Catalase Involved in Oxidative Cyclization of the Tetracyclic Ergoline of Fungal Ergot Alkaloids.

A dedicated enzyme for the formation of the central C ring in the tetracyclic ergoline of clinically important ergot alkaloids has never been found. Herein, we report a dual role catalase (EasC), unexpectedly using O2 as the oxidant, that catalyzes the oxidative cyclization of the central C ring from a 1,3-diene intermediate. Our study showcases how nature evolves the common catalase for enantioselective C-C bond construction of complex polycyclic scaffolds.

Total Syntheses of Pyroclavine, Festuclavine, Lysergol, and Isolysergol via a Catalytic Asymmetric Nitro-Michael Reaction.

A catalytic enantioselective construction of vicinal stereocenters is reported. The reaction takes advantage of thiourea-catalyzed intramolecular nitronate addition onto α,ß-unsaturated ester to afford exceptional levels of enantioselectivity (up to 97 % ee) with moderate diastereoselectivity (up to 4:1). Using this method, a cross-conjugated ester was synthesized in few steps, from which a 6-endo-trig cyclisation led to the formation of all required functionalities for total syntheses of ergot alkaloids. The strategy not only offers first total syntheses of ergot alkaloids, festuclavine (1 c), and pyroclavine (1 e), and but also an efficient and general approach to other congeners such as, lysergol (1 b), and isolysergol (1 d).

Total Synthesis of (-)-Chanoclavine I and an Oxygen-Substituted Ergoline Derivative.

An efficient and direct route to ergot alkaloid (-)-chanoclavine I (3) is described using the inexpensive compound (2R)-(+)-phenyloxirane (15) as a chiral pool in 13 steps with 17% overall yield. Key features of the synthesis include a palladium-catalyzed intramolecular aminoalkynylation of terminal olefin and a rhodium-catalyzed intramolecular [3 + 2] annulation. An oxygen-substituted ergoline derivative (-)-25 was also achieved by using the same strategy.

Total Syntheses of Festuclavine, Pyroclavine, Costaclavine, epi-Costaclavine, Pibocin A, 9-Deacetoxyfumigaclavine C, Fumigaclavine G, and Dihydrosetoclavine.

A new approach for the divergent total synthesis of eight ergot alkaloids is reported. The approach allows the first total syntheses of pyroclavine, pibocin A, 9-deacetoxyfumigaclavine C, and fumigaclavine G and also enables the efficient synthesis of festuclavine, costaclavine, epi-costaclavine, and dihydrosetoclavine. The main feature of the synthesis is the use of an unprecedented Pd-catalyzed intramolecular Larock indole annulation/Tsuji-Trost allylation cascade to assemble the tetracyclic core in one step.

Synthesis of (+)-Lysergol and Its Analogues To Assess Serotonin Receptor Activity.

An efficient synthesis of ergot alkaloid lysergol and its analogues is described, providing compounds for functional evaluation at the human 5-HT1A, 5-HT2A, 5-HT2B, or 5-HT2C receptors. Key features of the synthesis include the development of a tandem reaction to construct the multifunctionalized piperidine skeleton and use of a rhodium-catalyzed [3 + 2] annulation in the late-stage indole formation.

New route to the ergoline skeleton via cyclization of 4-unsubstituted indoles.

A new route to the ergoline skeleton has been developed that does not require prior functionalization of the indole 4-position. The indole nucleus is introduced late in the synthesis to allow for eventual efficient introduction of substituents in this region. Key steps include Negishi coupling of a three-carbon chain to a bromonicotinate ester, Fischer indole synthesis to facilitate incorporation of substituents via phenylhydrazines, and Pd-catalyzed cyclization to form the ergoline C ring.

Antibacterial and synergy of clavine alkaloid lysergol and its derivatives against nalidixic acid-resistant Escherichia coli.

