scholarly journals Synthesis and Cytotoxicity Evaluation of C4- and C5-Modified Analogues of the α,β-Unsaturated Lactone of Pironetin

ChemMedChem ◽  
2017 ◽  
Vol 12 (7) ◽  
pp. 520-528 ◽  
Author(s):  
David S. Huang ◽  
Henry L. Wong ◽  
Gunda I. Georg
Keyword(s):  
Unsaturated Lactone

Abstract 90: Inimitable Ouabain: The Endogenous Circulating Cardiotonic Steroid that Singularly Stimulates Sodium Potassium Pump Activity at Low Doses

2017 ◽  
Vol 121 (suppl_1) ◽  
Author(s):  
Yeon Jae Kim ◽  
Elisha Hamilton ◽  
William Hannam ◽  
Chia-Chi Liu ◽  
Rachel Teh ◽  
...  
Keyword(s):  
Low Dose ◽  
Lactone Ring ◽  
Cardiac Contractility ◽  
Cancer Cell Line ◽  
Structural Components ◽  
Sodium Potassium ◽  
Sugar Moiety ◽  
Unsaturated Lactone ◽  
Sodium Potassium Pump ◽  
The Difference

Rationale: Cardiotonic steroids (CTS), such as digoxin, have been used to treat heart failure (HF) for over 200 years. They inhibit the sodium-potassium pump (NKP), and increase cardiac contractility by inhibiting efflux of sodium through the pump (“digitalis hypothesis”). CTS possess three structural components: a saturated/unsaturated lactone ring, steroid core, and sugar moiety, each of which may be involved in NKP inhibition/stimulation. It is now known that inhibition of the NKP in patients with HF increases mortality, and all major beneficial treatments increase its activity. Endogenous circulating CTS such as ouabain are generally thought to inhibit the NKP, despite studies sporadically reporting ouabain-induced pump stimulation. This study aims to identify whether ouabain-induced pump stimulation occurs, and if so, which structural components are involved in causing pump stimulation. Methods & Results: Cardiac myocytes were isolated from male New Zealand White rabbits, placed in a Tyrode’s solution, and whole-cell patch clamped. They were exposed to 0-30nM ouabain, 0-50nM dihydroouabain (ouabain with a saturated lactone ring) or 0-500nM ouabagenin (ouabain lacking a sugar moiety) for 1 min, followed by a potassium-free solution, with the difference in current yielding the NKP current. Compared to the 0.47±0.05 pA/pF Tyrode’s solution control (n=11), 5nM ouabain significantly increased NKP current to 0.69±0.09 pA/pF ( P <0.05, n=6). Exposure to dihydroouabain or ouabagenin did not significantly change NKP current in the studied concentration range. Cell viability assays carried out on the breast cancer cell line MCF7, which have an NKP structure extremely similar to that of cardiomyocytes, showed significantly elevated viability above control values (n=2) following 24h treatment with 0-9nM ouabain; maximum viability was 116±5% at 0.28nM ( P <0.05, n=4). A significant change in viability was not observed for ouabagenin or digoxin in the same concentration range. Conclusion: Low-dose ouabain uniquely stimulates NKP activity. Low-dose dihydroouabain and ouabagenin do not, suggesting that a sugar moiety and unsaturated lactone ring are required for pump stimulation. Ouabain in its unaltered form may be a potential treatment for HF.

