Highly Aromatic Norditerpenoid Heterodimers and Monomers from Trigonostemon fragilis

Four new norditerpenoid heterodimers with different dimerization patterns-namely,trigofragiloids A-C(denoted as compounds 1-3)and(+)-and(-)-trigofragiloid D(compound 4)-and three new phenanthrenone norditerpenoids-namely,trigofragiloids E-G(compounds 5-7)-were isolated from Trigonostemon fragilis.Compounds 1 and 2 feature a novel heterodimeric carbon skeleton formed by the conjugation of a tetra-norditerpenoid and an ennea-norditerpenoid;they have been identified as class 2 atropisomers by means of quantum chemical calculations.Compound 3 is an unprecedented phenylpropanoid-norditerpenoid adduct with a new dimerization pattern.Compounds(+)-and(-)-4 are the first example of S-shaped 1,4-dioxane-fused norditerpenoid dimers.Inspired by the structure elucidation of compound 4,two co-occurring analogues,actephilol A and epiactephilol A,were structurally revised as a pair of geometrical isomers and were identified as two pairs of enantiomers,(+)-and(-)-8 and(+)-and(-)-9,respectively.Their structures were characterized using a combined method.Notably,compound 7 exhibits remarkable adenosine triphosphate-citrate lyase(ACLY)inhibition with a halfmaximal inhibition concentration(IC50)value of(0.46±0.11)lmol·L^(-1),as active as the positive control BMS-303141,and a molecular docking study offers deep insight into the interaction between compound 7 and ACLY.

New apotirucallane-type triterpenoids from Chisocheton paniculatus

Two new apotirucallane triterpenoids,namely chisiamols G(1)and H(2),featuring a 21,23-lactone,together with five known triterpenoids,were isolated from the twigs of Chisocheton paniculatus.The structures of the new compounds were elucidated on the basis of spectroscopic and chemical methods.

Natural products inspired[3+2]cycloaddition enables efficient construction of hydroxylated tetrahydrofuran acetals and concise syntheses of lignans

Mimicking biosynthetic pathways of hongkonoids led to the development of a new Cu(Ⅰ)-catalyzed[3+2]cycloaddition ofα-hydroxyketone andβ-keto enol ethers,affording tetrahydrofuran acetals in a highly diastereoselective manner and 100%atom economy.Computational studies on the mechanism disclosed a concerted but asynchronous Michael addition/aldol reaction.Of the same importance,this methodology provides a practical biomimetic approach for one-step construction of the dibenzylbutyrolactol lignan backbone starting from two phenyl propane derivatives,opening up a powerful new approach for lignan synthesis,which is showcased by succinct total syntheses of two biologically important aryltetralin-type lignans,β-apopicropodophyllin and cycloolivil.Given the mild and operationally simple conditions,the developed chemistry might have a promising prospect in potential industrial applications.

A new class of potent liver injury protective compounds: Structural elucidation, total synthesis and bioactivity study

A new class of potent liver injury protective compounds,phychetins A-D(1-4)featuring an unique 6/6/5/6/5 pentacyclic framework,were isolated and structurally characterized from a Chinese medicinal plant Phyllanthus franchetianus.Compounds 2-4 are three pairs of enantiomers that were initially obtained in a racemic manner,and were further separated by chiral HPLC preparation.Compounds 1-4 were proposed to be originated biosynthetically from a coexisting lignan via an intramolecular Friedel-Crafts reaction as the key step.A bioinspired total synthesis strategy was thus designated,and allowed the effective syntheses of compounds 2-4 in high yields.Some of compounds exhibited significant anti-inflammatory activities in vitro via suppressing the production of pro-inflammatory cytokine IL-1β.Notably,compound 4,the most active enantiomeric pair in vitro,displayed prominent potent protecting activity against liver injury at a low dose of 3 mg/kg in mice,which could serve as a promising lead for the development of acute liver injury therapeutic agent.