Antibacterial activity of lysergol (1) and its semi-synthetic derivatives (2-14) and their synergy with the conventional antibiotic nalidixic acid (NA) against nalidixic acid-sensitive (NASEC) and nalidixic acid-resistant (NAREC) strains of Escherichia coli were evaluated. Lysergol (1) and derivatives (2-14) did not possess antibacterial activity of their own, but in combination, they significantly reduced the minimum inhibitory concentration (MIC) of NA. All the derivatives showed two- to eightfold reduction in the MIC of NA against NAREC and NASEC. Further, lysergol (1) and its derivatives 10 and 11 brought down eightfold reductions in the MIC of tetracycline (TET) against multidrug-resistant clinical isolate of E. coli (MDREC). Treatment of these strains with the combinations of antibiotics and lysergol and its derivatives 10 and 11 (at reduced concentrations) significantly decreased the viability of cells. In an another observation, lysergol and its derivatives 10 and 11 inhibited ATP-dependent efflux pumps, which was evident by ATPase inhibition and down-regulation of multidrug ABC transporter ATP-binding protein (yojI) gene. These results may be of great help in antibacterial drug development from a very common, inexpensive, and non-toxic natural product.

Special ergolines efficiently inhibit the chemokine receptor CXCR3 in blood.

The structure-activity relationship of highly potent special ergolines which selectively block the chemokine receptor CXCR3 is reported. The most potent compounds showed IC(50) values below 10nM in both ligand binding and Ca(2+)-mobilization assays. However, these compounds were poorly active in an assay that measures receptor occupancy in blood. Introduction of polar substituents led to derivatives with IC(50) values below 10nM in this assay. Among them was compound 11a which showed both a favorable PK profile and cross reactivity with rodent CXCR3 making it a promising tool compound to further explore the role of CXCR3 in animal models.

Enantioselective total synthesis of (+)-lysergic acid, (+)-lysergol, and (+)-isolysergol by palladium-catalyzed domino cyclization of allenes bearing amino and bromoindolyl groups.

Enantioselective total synthesis of the biologically important indole alkaloids (+)-lysergol, (+)-isolysergol, and (+)-lysergic acid is described. Key features of these total synthesis include (1) a facile synthesis of a chiral 1,3-amino alcohol via the Pd(0)- and In(I)-mediated reductive coupling reaction between L-serine-derived 2-ethynylaziridine and formaldehyde; (2) the Cr(II)/Ni(0)-mediated Nozaki-Hiyama-Kishi (NHK) reaction of an indole-3-acetaldehyde with iodoalkyne; and (3) Pd(0)-catalyzed domino cyclization of an allene bearing amino and bromoindolyl groups. This domino cyclization enabled direct construction of the C/D ring system of the ergot alkaloids skeleton, as well as the creation of the C5 stereogenic center with transfer of the allenic axial chirality to the central chirality.

Enantioselective synthesis of (+)-isolysergol via ring-closing metathesis.

The first enantioselective synthesis of (+)-isolysergol was completed in 12 steps from commercially available materials by a novel approach that features a late stage microwave-mediated, diastereomeric ring-closing metathesis catalyzed by a chiral molybdenum catalyst to simultaneously form the D ring and set the stereocenter at C(8).

Total synthesis of (+/-)-lysergic acid, lysergol, and isolysergol by palladium-catalyzed domino cyclization of amino allenes bearing a bromoindolyl group.

Ergot alkaloids and their synthetic analogs have been reported to exhibit broad biological activity. We investigated direct construction of the C/D ring system of ergot alkaloids based on palladium-catalyzed domino cyclization of amino allenes. With this biscyclization as the key step, total synthesis of (+/-)-lysergic acid, (+/-)-lysergol, and (+/-)-isolysergol was achieved.

Ergoline derivatives as highly potent and selective antagonists at the somatostatin sst 1 receptor.

Non-peptidic compounds containing the octahydro-indolo[4,3-fg]quinoline (ergoline) structural element have been optimized into derivatives with high affinity (pK(d) r sst(1)>9) and selectivity (>1000-fold for h sst(1) over h sst(2)-h sst(5)) for the somatostatin sst(1) receptor. In functional assays, these ergolines act as antagonists at human recombinant sst(1) receptors. Pharmacokinetic studies in rodents reveal good oral bioavailability and brain penetration for some of these compounds.

Novel ergopeptides as dual ligands for adenosine and dopamine receptors.

