General Synthesis of Potentially Antiviral α‐Adamantyl Carbonyl Compounds

Reetz, Manfred T.; Maier, Wilhelm F.; Schwellnus, Konrad; Chatziiosifidis, Ioannis

doi:10.1002/anie.197900721

Cited by 17 publications

(8 citation statements)

References 5 publications

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“…deprotonation of piperidine of 6a and 6b with 1.2 equiv of n -butyllithium followed by reaction with methyl iodide afforded amides 7a and 7b in 87% and 85% yields, respectively. The ethyl ester portion of 7a and 7b was converted to 3-oxopropanoate group using a modified Masamune procedure, 39 which furnished β -keto esters 8a and 8b in 82% and 86% yields, respectively. Compounds 8c and 8d were obtained with high yields from 6c and 6b , respectively, using a similar procedure.…”

Section: Resultsmentioning

confidence: 99%

Pyrazolopyrimidines as Potent Stimulators for Transient Receptor Potential Canonical 3/6/7 Channels

Ding

Zhu

et al. 2017

J. Med. Chem.

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Transient receptor potential canonical 3/6/7 (TRPC3/6/7) are highly homologous receptor-operated non-selective cation channels. Despite their physiological significance, very few selective and potent agonists are available for functional examination of these channels. Using a cell-based high throughput screening approach, a lead compound with the pyrazolopyrimidine skeleton was identified as a TRPC6 agonist. Synthetic schemes for the lead and its analogues were established, and structural–activity relationship studies were carried out. A series of potent and direct agonists of TRPC3/6/ 7 channels were identified, and among them, 4m–4p have a potency order of TRPC3 > C7 > C6, with 4n being the most potent with an EC50 of <20 nM on TRPC3. Importantly, these compounds exhibited no stimulatory activity on related TRP channels. The potent and selective compounds described here should be suitable for evaluation of the roles of TRPC channels in the physiology and pathogenesis of diseases, including glomerulosclerosis and cancer.

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Section: Resultsmentioning

confidence: 99%

Pyrazolopyrimidines as Potent Stimulators for Transient Receptor Potential Canonical 3/6/7 Channels

Ding

Zhu

et al. 2017

J. Med. Chem.

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“…40 Carboxylic acid derivative 23-S was converted to ethyl ester 24-S in 85% isolated yield with carbonyl diimidazole (CDI) and ethanol and to carboxamide derivative 25-S in 83% isolated yield with CDI and ammonia. 45 Similarly, carboxylic acid derivative 27-S was converted to methyl ester 28-S with CDI and methanol.…”

Section: Resultsmentioning

confidence: 99%

Rhodamine Inhibitors of P-Glycoprotein: An Amide/Thioamide “Switch” for ATPase Activity

et al. 2009

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We have examined 46 tetramethylrosamine/rhodamine derivatives with structural diversity in the heteroatom of the xanthylium core, the amino substituents of the 3- and 6-positions, and the alkyl, aryl, or heteroaryl group at the 9-substituent. These compounds were examined for affinity and ATPase stimulation in isolated MDR3 CL P-gp and human P-gp-His10, for their ability to promote uptake of calcein AM and vinblastine in multidrug-resistant MDCKII-MDR1 cells, and for transport in monolayers of MDCKII-MDR1 cells. Thioamide 31-S gave KM of 0.087 μM in human P-gp. Small changes in structure among this set of compounds affected affinity as well as transport rate (or flux) even though all derivatives examined were substrates for P-gp. With isolated protein, tertiary amide groups dictate high affinity and high stimulation while tertiary thioamide groups give high affinity and inhibition of ATPase activity. In MDCKII-MDR1 cells, the tertiary thioamide-containing derivatives promote uptake of calcein AM and have very slow passive, absorptive, and secretory rates of transport relative to transport rates for tertiary amide-containing derivatives. Thioamide 31-S promoted uptake of calcein AM and inhibited efflux of vinblastine with IC50’s of ~2 μM in MDCKII-MDR1 cells.