Suadimins D—J,Monoterpenoid Indole-Quinoline and Bisindole Alkaloids from Melodinus suaveolens

Comprehensive Summary,Compounds 1—12,including seven complex monoterpenoid indole-quinoline and bisindole alkaloids,suadimins D—J(1—7)with previously unreported carbon-carbon linkages,were isolated and identified from the twigs and leaves of Melodinus suaveolens.Their structures were elucidated by a combination of diverse methods,especially the extensive spectroscopic data analysis and electric circular dichroism(ECD)calculations.The cytotoxicity of these compounds against three cancer cell lines was evaluated,some of which showed moderate activities with IC50 values ranging from 2.4 to 8.0μM.

Two Terpenoid Derivatives with Different 3/5/6/6/5-Fused Pentacyclic Skeletons from Hedyosmum orientale

Chemical investigation of Hedyosmum orientale led to the identification of two terpenoid derivatives,dyosmunoids A and B(1 and 2)featuring two different 3/5/6/6/5-fused pentacyclic ring systems,respectively.Compound 1 is the second natural product of this C_(25) terpenoid compound class,and compound 2 is a rare dinor-C25 terpenoid with a peroxide bridge.Their structural elucidation was achieved by the comprehensive analysis of spectroscopic data,single-crystal X-ray diffraction,and ECD calculation.Putative biosynthetic pathways for compounds 1 and 2 are proposed.Compound 2 exhibited strong antimalarial activity with an IC_(50) value of 0.42μmol·L^(-1).

Frontier studies on natural products:moving toward paradigm shifts

1 Introduction Natural products(NPs)historically serve as a valuable and productive source of bioactive compounds for drug development.The discovery of a range of alkaloids in the early1800s,including strychnine,morphine,etc.,heralded a new era of isolating plant-derived bioactive compounds in the field of NPs[1].

Attractive natural products with strained cyclopropane and/or cyclobutane ring systems

The strained cyclopropane and/or cyclobutane subunits occurred in many complex natural products including terpenoids, steroids and alkaloids. Natural products with cyclopropane and/or cyclobutane motifs not only furnished fascinating structures, but also exhibited versatile biological activities, such as cytotoxic, anti-HIM antimicrobial, antiviral, and immunosuppressive effects. This review covered a large array of structurally unique natural products with strained cyclopropane and/or cyclobutane motifs and summarized their structural features, distributions, biological activities, as well as biogenetic considerations.

Amphiphilic drug-drug conjugate for cancer therapy with combination of chemotherapeutic and antiangiogenesis drugs

The progression and metastasis of solid tumors strongly rely on the process of forming nascent blood vessels.However,using angiogenesis inhibitors alone does not meet the cancer treatment needs.Herein,we used the amphiphilic drug-drug conjugate(ADDC)strategy to fabricate a new drug conjugate with the combination of chemotherapeutic drug and antiangiogenesis drug together.With one-step esterification of hydrophilic floxuridine(FUDR)and hydrophobic pseudolaric acid B(PAB),the conjugate was synthesized.The amphiphilic property of FUDR-PAB conjugate induced the self-assembly to form nanoparticles in water.From further in vitro and in vivo experiments,this FUDR-PAB conjugate does not only have a high antitumor effect,but also shows efficient antianiogenesis property.These results offer a promising ADDC strategy for designing drugs with combination of chemotherapeutic drug and antiangiogenesis drug together.

Rearranged Dichapetalin-Type Triterpenoids with Cytotoxic Activity from Dichapetalum gelonioides

Dichagelinoids A—C(1—3),three unusual dichapetalin-type triterpenoids,together with two biogenetically related derivatives dichagelinoids D and E(4 and 5)were isolated and characterized by solid data from Dichapetalum gelonioides.Compounds 1—3 possess a common rearranged C ring and different C6—C2 modified motifs at the A rings.Biological evaluation revealed that compounds 1—3 showed distinct cytotoxic activity against the tested human cancer cell lines.