Metabolism of a monoterpene alcohol, linalool, by a soil pseudomonad

1977 ◽  
Vol 23 (3) ◽  
pp. 230-239 ◽  
Author(s):  
K. M. Madyastha ◽  
P. K. Bhattacharyya ◽  
C. S. Vaidyanathan
Keyword(s):  
Mineral Salt Medium ◽  
Enrichment Culture ◽  
Sole Source ◽  
Mineral Salt ◽  
Salt Medium ◽  
Culture Techniques ◽  
Unsaturated Lactone ◽  
Linalool Oxide

A microorganism of the genus Pseudomonas has been isolated from the soil by enrichment culture techniques with linalool(I) as the sole source of carbon and energy. The organism is also capable of utilizing limonene, citronellol, and geraniol as substrates but fails to grow on citral, citranellal, and 1,8-cineole. Fermentation of linalool by this bacterium in a mineral salt medium results in the formation of 10-hydroxylinalool(II), 10-carboxylinalool(III), oleuropeic acid(IX), 2-vinyl-2-methyl-5-hydroxyisopropyl-tetrahydrofuran(linalool oxide, V), 2-vinyl-2-methyl-tetrahydrofuran-5-one(unsaturated lactone, VI), and few unidentified minor metabolites. Probable pathways for the biodegradation of linalool are presented.

The Antibacterial Principle of Arctium minus. II. The Unsaturated Lactone Structure

1947 ◽  
Vol 69 (12) ◽  
pp. 3030-3032 ◽  
Author(s):  
Chester J. Cavallito ◽  
Fred K. Kirchner
Keyword(s):  
Unsaturated Lactone ◽  
Arctium Minus

FURTHER DEGRADATION REACTIONS OF ANNOTININE

1955 ◽  
Vol 33 (5) ◽  
pp. 849-860 ◽  
Author(s):  
F. A. L. Anet ◽  
Léo Marion
Keyword(s):  
Amino Acid ◽  
Benzene Ring ◽  
Potassium Permanganate ◽  
Lactone Ring ◽  
Neutral Substance ◽  
Unsaturated Lactone ◽  
Degradation Reactions ◽  
Vinyl Group ◽  
Color Reactions ◽  
Chromous Chloride

Both the hydroxylactone obtained by the action of chromous chloride on annotinine chlorohydrin, and the unsaturated lactone B prepared by the action of the same reagent on the hydroxylactone, contain a secondary nitrogen and a vinyl group. The unsaturated lactone A which accompanies the hydroxylactone is a cyclic allylamine which on oxidation with potassium permanganate yields an amino acid C14H19O4N. These facts make it possible to explain the reaction of chromous chloride with annotinine chlorohydrin. The amino acid can be de-hydrogenated to an acid containing a free carboxyl and a lactamic grouping (C14H15O3N) but no longer containing a lactone ring. The lactamic acid which seems to contain a benzene ring is readily decarboxylated to a neutral substance C13H15ON, showing color reactions and ultraviolet absorption similar to those of strychnine.

Synthesis of unsaturated lactone moieties by asymmetric hetero Diels–Alder reactions with binaphthol-titanium complexes

2001 ◽  
Vol 42 (7) ◽  
pp. 1263-1265 ◽  
Author(s):  
Monika Quitschalle ◽  
Mathias Christmann ◽  
Ulhas Bhatt ◽  
Markus Kalesse
Keyword(s):  
Diels Alder ◽  
Titanium Complexes ◽  
Unsaturated Lactone

ANNOTININE: THE REACTIONS OF THE CYCLIC ETHER FUNCTION

1954 ◽  
Vol 32 (3) ◽  
pp. 268-279 ◽  
Author(s):  
H. L. Meier ◽  
P. D. Meister ◽  
Léo Marion
Keyword(s):  
Chromic Acid ◽  
Cyclic Ether ◽  
The Other ◽  
Amino Group ◽  
Imino Group ◽  
Unsaturated Lactone ◽  
Clemmensen Reduction ◽  
Secondary Amino ◽  
Concentrated Solution ◽  
Chromous Chloride