Multivalent ligands are promising pharmacological tools that may be more efficacious for several diseases than highly selective single-target drugs. A combined therapy using dopaminergic agonists and adenosinergic antagonists is currently being evaluated for the treatment of Parkinson's disease. [(a) Kanda, T.; et al. Exp. Neurol. 2000, 162, 321-327. (b) Jenner, P. Expert Opin. Invest. Drugs 2005, 14, 729-738. (c) Kase, H.; et al. Neurology 2003, 61 (Suppl 6), S97-S100.] Here we prepared dual ligands acting on adenosine and dopamine receptors by applying a combinatorial approach based on the ergolene privileged structure. The potency and efficacy of these novel compounds were determined by radioligand binding studies and intracellular cAMP production assays in cells expressing adenosine and dopamine receptors. Selected compounds displayed dual dopamine agonist and adenosine antagonist activity. Molecules with this pharmacological profile are potentially useful for studying dopamine-adenosine cross-talk in the central nervous system and for testing the therapeutic potential of multivalent drugs for Parkinson's disease.

Novel secoergoline derivatives inhibit both GABA and glutamate uptake in rat brain homogenates: synthesis, in vitro pharmacology, and modeling.

Three of twelve secoergoline derivatives (Z ethyl 4-[(ethoxycarbonylmethyl)methylamino]-2-methyl-3-phenylpent-2-enoate, 8; ethyl 1,6-dimethyl-3-oxo-5-phenyl-1,2,3,6-tetrahydropyridine-2-carboxylate, 9; Z methyl 4-[(methoxycarbonylmethyl)methylamino)-2-methyl-3-phenylpent-2-enoate, 11), containing bioisosteric sequences of GABA and Glu, inhibited both GABA and Glu transport through cerebrocortical membranes specifically. Compounds 8, 9, and 11 appeared to be equipotent inhibitors of GABA and Glu transport with IC50 values between 270 and 1100 microM, whereas derivatives 1-7, 10, and 12 were without effects. In the presence of GABA and Glu transport-specific nontransportable inhibitors, inhibition of GABA and Glu transport by 8, 9, and 11 proceeded in two phases. The two phases of inhibition were characterized by IC50 values between 4 and 180 nM and 360-1020 microM and different selectivity sequences. These findings may indicate the existence of some mechanism possibly mediated by a previously unrecognized GABA-Glu transporter. Derivatives with the cis, but not the trans configuration of bulky ester groups (8 vs 7 and 11 vs 12) showed significant inhibitory effect (IC50 values of 270 microM vs >>1000 microM and 1100 microM vs >>1000 microM on GABA transport, respectively). The cis-trans selectivity can be explained by docking these secoergolines in a three-dimensional model of the second and third transmembrane helices of GABA transporter type 1.

Enantioefficient synthesis of alpha-ergocryptine: first direct synthesis of (+)-lysergic acid.

The first direct synthesis of (+)-lysergic acid (2a) suitable for scale-up has been achieved by the following reaction sequence. Bromoketones 4d or 4g were allowed to react with amine 5 followed by deprotection, and the resulting diketone 6c was transformed into the unsaturated ketone (+/-)-7 by the LiBr/Et(3)N system. Resolution afforded (+)-7, which was further transformed by Schöllkopf's method into the mixture of esters 2e and 2f. Upon hydrolysis the latter mixture afforded (+)-2a. The peptide part of alpha-ergocryptine (1) was prepared according to the Sandoz method; the stereoefficiency, however, has been significantly improved by applying a new resolution method and recycling the undesired enantiomer. Coupling the peptide part with lysergic acid afforded 1. Having synthetic (+)-7 in hand, we can claim the total synthesis of all the alkaloids which were prepared earlier from (+)-7 that had been obtained through degradation of natural lysergic acid.

In vitro antiplasmodial activities of semisynthetic N,N'-spacer-linked oligomeric ergolines.

