Guozheng Huang

Synthesis, biological evaluation, and computational studies of Tri- and tetracyclic nitrogen-bridgehead compounds as potent dual-acting AChE inhibitors and hH3 receptor antagonists.

Combination of AChE inhibiting and histamine H3 receptor antagonizing properties in a single molecule might show synergistic effects to improve cognitive deficits in Alzheimers disease, since both pharmacological actions are able to enhance cholinergic neurotransmission in the cortex. However, whereas AChE inhibitors prevent hydrolysis of acetylcholine also peripherally, histamine H3 antagonists will raise acetylcholine levels mostly in the brain due to predominant occurrence of the receptor in the central nervous system. In this work, we designed and synthesized two novel classes of tri- and tetracyclic nitrogen-bridgehead compounds acting as dual AChE inhibitors and histamine H3 antagonists by combining the nitrogen-bridgehead moiety of novel AChE inhibitors with a second N-basic fragment based on the piperidinylpropoxy pharmacophore with different spacer lengths. Intensive structure-activity relationships (SARs) with regard to both biological targets led to compound 41 which showed balanced affinities as hAChE inhibitor with IC50 = 33.9 nM, and hH3R antagonism with Ki = 76.2 nM with greater than 200-fold selectivity over the other histamine receptor subtypes. Molecular docking studies were performed to explain the potent AChE inhibition of the target compounds and molecular dynamics studies to explain high affinity at the hH3R.

Design, synthesis and in vitro evaluation of novel uni- and bivalent ligands for the cannabinoid receptor type 1 with variation of spacer length and structure.

Using rimonabant, a potent inverse agonist for cannabinoid receptor type 1 (CB1R), as parent ligand, a series of novel univalent and bivalent ligands were designed by variation of spacer length and its chemical structure. The ligands synthesized were evaluated for affinity and selectivity by radioligand displacement and a functional steady-state GTPase assay. The results showed the nature of the spacer influences the biological readout. Albeit all compounds show significantly lower affinities than rimonabant, this fact could be used to demonstrate that affinities and selectivity are influenced by the chemical structure and length of the spacer and might be helpful for designing bivalent probes for other GPCR receptors.

Rational Modification of the Biological Profile of GPCR Ligands through Combination with Other Biologically Active Moieties.

In recent years, G protein‐coupled receptor (GPCR) ligands have not only been modified by conducting structure–activity relationship studies of leads and known ligands, but several new approaches have emerged in which GPCR ligands were connected or merged with other biologically active molecules. Identical or related ligands were combined to bivalent ones. Orthosteric ligands were combined with allosteric ligands, sometimes leading to dualsteric ones, and also chemical structures were merged to dual‐acting or multifunctional compounds. In this article, we want to present some representative examples for these approaches at different GPCRs, showing the versatility of this approach, with a focus on our own work and references to related articles and reviews.

Novel convenient synthesis of (Z/E)-8-dodecenyl acetates, components of the Grapholitha molesta sex pheromone

Components of the Grapholitha molesta sex pheromone, (Z/E)-8-dodecenyl acetates (1, 2), were synthesized in five steps in 20% overall yield using 10-hydroxydecanoic acid (3) as starting material.

Isolation of new polyacetylenes from the roots of Eurycoma longifolia via high-speed counter-current chromatography

Eurycoma longifolia is a tropical plant of diverse applications in folk medicine, which occurs in Southeast Asia. In this study, pre-purified fraction (0.86g) of the crude extracts from the roots of E. longifolia, was subjected to preparative high-speed counter-current chromatography (HSCCC) with a two-phase solvent system composed of hexane-ethyl acetate-methanol-water (HEMWat) at a volume ratio of 5:2:5:2 (v/v). Longifolione A (1, 19mg, purity 96.0%) and longifolione C (3, 317mg, purity 96.2%), together with longifolione B (2, purity 77.6%) were isolated in one run. The whole mobile and stationary phase was then blown out, concentrated in vacuo, and subjected to second HSCCC purification. Using HEMWat at a volume ratio of 6:1:6:1.2 (v/v), this fraction yielded two more new polyacetylenenes, longifolione D (4, 5mg purity 94.5%) and longifolione E (5, 33mg purity 96.3%). All of these five compounds are new natural products and isolated from E. longifolia for the first time. The established protocol for large-scale isolation of these polyacetylenes from E. longifolia was simple, efficient, and economical.