Treatment of annotinine chlorohydrin with chromous chloride has been found to produce not only the already reported unsaturated lactone A (C16H21O2N), but also a second unsaturated lactone B (C16H21(23)O2N), and a hydroxylactone (C16H23O3N). Under the action of a concentrated solution of the same reagent the hydroxylactone is converted to the unsaturated lactone B. On hydrogenation the latter gives a dihydrolactone B which seems to contain a secondary amino group. Annotinine hydrate on treatment with thionyl chloride gives an unsaturated chlorolactone (C16H20O2NCl) which can be hydrogenated and subsequently dechlorinated to produce a third lactone C, different from either of dihydrolactones A or B, but which like the latter seems to contain an imino group. Oxidation of annotinine hydrate with chromic acid produces a hydroxyketone which can be converted into an oxime and, therefore, one of the hydroxyls of the hydrate is secondary while the other is probably tertiary. On the other hand, oxidation of annotinine with potassium permanganate gives rise to a lactam which by the Clemmensen reduction is converted to a mixture of lactam chlorohydrin and dihydrolactone A.

The constitution of the β,γ-unsaturated lactone C31H44O5obtained by oxidation of methyl oleana-11,13(18)-dien-28-oate

1967 ◽  
Vol 0 (0) ◽  
pp. 441-441
Author(s):  
R. A. Eade ◽  
G. Kornis ◽  
J. J. H. Simes
Keyword(s):  
Unsaturated Lactone

scholarly journals Towards Synthesis of Simplified Analogues of Pateamine A

2021 ◽  
Author(s):  
◽  
Tao Xu
Keyword(s):  
Ring Opening ◽  
Side Chain ◽  
Methyl Groups ◽  
Chain Fragment ◽  
Unsaturated Lactone ◽  
Structure Activity ◽  
Potent Inhibition ◽  
Nonsense Mediated Mrna Decay ◽  
Pateamine A ◽  
Future Work

<p>Pateamine A (22) is a natural product that was isolated from a marine sponge inhabiting the coast of New Zealand. It exhibits potent inhibition of protein synthesis and nonsense-mediated mRNA decay through binding with eIF4A isoforms. Due to the scarcity of pateamine A (22) in the natural source and the low yield of total synthesis of pateamine A, it is necessary to prepare structurally simplified analogues which would allow further research on structure-activity relationships (SAR) of pateamine A (22). Based on the structure-activity relationship studies reported by Romo and co-workers, a simplified triazole analogue 182 lacking methyl groups was synthesized by Hemi Cumming, a previous Ph.D. student who studied at Victoria University of Wellington. The antiproliferative activity of this analogue was found to be significantly lower than that of pateamine A, suggesting that the thiazole embedded within the molecule or the excised methyl groups are crucial for its potency.   Therefore, to further explore the necessary features for its selective activity for eIF4A isoforms, new thiazole analogues 183 – 186 and triazole analogues (10S)-and (10R)-analogue 187 were targeted in this project.    The preparation of the thiazole-containing macrocyclic core of analogues 183 and 184 was achieved. It features: (1) gold-catalysed thiazole formation through coupling between an alkyne fragment and a thioamide fragment; (2) preparation of the Z,E-dienoate moiety by base-induced ring-opening of a δ-substituted-α, β-unsaturated lactone; and (3) a modified Mukaiyama macrolactonisation. The synthesis of the triazole-containing macrocyclic core of (10S)-analogue 187 was completed. It features: (1) a copper-catalysed triazole formation through 1,3-dipolar cycloaddition between an alkyne fragment and an azide fragment; (2) preparation of the Z,E-dienoate moiety by base-induced ring-opening of δ-substituted-α, β-unsaturated lactone; and (3) a modified Mukaiyama macrolactonisation. Studies on the preparation of a side-chain fragment with suitable functionalities to allow coupling with the various macrocycles through olefination reactions were also conducted.  The attachment of the side-chain fragment onto the macrocyclic cores for the synthesis of the targeted analogues 183 and 184 and (10S)-analogue 187 will be investigated in future work. These experimental results will inform the synthesis of new generation analogues to further study the key structures required for effective binding to the protein target eIF4A and selectivity between isoforms.</p>

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