that RS-102221 is the first selective, high affinity 5-HT2C receptor antagonist to be described.

Animals↗

PubMed2002

Non-nucleoside HIV-1 reverse transcriptase (RT) inhibitors: past, present, and future perspectives.

Along with nucleoside reverse transcriptase inhibitors (NRTIs) and protease inhibitors (PIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs) have gained a definitive and important place in the treatment of HIV-1 infections, and are in rapid development. These compounds can be grouped into two classes: the first generation NNRTIs, mainly discovered by random screening, and the second generation NNRTIs, developed as a result of comprehensive strategies involving molecular modelling, rationale-based drug synthesis, biological and pharmacokinetic evaluations. The recent boom of NNRTIs is mainly due to their antiviral potency, high specificity and low toxicity. The rapid emergence of drug-resistant HIV-1 strains induced by the first generation drugs is a disadvantage bypassed, in part, by the broad spectrum second generation NNRTIs. Starting from the first generation, this review will focus on the second generation NNRTIs dealing with the recent and most interesting published results, highlighting the guidelines for the development of a third generation of NNRTIs.

Acquired Immunodeficiency Syndrome↗

PubMed2002

Marcfortine and paraherquamide class of anthelmintics: discovery of PNU-141962.

Three distinct chemical classes for the control of gastrointestinal nematodes are available: benzimidazoles, imidazothiazoles, and macrocyclic lactones. The relentless development of drug resistance has severely limited the usefulness of such drugs and the search for a new class of compounds preferably with a different mode of action is an important endeavor. Marcfortine A (1), a metabolite of Penicillium roqueforti, is structurally related to paraherquamide A (2), originally isolated from Penicillium paraherquei. Chemically the two compounds differ only in one ring; in marcfortine A, ring G is six-membered and carries no substituents, while in paraherquamide A, ring G is five-membered with methyl and hydroxyl substituents at C14. Paraherquamide A (2) is superior to marcfortine A as a nematocide. 2-Desoxoparaherquamide A (PNU-141962, 53) has excellent nematocidal activity, a superior safely profile, and is the first semi-synthetic member of this totally new class of nematocides that is a legitimate candidate for development. This review describes the chemistry, efficacy and mode of action of PNU-141962.

Animals↗

PubMed1996

Structure-antigastrin activity relationships of new spiroglumide amido acid derivatives.

A series of new spiroglumide amido acid derivatives was synthesized and evaluated for their ability to inhibit the binding of cholecystokinin (CCK) to guinea pig brain cortex (CCKB receptors) and peripheral rat pancreatic acini (CCKA receptors), as well as to inhibit in vitro the gastrin-induced Ca2+ increase in rabbit gastric parietal cells. Appropriate chemical manipulations of the structure of spiroglumide (CR 2194), i.e., (R)-4-(3,5-dichlorobenzamido)-5-(8-azaspiro[4.5]decan- 8-yl)-5-oxopentanoic acid, led to potent and selective antagonists of CCKB/gastrin receptors. Structure-activity relationships are discussed. Some of these new derivatives, as, for example, compound 54 (CR 2622), i.e., (S)-4-[[(R)-4'-[(3,5-dichlorobenzoyl)-amino]-5'-(8- azaspiro[4.5]decan-8-yl)-5'-oxo-pentanoyl]amino]-5- (1-naphthylamino)-5-oxopentanoic acid, exhibit activity 70-170 times greater than that of spiroglumide, depending upon the model used (IC50 = 2 x 10(-8) vs 140 x 10(-8) mol in binding inhibition of [3H]-N-Me-N-Leu-CCK-8 in guinea pig brain cortex and IC50 = 0.7 x 10(-8) vs 122.3 x 10(-8) mol in inhibition of gastrin-induced Ca2+ mobilization in parietal cells of rabbit, respectively). Computer-assisted conformational analysis studies were carried out in order to compare the chemical structure of both the agonist (pentagastrin) and the antagonist (54).

Animals↗

PubMed2003

Dietary ginger constituents, galanals A and B, are potent apoptosis inducers in Human T lymphoma Jurkat cells.

