An Approach toward 17-Arylsubstituted Marginatafuran-Type Isospongian Diterpenoids via a Palladium-Catalyzed Heck–Suzuki Cascade Reaction of 16-Bromolambertianic Acid

Isospongian diterpenes are a small but growing family of natural tetracyclic secondary metabolites isolated from marine organisms, primarily sponges and nudibranchs. A palladium-catalyzed domino Heck–Suzuki reaction sequence for the synthesis of the tetracyclic skeleton of marginatafuran-type isospongian diterpenoids with a wide variety of substituents in the C-17 position is reported. The proposed approach was based on selective transformations of the accessible plant diterpenoid lambertianic acid and includes an intramolecular Heck reaction of 16-bromolambertianic and arylation of the palladium intermediate with arylboronic acid. The influence of the nature of the substituent both in arylboronic acids and in the furan ring of 16-bromolambertianic acid on the direction and chemoselectivity of the reaction has been studied. The described derivatization of natural furanolabdanoid lambertianic acid produced new functionalized molecules for biological study and gave novel insights into the reactivity of complex molecular structures

Synthesis and Cytotoxic Activity of a New Group of Heterocyclic Analogues of the Combretastatins

A series of new analogs of combretastatin A-4 (CA-4, 1) with the A or B-ring replaced by a 3-oxo-2,3-dihydrofurocoumarin or a furocoumarin residue have been designed and synthesized by employing a cross-coupling approach. All the compounds were evaluated for their cytotoxic activity with respect to model cancer cell lines (CEM-13, MT-4, U-937) using conventional MTT assays. Structure-activity relationship analysis reveals that compounds 2, 3, 6–8 in which the (Z)-styryl substituent was connected to the 2-position of the 3-oxo-2,3-dihydrofurocoumarin core, demonstrated increased potency compared to 3-(Z)-styrylfurocoumarins 4, 5, 9–11. The methoxy-, hydroxyl- and formyl- substitution on the aromatic ring of the (Z)-styryl moiety seems to play an important role in this class of compounds. Compounds 2 and 3 showed the best potency against the CEM-13 cell lines, with CTD50 values ranging from 4.9 to 5.1 μM. In comparison with CA-4, all synthesized compounds presented moderate cytotoxic activity to the T-cellular human leucosis cells MT-4 and lymphoblastoid leukemia cells CEM-13, but most of them were active in the human monocyte cell lines U-937

Synthesis of Anti-Inflammatory Spirostene-Pyrazole Conjugates by a Consecutive Multicomponent Reaction of Diosgenin with Oxalyl Chloride, Arylalkynes and Hydrazines or Hydrazones

Steroid sapogenin diosgenin is of significant interest due to its biological activity and synthetic application. A consecutive one-pot reaction of diosgenin, oxalyl chloride, arylacetylenes, and phenylhydrazine give rise to steroidal 1,3,5-trisubstituted pyrazoles (isolated yield 46–60%) when the Stephens–Castro reaction and heterocyclization steps were carried out by heating in benzene. When the cyclization step of alkyndione with phenylhydrazine was performed in 2-methoxyethanol at room temperature, steroidal α,β-alkynyl (E)- and (Z)-hydrazones were isolated along with 1,3,5-trisubstituted pyrazole and the isomeric 2,3,5-trisubstituted pyrazole. The consecutive reaction of diosgenin, oxalyl chloride, phenylacetylene and benzoic acid hydrazides efficiently forms steroidal 1-benzoyl-5-hydroxy-3-phenylpyrazolines. The structure of new compounds was unambiguously corroborated by comprehensive NMR spectroscopy, mass-spectrometry, and X-ray structure analyses. Performing the heterocyclization step of ynedione with hydrazine monohydrate in 2-methoxyethanol allowed the synthesis of 5-phenyl substituted steroidal pyrazole, which was found to exhibit high anti-inflammatory activity, comparable to that of diclofenac sodium, a commercial pain reliever. It was shown by molecular docking that the new derivatives are incorporated into the binding site of the protein Keap1 Kelch-domain by their alkynylhydrazone or pyrazole substituent with the formation of more non-covalent bonds and have higher affinity than the initial spirostene core

Design, Synthesis and Assay of Novel Methylxanthine–Alkynylmethylamine Derivatives as Acetylcholinesterase Inhibitors

Xanthine derivatives have been a great area of interest for the development of potent bioactive agents. Thirty-eight methylxanthine derivatives as acetylcholinesterase inhibitors (AChE) were designed and synthesized. Suzuki–Miyaura cross-coupling reactions of 8-chlorocaffeine with aryl(hetaryl)boronic acids, the CuAAC reaction of 8-ethynylcaffeine with several azides, and the copper(I) catalyzed one-pot three-component reaction (A3-coupling) of 8-ethynylcaffeine, 1-(prop-2-ynyl)-, or 7-(prop-2-ynyl)-dimethylxanthines with formaldehyde and secondary amines were the main approaches for the synthesis of substituted methylxanthine derivatives (yield 53–96%). The bioactivity of all new compounds was evaluated by Ellman’s method, and the results showed that most of the synthesized compounds displayed good and moderate acetylcholinesterase (AChE) inhibitory activities in vitro. The structure-activity relationships were also discussed. The data revealed that compounds 53, 59, 65, 66, and 69 exhibited the most potent inhibitory activity against AChE with IC50 of 0.25, 0.552, 0.089, 0.746, and 0.121 μM, respectively. The binding conformation and simultaneous interaction modes were further clarified by molecular docking studies

