Hypercholesterolemia has posed a serious threat of heart diseases and stroke worldwide. Xanthine oxidase (XO), the rate-limiting enzyme in uric acid biosynthesis, is regarded as the root of reactive oxygen species (ROS) that generate atherosclerosis and cholesterol crystals. β-Hydroxy β-methylglutaryl-coenzyme A reductase (HMGR) is a rate-limiting enzyme in cholesterol biosynthesis. Although some commercially available enzyme inhibiting drugs have effectively reduced cholesterol levels, most of them have failed to meet potential drug candidates’ requirements. Here, we have carried out an in-silico analysis of secondary metabolites that have already shown good inhibitory activity against XO and HMGR in a wet lab setup. Out of 118 secondary metabolites reviewed, sixteen molecules inhibiting XO and HMGR were selected based on the IC50 values reported in in vitro assays. Further, receptor-based virtual screening was carried out against secondary metabolites using GOLD Protein-Ligand Docking Software, combined with subsequent post-docking, to study the binding affinities of ligands to the enzymes. In-silico ADMET analysis was carried out to explore their pharmacokinetic properties, followed by toxicity prediction through ProTox-II. The molecular docking of amentoflavone (GOLD score 70.54, ∆G calc. = − 10.4 Kcal/mol) and ganomycin I (GOLD score 59.61, ∆G calc. = − 6.8 Kcal/mol) displayed that the drug has effectively bound at the competitive site of XO and HMGR, respectively. Besides, 6-paradol and selgin could be potential drug candidates inhibiting XO. Likewise, n-octadecanyl-O-α-D-glucopyranosyl (6′ → 1″)-O-α-D-glucopyranoside could be potential drug candidates to maintain serum cholesterol. In-silico ADMET analysis has shown that these sixteen metabolites were optimal within the categorical range compared to commercially available XO and HMGR inhibitors, respectively. Toxicity analysis through ProTox-II revealed that 6-gingerol, ganoleucoin K, and ganoleucoin Z are toxic for human use. This computational analysis supports earlier experimental evidence towards the inhibition of XO and HMGR by natural products. Further study is necessary to explore the clinical efficacy of these secondary molecules, which might be alternatives for the treatment of hypercholesterolemia.

/pdf/potential-natural-inhibitors-of-xanthine-oxidase-and-hmg-coa-2axtr9te27.pdf

Potential natural inhibitors of xanthine oxidase and HMG-CoA reductase in cholesterol regulation: in silico analysis.

The current study provides a comprehensive overview and analysis of the lignan literature. Data for the current study were extracted from the electronic Web of Science Core Collection database via the search string TOPIC = ("lignan*") and processed by the VOSviewer software. The search yielded 10,742 publications. The ratio of original articles to reviews was 14.6:1. Over 80% of the analyzed papers have been published since the year 2000 and nearly 50% since the year 2010. Many of the publications were focused on pharmacology, chemistry, and plant sciences. The United States and Asian countries, such as China, Japan, South Korea, and India, were the most productive producers of lignan publications. Among the 5 most productive institutions was the University of Helsinki in Finland, the country that ranked 9th. Nineteen journals collectively published 3,607 lignan publications and were considered as core journals. Their impact factor did not correlate with the proportion of uncited papers. Highly cited publications usually mentioned phytoestrogen, isoflavone, daidzein, enterodiol, enterolactone, equol, genistein, and isoflavonoid. Cancer (e.g., breast cancer), cardiovascular disease, and antioxidation were the major themes. Clinical trials were estimated to contribute to 0.2-1.1% of the analyzed body of literature, so more of them should be conducted in the future to substantiate the beneficial effects and optimal dose of lignan intake in humans. Moreover, researchers can refer to these findings for future research directions and collaborations.

https://repositorium.sdum.uminho.pt/bitstream/1822/64329/1/document_53560_1.pdf

Lignans: Quantitative Analysis of the Research Literature

Review of lignans from 2019 to 2021: Newly reported compounds, diverse activities, structure-activity relationships and clinical applications.

5-Methoxyleoligin and leoligin are natural occurring lignans derived from Edelweiss (Leontopodium nivale ssp. alpinum), displaying potent pro-angiogenic and pro-arteriogenic activity. Cholesterol efflux from macrophages is associated with reverse cholesterol transport which inhibits the development of cardiovascular disease. Within this study, we developed a modular and stereoselective total synthesis of 5-methoxyleoligin which can be readily used to prepare a novel compound library of related analogs. The target 5-methoxyleoligin was synthesized exploiting a recently disclosed modular route, which allows also rapid synthesis of analogous compounds. All obtained products were tested towards macrophage cholesterol efflux enhancement and the performance was compared to the parent compound leoligin. It was found that variation on the aryl moiety in 2-position of the furan ring allows optimization of the activity profile, whereas the ester-functionality does not tolerate significant alterations.