The effects of the constituents isolated from ginger species including curcumin, 6-gingerol and labdane-type diterpene compounds on cell proliferation and the induction of apoptosis in the cultured human T lymphoma Jurkat cells were studied. Among the tested compounds, galanals A and B, isolated from the flower buds of a Japanese ginger, myoga (Zingiber mioga Roscoe), showed the most potent cytotoxic effect. Exposure of Jurkat human T-cell leukemia cells to galanals resulted in the induction of apoptotic cell death characterized by DNA fragmentation and caspase-3 activation. The mitochondrial damage pathway was suggested to be involved in galanal-induced apoptosis because the treatment of cells with galanals induced mitochondrial transmembrane potential (DeltaPsim) alteration and cytochrome c release. The anti-apoptotic Bcl-2 protein was downregulated by the galanal treatment together with enhancement of the Bax expression. In conclusion, the results from this study provide biological evidence that ginger-specific constituents other than curcuminoids are potential anticancer agents.

Apoptosis↗

PubMed2000

Adenosine is an agonist of the growth hormone secretagogue receptor.

Growth hormone secretagogues (GHSs) are synthetic compounds that induce GH release in several species, including man. The aim of the current study was to identify hypothalamic GHS receptor (GHS-R) agonists. This led to the discovery of adenosine as a GHS-R agonist. We demonstrate that adenosine as well as the A1 adenosine receptor agonist N6-R-phenylisopropyladenosine (R-PIA) induce calcium responses, with EC50 values of 50 nM and 0.5 nM, respectively, in cells which express recombinant human GHS-R. However, neither compound induces a calcium response in nontransfected cells. Binding experiments show that adenosine and the GHS compound MK-0677 bind to membranes from GHS-R expressing cells with nearly identical Bmax values (2.6 +/- 0.1 x 10(-10) mol/mg protein for adenosine and 2.0 +/- 0.3 x 10(-10) mol/mg protein for MK-0677). However, no binding to membranes from nontransfected cells could be detected. Furthermore, we show that the IC50 values for inhibition of the adenosine, R-PIA, and GHS induced calcium responses by the GHS-R antagonist [D-Arg1, D-Phe5, D-Trp7,9, D-Leu11]-substance P are similar. These findings strongly suggest that adenosine and R-PIA are agonists of the GHS-R. Interestingly, neither adenosine nor R-PIA were able to induce GH release from rat pituitary cells in vitro. The implications of the latter finding is discussed.

Adenosine↗

PubMed1977

Differentiation of opiate and neuroleptic receptor binding in rat brain.

For 6 large series of compounds derived from the piperidine moieties of spiperone, pimozide, haloperidol, pethidine, fentanyl and 4-methocarboxy-fentanyl, IC50 values were determined in the opiate and neuroleptic binding assay using [3H]-fentanyl and [3H]-haloperidol as ligands, respectively. The specificity and difference between both receptors were demonstrated on the basis of several criteria (1) the sterospecificity of the binding (2) the significant correlation between the in vitro activity of the drugs and their pharmacological potency in vivo, not withstanding some discrepancies which are probably of pharmacokinetic and/or metabolic origin (3) the ability to discriminate between morphinomimetic and neuroleptic drugs by the differential affinity for their specific receptro (4) the structure--activity relationships derived from the in vitro data indicating that the structural requirements for high affinity binding in vitro parallel those for high in vivo potency (5) a demonstration, on the basis of physicochemical principles, of the difference in binding mechanism between morphinomimetics and neuroleptics to their respective receptor.

Animals↗

PubMed1998

Prediction of in vivo nonlinear first-pass hepatic metabolism of YM796 from in vitro metabolic data.

Recent cumulative evidence suggests the possibility of predicting the in vivo metabolic clearance and/or hepatic availability (Fh) from in vitro metabolism data under linear conditions. Under nonlinear conditions, however, it is essential to consider the rate constant for the absorption (ka) for predicting Fh after oral administration, because the time profiles for the portal vein concentration depends on ka. In our study, we numerically solved the dispersion model under nonlinear conditions to propose a method to predict Fh after oral administration by taking ka into consideration. As a model compound, (S)-(-)-2,8-dimethyl-3-methylene-1-oxa-8-azaspiro [4,5] decane-L-tartrate monohydrate (YM796) was used. After oral administration, we found that the dose-normalized AUC (AUCoral/dose) was markedly increased in rats from 5.0 x 10(-6) to 33 x 10(-6) hr/ml.kg as the dose increased from 1 to 10 mg/kg, whereas the same value was relatively constant in dogs (87.7 x 10(-6) to 105 x 10(-6) hr/ml.kg at 1 to 10 mg/kg) and in humans (1260 x 10(-6) to 1768 x 10(-6) hr/ml.kg at 5 to 60 mg/body). Kinetic analysis indicated that AUCoral could be accurately predicted at each dose if ka value was assumed as 0.07 min-1 for all animal species examined in our study. These results suggest that it is possible to predict Fh even if the metabolism is composed of non-linear process by considering the absorption rate into the portal vein.