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“…The (±)-α-hydroxy stearic acid 3 is prepared in two steps from stearic acid 1 by bromination [ 24 ] using Hell-Volhard-Zelinsky condition giving compound 2 followed by hydrolysis in 88% overall yield (Scheme 2 ). The (±)-β-Hydroxy stearic acid 8 is synthesized by the procedure described by Masamune [ 25 , 26 ], which involves homologation of palmitic acid 5 [ 27 ] using in situ generated magnesium monomethylmalonate to a preformed acyl imidazole to produce the β-keto stearic acid methyl ester, which is reduced [ 28 ] with sodium borohydride in ethanol providing 7 . Saponification with 1 N NaOH resulted in the formation of (±)-β-hydroxy stearic acid 8 in 77% overall yield (Scheme 3 ).…”

Section: Resultsmentioning

confidence: 99%

Design and synthesis of nucleolipids as possible activated precursors for oligomer formation via intramolecular catalysis: stability study and supramolecular organization

et al. 2014

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BackgroundFatty acid vesicles are an important part of protocell models currently studied. As protocells can be considered as pre-biological precursors of cells, the models try to contribute to a better understanding of the (cellular) origin of life and emphasize on 2 major aspects: compartmentalization and replication. It has been demonstrated that lipid-based membranes are amenable to growth and division (shell replication). Furthermore compartmentalization creates a unique micro-environment in which biomolecules can accumulate and reactions can occur. Pioneering research by Sugawara, Deamer, Luisi, Szostak and Rasmussen gave more insight in obtaining autocatalytic, self-replicating vesicles capable of containing and reproducing nucleic acid sequences (core replication). Linking both core and shell replication is a challenging feat requiring thorough understanding of membrane dynamics and (auto)catalytic systems. A possible solution may lie in a class of compounds called nucleolipids, who combine a nucleoside, nucleotide or nucleobase with a lipophilic moiety. Early contributions by the group of Yanagawa mentions the prebiotic significance (as a primitive helical template) arising from the supramolecular organization of these compounds. Further contributions, exploring the supramolecular scope regarding phospoliponucleosides (e.g. 5’-dioleylphosphatidyl derivatives of adenosine, uridine and cytidine) can be accounted to Baglioni, Luisi and Berti. This emerging field of amphiphiles is being investigated for surface behavior, supramolecular assembly and even drug ability.ResultsA series of α/β-hydroxy fatty acids and α-amino fatty acids, covalently bound to nucleoside-5′-monophosphates via a hydroxyl or amino group on the fatty acid was examined for spontaneous self-assembly in spherical aggregates and their stability towards intramolecular cleavage. Staining the resulting hydrophobic aggregates with BODIPY-dyes followed by fluorescent microscopy gave several distinct images of vesicles varying from small, isolated spheres to higher order aggregates and large, multimicrometer sized particles. Other observations include rod-like vesicle precursors. NMR was used to assess the stability of a representative sample of nucleolipids. 1D 31P NMR revealed that β-hydroxy fatty acids containing nucleotides were pH-stable while the α-analogs are acid labile. Degradation products identified by [1H-31P] heteroTOCSY revealed that phosphoesters are cleaved between sugar and phosphate, while phosphoramidates are also cleaved at the lipid-phosphate bond. For the latter compounds, the ratio between both degradation pathways is influenced by the nucleobase moiety. However no oligomerization of nucleotides was observed; nor the formation of 3′-5′-cyclic nucleotides, possible intermediates for oligonucleotide synthesis.ConclusionsThe nucleolipids with a deoxyribose sugar moiety form small or large vesicles, rod-like structures, vesicle aggregates or large vesicles. Some of these aggregates can be considered as intermediate forms in ve...

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General Synthesis of Potentially Antiviral α‐Adamantyl Carbonyl Compounds

Abstract: The antiviral activity of some α‐adamantyl carbonyl compounds of type (3) is greater than that of 1‐amino‐adamantane. Syntheses of the kind shown below are therefore of considerable interest.

Cited by 17 publications

References 5 publications

Pyrazolopyrimidines as Potent Stimulators for Transient Receptor Potential Canonical 3/6/7 Channels

Pyrazolopyrimidines as Potent Stimulators for Transient Receptor Potential Canonical 3/6/7 Channels

Rhodamine Inhibitors of P-Glycoprotein: An Amide/Thioamide “Switch” for ATPase Activity

Design and synthesis of nucleolipids as possible activated precursors for oligomer formation via intramolecular catalysis: stability study and supramolecular organization

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