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PubMed1977

Excretion of pyrrolic metabolites in the bile of rats given the pyrrolizidine alkaloid retrorsine or the bis-N-ethylcarbamate of synthanecine A.

(1) A comparison has been made in male rats between the biliary excretion of pyrrolic metabolites from the pyrrolizidine alkaloid retrorsine and a synthetic analogue 1-methyl-2,3-pyrroline-bis-N-ethyl-carbamate (Synthanecine A bis-N-ethylcarbamate). (2) When bile duct-cannulated rats were given retrorsine (40 mg/kg) and the bile collected at 1 h intervals, the relative concentration of pyrrolic metabolites was greatest in the first 1 h sample and was negligibly small by 7 h after dosing. By 7 h, about 25% of the dose had been excreted as pyrrolic metabolites. (3) In rats given [3H]synthanecine A bis-N-ethylcarbamate (40 mg/kg), the amounts of radioactivity and the relative levels of pyrrolic metabolites in the bile were greatest in the first 0.5 h sample and became negligibly small by 4 h after dosing. Within this time, about 25% of the dose had been excreted as [3H]radioactivity in the bile only about 5% as pyrrolic metabolites. (4) When rats were given [3H]2,3-bishydroxymethyl-1-methyl pyrrole (10 mg/kg), a proposed pyrrolic metabolite of synthanecine A bis-N-ethylcarbamate, about 17% of the dose was excreted for as [3H]radioactivity in the bile but only about 3% could be accounted for as pyrrolic metabolites. (5) Thin-layer chromatography of bile from rats given [3H]2,3-bishydroxy-methyl-1-methylpyrrole or [3H]synthanecine A bis-N-ethylcarbamate showed little redioactivity or Ehrlich-positive pyrrolic metabolites with an RF value corresponding to that of 2,3-bishydroxymethyl-1-methylpyrrole. A large proportion of the radioactivity label and most of the Ehrlich positive pyrrolic metabolites were associated with highly polar derivatives at the origin of the TLC plate. (6) It was concluded that biliary excretion plays an important role in the disposal of metabolites from both retrorsine and synthanecine A bis-N-ethyl-carbamate though not for the parent compounds. The expected hydroxy-methyl pyrrolic metabolites undergo further modification to more polar derivatives. In the case of retrorsine, these retained their abilities to react with Ehrlich reagent, while with pyrrolic metabolites from synthanecine A bis-N-ethylcarbamate, substatial conversion to Ehrlich negative derivatives occurred. (7) When bile of rats given [3H]synthanecine A bis-N-ethylcarbamate was injected intraduodenally into recipient animals, reabsorbtion of the radioactive label accounted for less than 4% of the dose given to the donor animals, indicating the enterohepatic circulation is probably only of minor importance influencing the elimination of these compounds.

Animals↗
PubMed1977

Vascular changes in the lungs of rats after the intravenous injection of pyrrole carbamates.

The effects on the lung of some synthetic compounds related to monocrotaline pyrrole have been studied and compared with those previously found with that compound. When injected into a systemic vein doses of pyrrole mono- and dicarbamate produced acute pulmonary oedema. Pyrrole alcohol and ethyl carbamate had no such effect and although furyl carbamate did not cause pleural effusion in rats it did so in mice. Like monocrotaline pyrrole, when injected into other vessels the pyrrole carbamates produced oedema in the region of the first capillary bed encountered. When colloidal carbon was injected intravenously after the pyrrole carbamates, carbon "labelling" was seen in both the post-capillary venules and the capillaries of the lungs. On the whole, venular "labelling" occurred before capillary "labelling" which was best seen when the carbon was injected more than 4 hr after the pyrrole. The distribution of the carbon as seen by electron microscopy is described. No "labelling" was seen after furyl carbamate. The effects of the synthetic pyrrole esters were similar to those of monocrotaline pyrrole. Although both the pyrrole carbamates were less active on a molecular basis they had a broader action on the pulmonary vasculature causing venular as well as capillary "labelling". To affect the lungs acutely the compound had to have the pyrrole ring structure and at least one ester side-chain.