Absorption↗

PubMed1993

Further assessment of the antagonist properties of the novel and selective 5-HT1A receptor ligands (+)-WAY 100 135 and SDZ 216-525.

In vitro biochemical and electrophysiological methods were used to assess the potential antagonist properties of the novel compounds (+)-WAY 100 135 [N-tert-butyl-3,4-(2-methoxyphenyl)piperazin-1-yl-2- phenylpropanamide dihydrochloride] and SDZ 216-525 [methyl 4-(4-(4-(1,1,3-trioxo-2H-1,2-benziosothiazol-2-yl)butyl)- 1-piperazinyl)1H-indole-2-carboxylate] at pre- (i.e. somatodendritic autoreceptors) and postsynaptic 5-HT1A receptors in the rat brain. Both (+)-WAY 100 135 and SDZ 216-525 were pure antagonists at postsynaptic 5-HT1A receptors negatively coupled to adenylate cyclase in rat hippocampal membranes. Competitive prevention of the inhibition by the 5-HT1A receptor agonists 8-OH-DPAT [8-hydroxy-2-(di-n-propylamino)tetralin], 5-HT (5-hydroxytryptamine), S-20499 [(+)-4-(N-(5-methoxychroman-3-yl)-N-propylamino)butyl-8-azaspir o(4,5)decane- 7,9-dione] and lesopitron occurred with a pA2 of 8.7 for (+)-WAY 100 135 and 9.9 for SDZ 216-525. The higher potency of the latter compound was also noted at the level of presynaptic 5-HT1A receptors where both (+)-WAY 100 135 and SDZ 216-525 prevented the negative influence of 5-HT1A receptor agonists (8-OH-DPAT, flesinoxan or lesopitron) on the nerve impulse flow within dorsal raphe nucleus 5-HT neurones in brain stem slices. At high concentrations, both (+)-WAY 100 135 (> 1 microM) and SDZ 216-525 (> or = 0.1 microM) inhibited the spontaneous cell discharge through different mechanisms. The blockade of alpha 1-adrenoceptors by (+)-WAY 100 135 apparently accounted for its inhibitory influence on the firing of 5-HT neurones, whereas 5-HT1A receptor agonist properties were responsible for the effect of SDZ 216-525. Although approximately 10 times less potent than SDZ 216-525, (+)-WAY 100 135 is therefore a pure antagonist at both pre- and postsynaptic 5-HT1A receptors in the rat brain.

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

PubMed1999

Potent antinociceptive effects of TRK-820, a novel kappa-opioid receptor agonist.

TRK-820, a new type of 4,5-epoxymorphinan derivative, was investigated in vivo for antinociceptive activities and its selectivity on various opioid receptors in mice. TRK-820 given s.c. or p.o. was found to be 351- and 796-fold more potent than U50,488H with acetic acid-induced abdominal constriction test. The duration of the antinociceptive effect produced by TRK-820 was longer than that produced by mu-opioid receptor agonist morphine or other kappa-opioid receptor agonists. In addition, with four other antinociceptive assays, low temperature hot plate (51 degrees C), thermal tail flick, mechanical tail pressure and tail pinch tests, TRK-820 was also found to be 68- to 328-fold more potent than U-50488H, and 41- to 349-fold more potent than morphine in producing antinociception, as comparing the weight of the different compound. However, TRK-820 was less active in inhibiting the high temperature (55 degrees C) hot plate response. The antinociceptive effects produced by TRK-820 were inhibited by nor-BNI, but not by naloxone or naltrindole (NTI) with the abdominal constriction test, indicating that the antinociception is selectively mediated by the stimulation of kappa-, but not mu- or delta-opioid receptors. Co-administration of TRK-820 with morphine slightly enhanced the antinociception induced by morphine in the mouse hot plate test. On the other hand, pentazocine significantly reduced the morphine-induced antinociception. TRK-820 produced sedation at doses, which are much higher than the doses for producing antinociception. These results indicate that the potent antinociception induced by TRK-820 is mediated via the stimulation of kappa-, but not mu- or delta-opiod receptors.