Inhibition of Acetylcholinesterase by Novel Lupinine Derivatives

Alzheimer’s disease (AD) is a neurodegenerative disease characterized by progressive memory loss and cognitive impairment due in part to a severe loss of cholinergic neurons in specific brain areas. AD is the most common type of dementia in the aging population. Although several acetylcholinesterase (AChE) inhibitors are currently available, their performance sometimes yields unexpected results. Thus, research is ongoing to find potentially therapeutic AChE inhibitory agents, both from natural and synthetic sources. Here, we synthesized 13 new lupinine triazole derivatives and evaluated them, along with 50 commercial lupinine-based esters of different carboxylic acids, for AChE inhibitory activity. The triazole derivative 15 [1S,9aR)-1-((4-(4-(benzyloxy)-3-methoxyphenyl)-1H-1,2,3-triazol-1-yl)methyl)octahydro-2H-quinolizine)] exhibited the most potent AChE inhibitory activity among all 63 lupinine derivatives, and kinetic analysis demonstrated that compound 15 was a mixed-type AChE inhibitor. Molecular docking studies were performed to visualize interaction between this triazole derivative and AChE. In addition, a structure-activity relationship (SAR) model developed using linear discriminant analysis (LDA) of 11 SwissADME descriptors from the 50 lupinine esters revealed 5 key physicochemical features that allowed us to distinguish active versus non-active compounds. Thus, this SAR model could be applied for design of more potent lupinine ester-based AChE inhibitors

Phenolic compounds from <i>Glycyrrhiza pallidiflora</i> Maxim. and their cytotoxic activity

<p>Twenty-one phenolic compounds (<b>1</b>–<b>21</b>) including dihydrocinnamic acid, isoflavonoids, flavonoids, coumestans, pterocarpans, chalcones, isoflavan and isoflaven, were isolated from the roots of <i>Glycyrrhiza pallidiflora</i> Maxim. Phloretinic acid (<b>1</b>), chrysin (<b>6</b>), 9-methoxycoumestan (<b>8</b>), isoglycyrol (<b>9</b>), 6″-O-acetylanonin (<b>19</b>) and 6″-O-acetylwistin (<b>21</b>) were isolated from <i>G. pallidiflora</i> for the first time. Isoflavonoid acetylglycosides <b>19</b>, <b>21</b> might be artefacts that could be produced during the EtOAc fractionation process of whole extract. Compounds <b>2</b>–<b>4</b>, <b>10</b>, <b>11</b>, <b>19</b> and <b>21</b> were evaluated for their cytotoxic activity with respect to model cancer cell lines (CEM-13, MT-4, U-937) using the conventional MTT assays. Isoflavonoid calycosin (<b>4</b>) showed the best potency against human T-cell leukaemia cells MT-4 (CTD₅₀, 2.9 μM). Pterocarpans medicarpin (<b>10</b>) and homopterocarpin (<b>11</b>) exhibit anticancer activity in micromolar range with selectivity on the human monocyte cells U-937. The isoflavan (3<i>R</i>)-vestitol (<b>16</b>) was highly selective on the lymphoblastoid leukaemia cells CEM-13 and was more active than the drug doxorubicin</p

Selecting a Green Strategy on Extraction of Birch Bark and Isolation of Pure Betulin Using Monoterpenes

The aim of this work is to study sustainable approaches to pure betulin using green low-polar solvents from natural feedstockpine monoterpenes and limonene. The conventional methods of extracting outer birch bark (OBB) lead to extracts that contain only 50%–75% of betulin, while refining processes of OBB extracts are usually labor consuming and employ toxic solvents. The extractions of OBB using monoterpenes and their hydrogenated analogs at boiling and microwave-assisted conditions turned out to be insufficiently selective and lead to a significant uptake of extractants on the depleted bark. To obtain pure betulin, the sequence including energy-saving extraction of OBB with a green solvent (ethyl acetate, EtOAc), saponification of the extract, and purification of betulin in limonene or hydrogenated monoterpenes was proposed. The protocol of processing primary extracts with stable monoterpeneslimonene, pinane, and hydrogenated turpentine oilensured separation of pure betulin (95%–97%) with high yields (75%–82%) and the effective recycling of extractants (81%–87%). The refining of plant metabolites in monoterpenes can be regarded as a promising method, successfully competing with the known multistep processes and methods employing toxic solvents