Unconventional application of the Mitsunobu reaction: Selective flavonolignan dehydration yielding hydnocarpins

Summary Various Mitsunobu conditions were investigated for a series of flavonolignans (silybin A, silybin B, isosilybin A, and silychristin A) to achieve either selective esterification in position C-23 or dehydration in a one-pot reaction yielding the biologically important enantiomers of hydnocarpin D, hydnocarpin and isohydnocarpin, respectively. This represents the only one-pot semi-synthetic method to access these flavonolignans in high yields.

Diversity-oriented synthesis of amide derivatives of tricyclic thieno[2,3-d]pyrimidin-4(3H)-ones and evaluation of their influence on melanin synthesis in murine B16 cells

Abstract A diversity-oriented synthesis of amide-containing thieno[2,3-d]pyrimidin-4(3H)-ones is reported. All compounds were tested for their influence on melanin synthesis in murine B16 cells. The azepine fragment in thieno[2,3-d]pyrimidin-4(3H)-one skeleton significantly increases the melanin content.

Synthesis and in vitro biological evaluation of novel diaminothiophene scaffolds as antitumor and anti-influenza virus agents. Part 2

On the basis of high-throughput screening, fragment-based drug discovery, structure–activity relationships and building block analysis methods, herein we report the synthesis and biological evaluation of a novel series of diethyl 2,5-diaminothiophene-3,4-dicarboxylate derivatives. All of the prepared Schiff bases (with mono-, di- and poly-substituents at the aromatic portion), mono- and bis-amides of diethyl 2,5-diaminothiophene-3,4-dicarboxylate, were evaluated against various human cancer and non-cancerous (only for active compounds) cell lines, as well as influenza A (subtypes FM/1/47/H1N1, hanfang/359/95/H3N2) and B (subtype jifang/13/97) viruses. The obtained results suggest that some selected compounds revealed promising antitumor and antiviral activities and may serve as lead compounds for further drug discovery and development.

Cytotoxic properties of the alkaloid rutaecarpine and its oligocyclic derivatives and chemical modifications to enhance water-solubility

The alkaloid rutaecarpine and its derivatives have been described as cytotoxic and hold potential as antitumor agents. Nevertheless, their synthesis is demanding and compounds display poor water solubility. Herein, we describe the synthesis of two sets of rutaecarpine derivatives with amine functions to improve solubility. Using a classic shake-flask experiment and a potentiometric titration platform, the water solubility of the compounds was determined. Solubility improved significantly with the amine functions connected over the indole-N atom. Reduction of metabolic activity and cell viability on HeLa cells was in the same range or better for these derivatives compared to the chemically unaltered parent compounds prepared in a new synthetic procedure established in our group.

Total synthesis of rupestine G and its epimers

Rupestine G is a guaipyridine sesquiterpene alkaloid isolated from Artemisia rupestris L. The total synthesis of rupestine G and its epimers was accomplished employing a Suzuki reaction to build a terminal diene moiety. The diene was further elaborated into the desired guaipyridine structure by a ring-closing metathesis reaction. Over all, rupestine G and its three epimers were obtained as a mixture in a sequence of nine linear steps with 18.9% yield. Rupestine G and its optically pure isomers were isolated by chiral preparative HPLC and fully characterized by 1H ,13C NMR, HRMS, optical rotation value, and experimental and calculated electronic circular dichroism spectroscopy.