Administration, Oral↗

PubMed1994

Alpha-spirocyclopentyl- and alpha-spirocyclopropyl-gamma-butyrolactones: conformationally constrained derivatives of anticonvulsant and convulsant alpha,alpha-disubstituted gamma-butyrolactones.

To further study the putative gamma-butyrolactone site of the GABAA/chloride channel complex, constrained derivatives of convulsant and anticonvulsant alpha,alpha-disubstituted gamma-butyrolactones (alpha-spirocyclopropyl- and alpha-spirocyclopentyl-gamma-butyrolactones) were synthesized and evaluated biologically. Most of the spirocyclopropyl agents were anticonvulsants when tested against pentylenetetrazole-induced seizures in mice. These agents effectively displaced 35[S]-tert-butylbicyclophosphorothionate (35[S]-TBPS), a ligand for the picrotoxin binding site of the GABAA/chloride channel, from rat neuronal membranes and affected the GABA-mediated current in hippocampal neurons. The monomethyl-substituted spirocyclopropyl agent with a methyl group cis to the carbonyl (15) potentiates GABA-induced current whereas the trans derivative (16) blocks the current. The only anticonvulsant in the spirocyclopentyl series was the unsubstituted spirocyclopentyl compound 2. All the other substituted spirocyclopentyl targets were inactive in vivo at the highest dose tested except for convulsant 9, which has a trans 2,5-dimethyl-substituted cyclopentyl ring. All the spirocyclopentyl derivatives displaced 35[S]-TBPS from rat neuronal membranes very effectively, and they also all potentiated GABA-induced chloride current except for convulsant 9 which blocked the current. From the data obtained in this investigation, it appears that when the volume occupied above and below the lactone ring is as large as that occupied by spirocyclopentyl agent 9, convulsant activity is observed. Groups with less volume in these areas either are inactive in the behavioral test or have anticonvulsant activity. When bound to the GABAA/chloride channel, the larger molecules may stabilize the closed state of the channel whereas the smaller molecules may stabilize the open state.

4-Butyrolactone↗

PubMed2001

Angiosperm bark volatiles disrupt response of Douglas-fir beetle, Dendroctonus pseudotsugae, to attractant-baited traps.

Antennally active, bark-derived, angiosperm volatiles were tested singly and in groups for their ability to disrupt the response of the Douglas-fir beetle (DFB), Dendroctonus pseudotsugae, to attractant-baited multiple-funnel traps. One compound, conophthorin, was active alone in reducing the response of beetles to the baited traps. Further experiments showed disruptive activity in two aliphatic green-leaf alcohols [1-hexanol and (Z)-3-hexen-1-ol], as well as guaiacol and benzyl alcohol, and three aliphatic aldehydes [nonanal, hexanal, and (E)-2-hexenal] but not in two aromatic aldehydes (benzaldehyde and salicylaldehyde). Every binary combination that included conophthorin or any two of the other groups, except aromatic aldehydes, significantly reduced the response of beetles to baited traps. Various ternary mixtures and the complete mixture of all the groups were generally the most effective treatments. These results provide evidence that DFBs recognize and avoid nonhosts while flying rather than landing on candidate hosts and testing them while in contact with the tree. Nonhost angiosperm bark volatiles may have practical utility on their own or in combination with the antiaggregation pheromone 3-methylcyclohex-3-en-1-one (MCH) to protect single trees, logs, or stands from attack by the DFB.

Alcohols↗

PubMed1992

Increased rates of punished responding produced by buspirone-like compounds in rats.

Buspirone has been reported to have effects on punished responding in rats which are considerably smaller and less reliable than those produced by benzodiazepines. A recent study, however, found that buspirone and ipsapirone increased operant responding suppressed by a stimulus which preceded unavoidable shock, suggesting that conditioned emotional response protocols may be more sensitive than punishment procedures. This hypothesis was not supported by the results of the present study. The food-reinforced lever pressing of rats was maintained by a multiple VI schedule with punished and unpunished components. The experimental parameters were similar to those used in the previous conditioned emotional response study. The benzodiazepines, chlordiazepoxide and clorazepate, as well as buspirone (at one dose) and ipsapirone (at several doses), increased rates of punished responding. The 5-hydroxytryptamine-1A receptor ligands 8-hydroxy-2-(di-n-propylamino)tetralin and MDL 73005EF did not reliably produce similar effects, although increased rates of punished responding were seen in some animals. Haloperidol, imipramine and idazoxan did not increase punished response rates. Although the increases in punished responding produced by buspirone were smaller than those produced by chlordiazepoxide and clorazepate, the effect of ipsapirone was quantitatively similar to that of the benzodiazepines.