Picomolar antimalarial agent from a Chinese medicinal plant

In our long-term efforts searching for antimalarial agents from Chinese medicinal plants,seven novel dimeric sesquiterpenoids(1–7)with significant antimalarial activity were isolated and characterized from the whole plants of Sarcandra glabra subsp.brachystachys by solid data acquired by diverse methods.Among them,compound 3 with an EC50 value of 4.3 pM against the chloroquine-resistant Plasmodium falciparum is the most potent antimalarial agent reported hitherto,about 1,000-fold stronger than artemisinin.This article further consolidates and refines our previously delineated structure-activity relationship for this antimalarial compound class.

Cephalotane-Type Norditerpenoids from Cephalotaxus fortunei var.alpina

A chemical investigation of the 95%EtoH extract of the seeds of Cephalotaxus fortunei var.alpina led to the isolation of nine new cephalotane-type norditerpenoids,ceforalides A-I(1-9),and two known analogues(10 and 11).Compounds 1-8 belong to a rare class of A-ring-contracted cephalotane-type norditerpenoids,of which compound 8 incorporates a unique tetrasubstituted 2,5-cyclohexadienone A-ring.Compound 9 is a rare 13,14-seco-17-nor-cephalotane-type diterpenoid.Their structures were determined based on NMR,HRESIMS,ECD,and X-ray diffraction analysis.Biological tests revealed compounds 10 and 11 displayed moderate antimalarial activity.

A new class of HIV-1 inhibitors and the target identification via proteomic profiling

Anti-HIV screening with the MT-4/MTT assay on a focused library of structurally diverse natural products has led to the discovery of a group of steroids with potent activities, which include four new ergostane-type steroids, named amotsterols A-D （1-4）, together with two known analogs. Among them, the most potent amotsterol D （4） exhibited anti-HIV activity against wild- type and some clinically relevant multidrug resistant HIV-I strains. Subsequent studies on its target identification through a proteomic approach found that compound 4 might target PKM2, a rate limiting enzyme ofglycolysis, in host cells to restrict HIV replication. The docking model of compound 4 to PKM2 showed that the two hydroxyl groups of 4 form hydrogen bonds with the two parallel Y390 in each subunit of PKM2 separately, and the ring C of 4 is sandwiched between the two parallel aromatic rings ofF26. The identified hit compound may have the potential to be further developed as a novel anti-HIVagent. These results demonstrated that an integrated approach, which combines new chemical structures and phenotypic screening with a proteomic approach, could not only identify novel HIV-1 inhibitors, but also elucidate the unknown targets of compound interactions in antiviral drug discovery.

Macrocyclic Nonapeptides Incorporating Uncharacterized Amino Acids with Inhibitory Effects on Th17 Differentiation

Four unprecedented macrocyclic nonapeptides,orberryamides A–D(1–4),were isolated from Glycosmis pentaphylla(orangeberry)and structurally characterized by obtaining solid data from numerous analytical measurements.Compound 1 incorporated a new amino acid residue,named orangeberrine(Orgb),compounds 2 and 3 integrated the rare,nonproteinogenic amino acid residues(Kyn and Dioia,respectively),and compound 4 existed as two major conformational isomers in solution at ambient temperature.The biosynthetic pathways proposed for compounds 1–4 are of considerable biological significance for the modification and metabolism of tryptophan(Trp)and/or Trp containing proteins in nature.Besides,compounds 1–4 suppressed Th17 differentiation significantly,and the effects of 1–3 was achieved through targeting the ligand-binding domain(LBD)of the retinoic acid-related orphan receptor gamma t(RORγt).

Concise Total Synthesis of Dysoxylactam A and a Simplified Analog

A total synthesis of 17-membered macrocyclolipopeptide dysoxylactam A,a potent agent reversing P-glycoprotein(P-gp)-mediated multidrug resistance(MDR)in cancer cells,was developed from the starting material(S)-2-methylbutanal in a linear sequence of 12 steps with 23.2%overall yield.The key steps include proline-catalyzed asymmetric aldol reaction,Evans aldol reaction and Krische allylation to construct the multiple stereocenters containing fragment,and ring-closing metathesis to furnish the macrocycle.This total synthesis facilitates the preparation of large amount samples of dysoxylactam A and the side chain simplified derivatives for further biological tests and preliminary structure-activity relationship exploration.