Starting from three monomeric ergolines (terguride 1, festuclavine 2, pergolide 3) N,N'-spacer-linked oligomeric derivatives were prepared using different aliphatic or arylalkyl spacers. The compounds have been evaluated for their in vitro antiplasmodial activity against the chloroquine-sensitive strain poW and the chloroquine-resistant clone Dd2 of Plasmodium falciparum. Additionally, the cytotoxic effects against mouse fibroblasts (NIH 3T3) in vitro, and human hepatocytes were evaluated. All monomers displayed only a weak antiplasmodial effect, but N-1,N-1'-spacer-linked dimerization substantially enhanced their antiplasmodial activity. The best activities were observed for compounds showing a distance of six carbon atoms between two monomers, which can be obtained by aliphatic or p-xylene linkers. The N-6,N-6'-spacer-linked depropylpergolide dimer 3i exhibited the highest antiplasmodial activity of all compounds tested (IC(50) values: 0.14 and 0.13 microM against poW and Dd2, respectively). Unfortunately, it displayed toxic effects against the mouse fibroblast cell line NIH 3T3 (IC(50): 0.1+/-0.09 microM) and also against human hepatocytes at 100 microM (LDH-leakage: 15.58+/-0.87 microkat/L; GSH-level: 8.15+/-0.78 nmol/10(6) cells). However, the N-1,N-1'-spacer-linked trimer of festuclavine (2f), and also the N-1,N-1'-spacer-linked tetramer of terguride (1g) possessed remarkable antiplasmodial activities (IC(50): 0.54 and 1.53 microM, respectively, against Dd2) lacking cytotoxicity.

seco-C/D ring analogues of ergot alkaloids. Synthesis via intramolecular Heck and ring-closing metathesis reactions.

[reaction: see text] Intramolecular Heck and ring-closing metathesis reactions on key intermediates 10 and 15, respectively, provide efficient entries into seco-C/D ring analogues of Ergot alkaloids 12 and 16, compounds of potential synthetic and biological interest.

A practical synthesis of cabergoline.

Cabergoline is an N-acylurea derived from 9,10-dihydrolysergic acid, which is a potent prolactin inhibitor. It is marketed by Pharmacia as Dostinex for the treatment of hyperprolactinemia and is currently under active development for the treatment of a variety of CNS disorders. In the existing process, the N-acylurea is formed by the reaction of an amide with a large excess of ethyl isocyanate at elevated temperatures. An improved process was developed that eliminates this hazardous reaction. The amide is reacted with phenyl chloroformate and then with ethylamine, which provides a mild and efficient means of forming the unsymmetrical N-acylurea.

Tc and Re chelates of 8alpha-amino-6-methyl-ergoline: synthesis and affinity to the dopamine D2 receptor.

The influence of structural changes at the 8alpha-amino position of 8alpha-amino-6-methyl-ergoline on the lipophilicity and affinity to the D2 receptor was studied. 8alpha-amino-6-methyl-ergoline (1) was converted into the derivatives (2a-f) by mercaptoacetylation of the amino group to make it possible to prepare the rhenium and technetium complexes (3, 4a,b). Binding tests on cloned human dopamine D2 receptors show that the affinities of the coordination compounds (IC50 values between 50 and 240 nM) are less than those of the derivatives 2a-f (IC50=3-50 nM) but more than those of the parent compound 1. Biodistribution studies of the Tc complexes 4a,b performed on Wistar rats show a slow blood clearance with substantial accumulation and retention in the liver and kidneys and low brain uptake.

[Intramolecular alkylation of aromatic compounds. 35. Di- and tetrahydropyridinemethylindolines as potential precursors of ergolines] . / Intramolekulare Aromatenalkylierungen. 35. Mitt.: Di- und Tetrahydropyridinylmethylindoline als potenzielle Vorstufen zu Ergolinen.

In the presence of methyl chloroformate, compound 6a is reduced by NaCNBH3 yielding the 1,6-dihydropyridine derivative 7. Under the same conditions the indoline 10 accessible from 6a via 9a gives a mixture of the 1,4- and 1,6-dihydropyridine derivatives 11 and 12. As by-product of the reduction the borane adduct 13 is detected. In contrast the methoiodide 1 is reduced by NaBH4 or DIBAH giving a separable mixture of the diastereomers of the tetrahydropyridines 2 and 3; on catalytic hydrogenation the piperidine derivative 4 is formed. Cleavage of the enolether moiety in 3a and 7 provides the corresponding piperidones 5 and 14, respectively. Using prolonged reaction time 7 is hydrolized quantitatively furnishing the 1,4-diketone 15.