Animals↗

PubMed1994

Are the cardiovascular effects and '5-HT syndrome' induced by MDL 73,975 and flesinoxan in the dog mediated by 5-HT1A receptors?

The cardiovascular effects of the 5-HT1A receptor agonists MDL 73,975 (8-[2-(2,3-dihydro-8-methoxy-1,4-benzodoxin-2-yl)methylaminol++ +]-ethyl]-8- azaspiro[4,5]decane-7,9-dione hydrochloride) and flesinoxan (10-300 micrograms/kg subcutaneously, s.c.), the 5-HT1A receptor antagonist NAN 190 (2-[4-[4-(2-methoxyphenyl)-1-piperazinyl]butyl]-1H-isoindole-1,3(2H)- dione,1,2-ethanedioate), and the alpha 1-adrenoceptor antagonist prazosin have been investigated in conscious normotensive and renal hypertensive dogs. In normotensive dogs the increases in heart rate and respiratory rate induced by both agonists were dose-related, as were the decreases in systolic and diastolic blood pressure induced by MDL 73,975. Both compounds caused a dose-related increase in the intensity of the '5-HT syndrome'. After pretreatment with NAN 190 (100 micrograms/kg s.c.) the increases in heart rate, respiratory rate and symptoms of the '5-HT syndrome' were significantly reduced but the decreases in systolic and diastolic pressure were additive. Pretreatment with prazosin (100 micrograms/kg s.c.) antagonized the '5-HT syndrome' and the increase in respiratory rate. Similar responses were evident in renal hypertensive dogs. Tolerance did not develop to the increases in heart rate, respiratory rate and manifestations of the '5-HT syndrome' in normotensive dogs during 5 days of treatment with MDL 73,975 or flesinoxan. In conclusion, MDL 73,975 and flesinoxan induced a 5-HT1A receptor-mediated fall in blood pressure but the changes in heart rate, respiratory rate and the '5-HT syndrome' are probably mediated by alpha 1-adrenoceptors.

Analysis of Variance↗

PubMed1991

Pharmacologic profile of a new anxiolytic, DN-2327: effect of Ro15-1788 and interaction with diazepam in rodents.

In order to characterize the pharmacologic profile of DN-2327, an isoindoline benzodiazepine (BZD) receptor ligand, its interactions with Ro15-1788 and diazepam were analyzed in rodents. The anti-conflict action of DN-2327 in two conflict tests using rats, the punished water-lick conflict (Vogel conflict) and the punished bar-pressing conflict test, was completely attenuated by treatment with Ro15-1788. The anti-convulsive (pentylenetetrazol [PTZ] induced convulsion) effect of DN-2327 was also reduced by Ro15-1788. These results suggest that the anti-conflict and anti-convulsive actions of DN-2327 may be mediated via BZD receptors. On the other hand, DN-2327 only slightly affected the motor coordination in mice and rats, as estimated by the inclined screen test and the climbing test, respectively; however, the compound attenuated the motor incoordination produced by diazepam. Furthermore, the pentobarbital potentiating effect of diazepam was reduced by pretreatment with DN-2327 in mice. In the Vogel conflict test, additive effects were observed upon the conflict test, additive effects were observed upon the concomitant administration of subeffective doses (5 mg/kg, PO) of DN-2327 and diazepam. DN-2327 at 20 mg/kg, PO, did not reduce but slightly potentiated the anti-conflict effect of the maximum effective dose of diazepam. For PTZ-induced convulsions, DN-2327, 0.5 and 20 mg/kg, PO, doses which produced partial and complete anti-convulsive effects, respectively, in rats did not reduce but increased additively the effects of diazepam. DN-2327 at 10 and 20 mg/kg, PO, doses which both produced partial anti-convulsive effects in mice, showed an additive effect with the partial effects of diazepam.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1993

Cytostatic and cytotoxic properties of the marine product bistratene A and analysis of the role of protein kinase C in its mode of action.