Animals↗
PubMed2006

Cyclo[n]pyrroles: size and site-specific binding to G-quadruplexes.

Inhibiting the enzyme telomerase by stabilizing the G-quadruplex has potential in anticancer drug design. Diprotonated cyclo[n]pyrroles represent a set of expanded porphyrin analogues with structures similar to that of telomestatin, a natural product known to bind to and stabilize G-quadruplexes. As a first step toward testing whether cyclo[n]pyrroles display a similar function, a series of diprotonated cyclo[n]pyrroles (where n = 6, 7, and 8) was each added to the human telomere repeat sequence d(T(2)AG(3))(4) and examined with mass spectrometry, ion mobility, and molecular dynamics calculations. Nano-ESI-MS indicated that the smaller the cyclo[n]pyrrole, the more strongly it binds to the telomeric sequence. It was also found that cyclo[6]pyrrole bound to d(T(2)AG(3))(4) better than octaethylporphyrin, a finding rationalized by cyclo[6]pyrrole having a 2+ charge, while octaethylporphyrin bears no charge. Ion mobility measurements were used to measure the collision cross section of each d(T(2)AG(3))(4)/cyclo[n]pyrrole complex. Only one peak was observed in the arrival time distributions for all complexes, and the experimental cross sections indicated that only structures with d(T(2)AG(3))(4) in an antiparallel G-quadruplex arrangement and each cyclo[n]pyrrole externally stacked below the G-quartets occur under these experimental conditions. When the cyclo[n]pyrroles were intercalated or nonspecifically bound to the quadruplex, or if conformations different than antiparallel were considered for d(T(2)AG(3))(4), the theoretical cross sections did not match experiment. On this basis, it is inferred that (1) external stacking represents the dominant binding mode for the interaction of cyclo[n]pyrroles with d(T(2)AG(3))(4) and (2) the overall size and charge of the cyclo[n]pyrroles play important roles in defining the binding strength.

Binding Sites↗
PubMed2006

Alkylthio unit as an alpha-pyrrole protecting group for use in dipyrromethane synthesis.

The synthesis of porphyrin precursors requires the successive introduction of substituents at the pyrrole alpha- and alpha'-positions (2- and 5-, respectively). An alpha-pyrrole substituent that serves as a temporary masking agent and is not deactivating would greatly facilitate such syntheses, particularly for beta-(3,4)-unsubstituted pyrroles, but has heretofore not been available. A series of alpha-RS groups (R = Me, Et, n-decyl, Ph) have been investigated in this regard, including the determination of the kinetics of substitution at the pyrrolic 3-, 4-, and 5-positions and the application to dipyrromethane formation. The RS group was readily introduced into the pyrrole alpha-position by the reaction of 2-thiocyanatopyrrole (prepared from pyrrole, ammonium thiocyanate, and iodine) and the corresponding Grignard reagent RMgBr. Each 2-alkylthio group activated the pyrrole ring toward deuteration at the 3- or 5- (vs 4-) position. The dipyrromethane synthesis was carried out using a 2:1 ratio of 2-(RS)pyrrole/benzaldehyde with a catalytic amount of InCl3 at room temperature in the absence of any solvent. The alpha-RS group was removed by hydrodesulfurization using Raney nickel or nickel complexes. This stoichiometric synthesis using the alpha-RS-protected pyrrole is in contrast to the traditional synthesis that employs an aldehyde and 25-100 mol equiv of pyrrole. Six meso-substituted dipyrromethanes were prepared by the reaction of 2-(n-decylthio)pyrrole/aldehyde/InCl3 (2.2:1:0.2 ratio) followed by hydrodesulfurization. Other reactions of the 1,9-bis(RS)dipyrromethane include oxidation to give (i) the 1,9-bis(RS)dipyrrin or (ii) the 1,9-bis(RSO2)dipyrromethane, which underwent subsequent complexation with dibutyltin dichloride. In summary, under mild reaction conditions, the 2-alkylthio group is readily introduced to the pyrrole nucleus, directs electrophilic substitution to the 5-position, and is readily removed as required for elaboration of porphyrinic precursors.

Alkylation↗