/pdf/design-and-synthesis-of-a-compound-library-exploiting-5-c03r8lv2xi.pdf

Design and Synthesis of a Compound Library Exploiting 5-Methoxyleoligin as Potential Cholesterol Efflux Promoter.

Enantioselective syntheses of furan lignans (-)-dihydrosesamin and (-)-acuminatin and furofuran lignans (-)-sesamin and (-)-methyl piperitol were achieved in up to only three steps in 43%, 42%, 63%, and 60% overall yield,respectively, with high optical purity through stereoselective intramolecular radical cyclization of suitably substituted epoxy olefinic ethers using bis(cyclopentadienyl)titanium(III) chloride as the radical initiator. The key intermediate, chiral epoxy alcohol 4, was prepared by the Sharpless kinetic resolution method. The titanium(III) initiator was prepared in situ from commercially available titanocene dichloride and activated zinc dust in tetrahydrofuran.

Concise Enantioselective Synthesis of Furan Lignans (‐)‐Dihydrosesamin and (‐)‐Acuminatin and Furofuran Lignans (‐)‐Sesamin and (‐)‐Methyl Piperitol by Radical Cyclization of Epoxides.

Recently, a natural compound leoligin, a furan-type lignan, was discovered as an interesting hit compound with an anti-inflammatory pharmacological activity profile. We developed a modular and stereoselective approach for the synthesis of the edelweiss-derived lignan leoligin and used the synthetic route to rapidly prepare leoligin analogs even on the gram scale. Proof of concept of this approach together with cell-based bio-assays gained structural analogs with increased selectivity towards vascular smooth muscle versus endothelial cell proliferation inhibition, a major benefit in fighting vascular neointima formation. In addition, we identified the structural features of leoligin analogs that define their ability to inhibit the pro-inflammatory NF-κB pathway. Results are discussed in the context of structural modification of these novel synthetic lignans.

/pdf/leoligin-inspired-synthetic-lignans-with-selectivity-for-4pv7cu719i.pdf

Leoligin-inspired synthetic lignans with selectivity for cell-type and bioactivity relevant for cardiovascular disease

(-)-Zampanolide (1), a natural product isolated from a marine sponge, is a microtubule-stabilizing agent that exhibits activity in the nanomolar range against various cancer cells, including in P-gp pump overexpressing cells. This attribute makes (-)-zampanolide an interesting target for further investigation. In this work, a new method for a modular and convergent total synthesis of optically pure zampanolide was investigated, which would also allow the generation of “zampanalogs” following the same basic strategy. Their biological activity may then be assessed to allow the elucidation of structure-activity relationships of (-)-zampanolide and its analogs in tubulin binding.  The synthetic plan consisted of the modular combination of four major fragments, which would be connected in the late stages of the synthesis and could therefore be easily exchanged to allow the generation of analogs. The C15-C16 bond would be connected via an alkynylation reaction, and a subsequent reductive methylation would install the trisubstituted alkene. The connections at C1 and C3 could be achieved through a Bestmann ylid linchpin reaction, while the macrolactonization would be completed using a ring-closing metathesis to form the C8-C9 alkene. The side chain could be attached at C20 using one of the established aza-aldol methods.  The fragments necessary for the formation of the macrocycle were synthesized successfully. The purification strategy throughout the synthetic route was rationalized and provides an improvement with respect to yield and time compared to work previously done in this research group. Alongside these fragments, modified fragments that were originally intended to serve as model systems were synthesized, which could also be used as building blocks in the synthesis of “zampanalogs”.  Several methods for a stereoselective alkynylation at C15 were tested. These led to only meager successes, so an approach using a non-stereoselective alkynylation, followed by oxidation and a stereoselective CBS-reduction, was chosen. For the installation of the trisubstituted alkene a reductive methylation with vitride was tested, but this only led to the reduction of the alkyne without methylation. This product may be employed for the synthesis of C17-desmethyl analogs. The reductive methylation at C16-C17 was ultimately achieved using the Gilman reagent in a similar manner to the installation of the C5 methyl group in the C3-C8 fragment.  A linchpin strategy with the Bestmann ylid simultaneously formed the connectivity at C1 and C3. This process was successfully performed on multiple substrates arising from the model systems used in the alkynylation and reductive methylation reactions, yielding precursors to the ring-closing metathesis and potentially enabling the synthesis of various analogs.  The ring-closing metathesis proved to be difficult in analogs lacking the C17 methyl group and cis-tetrahydropyran ring, and due to this tendency further investigations are necessary. Once the macrocycle has been closed, a global deprotection and oxidation of hydroxy groups is necessary to allow for the installation of the sidechain.

Sophie Geyrhofer

Papers

Leoligin-inspired synthetic lignans with selectivity for cell-type and bioactivity relevant for cardiovascular disease

Design and Synthesis of a Compound Library Exploiting 5-Methoxyleoligin as Potential Cholesterol Efflux Promoter.

Chasing "Zampanalogs": Advancing the Synthesis of the Zampanolide Macrocycle

The role of extracellular serotonin and MDMA in the sensitizing effects of MDMA