Bistratene A is a polyether which was isolated from the marine ascidian Lissoclinum bistratum Sluiter. The hypothesis has been tested that the cytostatic effect of bistratene A is mediated by modulation of protein kinase C (PKC). Human-derived A549 lung and MCF-7 breast adenocarcinoma cells are extremely sensitive to growth inhibition induced by activators of PKC. Therefore, the effect of bistratene A on these cell lines was compared with that of the known PKC activator 12-O-tetradecanoylphorbol-13-acetate (TPA). The ability of bistratene A to modulate PKC activity in cellular cytosol was assessed to determine the involvement of PKC in the induction of cytostasis. Bistratene A inhibited the growth of both cell lines and initial seeding density determined its cytostatic potency. IC50 values were between 1.0 and 2.9 nM. Bistratene A also had a profound effect on the colony forming ability of A549 cells, preventing clonal growth at 5 nM. Using the incorporation of [3H]thymidine into cells to assess DNA synthetic activity and the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay to define cytotoxicity, the compound was found to have both cytostatic and cytotoxic properties. Bistratene A decomposed by 50% after only 2.8 hr in cell culture medium. TPA induced rapid motility and the formation of a network of branched colonies in both cell lines grown on Matrigel, whereas bistratene A did not cause the same effect. Cell cytosol was analysed for phorbol ester binding sites after treatment with bistratene A or TPA. Incubation with TPA (10 nM) caused a reduction in binding sites to 57% of binding in control cells after 30 min and to 35% after 24 hr. Bistratene A did not cause a significant change in binding sites. Assays of PKC activity in cellular cytosol revealed that bistratene A was unable to activate or inhibit the enzyme at concentrations of up to 10 microM. The results suggest that bistratene A is an exquisitely potent cytostatic agent in the two cell lines studied, but modulation of PKC is not involved in the mode of action by which it elicits this effect.

Acetamides↗

PubMed2006

Discovery of fatty acid ester metabolites of spirolide toxins in mussels from Norway using liquid chromatography/tandem mass spectrometry.

Cultured mussels sampled in the spring of 2002 and 2003 from Skjer, a location in the Sognefjord, Norway, tested positive in the mouse bioassay for lipophilic toxins. In a previous report, it was established that a number of spirolides, cyclic imine toxins produced by the phytoplankton Alexandrium ostenfeldii, were present in the mussels and were responsible for the observed toxicity. The main toxin proved to be a new compound named 20-methyl spirolide G. In subsequent studies, a delayed onset of spirolide-like symptoms in the mouse bioassay exceeding the usual time limit of 20 min was observed in some samples, with symptoms and death appearing as long as 45-50 min after injection. It is well known that shellfish can extensively metabolize other toxins, such as okadaic acid and the dinophysistoxins, to fatty acid acyl esters and it is also known that a delayed onset of toxic symptoms with such metabolites can occur. Analyses performed with liquid chromatography/tandem mass spectrometry (LC/MS/MS) have revealed a complex mixture of esters of 20-methyl spirolide G in the contaminated mussels. Precursor ion scanning has delineated the range of fatty acid esters involved, while product ion scanning has provided information on structure. Identity was also supported through reaction of 20-methyl spirolide G with palmitic anhydride, which produced a derivative with a retention time and spectrum identical with one putative metabolite, 17-O-palmitoyl-20-methyl spirolide G.

Acylation↗

PubMed1998

Characterization of acylfulvene histiospecific toxicity in human tumor cell lines.

PURPOSE: Acylfulvene derivatives demonstrate marked efficacy in xenograft carcinoma models as compared with the parent illudin compounds. To elucidate the increased therapeutic efficacy of acylfulvene analogs, we compared them with the illudin compounds in terms of their in vitro cytotoxicity, cellular accumulation and DNA incorporation. METHODS: The cytotoxicity of various acylfulvene analogs was tested in vitro against a variety of tumor cell lines. Radiolabelled acylfulvene analog was prepared and used for cellular accumulation and DNA incorporation studies. RESULTS: The prototype acylfulvene analog retained selective histiospecific toxicity towards myeloid leukemia and various carcinoma cell lines. In vitro killing of tumor cells by acylfulvene required up to a 30-fold increase in molecules per cell, as compared with illudin S, indicating that acylfulvene was less toxic on a cellular level. At equitoxic concentrations, acylfulvene incorporation into genomic tumor cell DNA was equivalent to illudin S suggesting that cellular metabolism has a role in acylfulvene cytotoxicity. Analysis of cellular accumulation of acylfulvene into tumor cells revealed a markedly higher Vmax for tumor cells, and a lower Vd for diffusion accumulation into other cells. CONCLUSIONS: The combination of higher Vmax and lower Vd may explain the increased in vivo efficacy of acylfulvene.

Antibiotics, Antineoplastic↗