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Eleven new nitrogenous meroterpenoids, cinerols A-K (1-11), were isolated from the marine sponge Dysidea cinerea collected in the South China Sea, and their structures were determined by detailed spectroscopic analysis. Cinerols A (1) and B (2) feature a rare 5H-pyrrolo[1,2a]benzimidazole moiety, while cinerols C-G (3-7) are examples of rare meroterpene benzoxazoles. The cinerols are noncytotoxic to human melanoma A375 cells at the concentration of 32 μM; however, selected cinerols exhibit moderate inhibitory activity against one or more of protein-tyrosine phosphatase 1B, ATP-citrate lyase, and SH2 domain-containing phosphatase-1 with IC50 values of 2.8-27 μM.

The chemical investigation of the marine sponge Dysidea frondosa discovered a pair of unprecedented bioconjugates that are composed of a meroterpene and an unusual psammaplysin alkaloid. The structures of frondoplysins A (1) and B (2) were characterized by analysis of HRMS and NMR data coupled with single-crystal X-ray diffraction. Frondoplysin A was found to be a potent inhibitor targeting protein-tyrosine phosphatase 1B (PTP1B) with an IC50 value of 0.39 μM.

Four indole alkaloids, alstonlarsines A–D (1–4), were isolated from Alstonia scholaris and structurally characterized. Compound 1 possesses a new carbon skeleton with a cage-shaped 9-azatricyclo[4.3.1.03,8]decane motif, and compounds 2–4 feature a rare carbon skeleton that was found in nature for the first time. Plausible biosynthetic routes for 1–4 are proposed. Compound 1 showed DRAK2 inhibitory activity with an IC50 value of 11.65 ± 0.63 μΜ.

Poor medication adherence is one of the leading causes of suboptimal glycaemic control in approximately half of the patients with type 2 diabetes mellitus (T2DM). Long-acting antidiabetic drugs are clinically needed for improving patients' compliance. Dipeptidyl peptidase-4 (DPP-4) inhibitors play an increasingly important role in the treatment of T2DM because of their favorable properties of weight neutrality and hypoglycemia avoidance. Herein, we report the successful discovery and scale-up synthesis of compound 5, a structurally novel, potent, and long-acting DPP-4 inhibitor for the once-weekly treatment of T2DM. Inhibitor 5 has fast-associating and slow-dissociating binding kinetics profiles as well as slow clearance rate and long terminal half-life pharmacokinetic properties. A single-dose oral administration of 5 (3 mg/kg) inhibited80% of DPP-4 activity for more than 7 days in diabetic mice. The long-term antidiabetic efficacies of 5 (10 mg/kg, qw) were better than those of the once-weekly trelagliptin and omarigliptin, especially in decreasing the hemoglobin A1c level.

Hedyorienoids A (1) and B (2), two sesquiterpenoid dimers, were isolated and characterized from Hedyosmum orientale. Compound 1 was an unprecedented heterodimer of two different classes of sesquiterpenoids furnished by forming an unusual 1,3-dioxolane ring, while compound 2 possessed a new dimerization pattern of two guaiane-type sesquiterpenoids. Biosynthetic pathways for 1 and 2 were proposed with the coexisting monomers chloranthalactone A (3) and hedyosumin A (4) as the precursors. Compounds 2 and 3 showed significant NF-κB inhibitory activity.

Eight enantiomeric pairs of new meromonoterpenoids (1a/1b-8a/8b) and four known compounds (9-12) were isolated from Rhododendron nyingchiense. Their structures were established by spectroscopic methods, quantum chemical calculations, and X-ray crystallography. The enantiomeric pairs were acquired from scalemic mixtures by chiral-phase HPLC and showed diverse heterocyclic frameworks. Compounds 1a/1b possess a rare 6/7/5/5 heterocyclic system, and 2a/2b incorporate a new 6/6/3/5 heterocyclic system featuring a quinone motif. Compounds 3a/3b represent the first meroterpenoids with a 6/6/5 ring system from the Rhododendron genus. Putative biosynthetic pathways of these compounds are proposed. Compounds 1b, 2a-4a, 8a, 8b, and 11 exhibited weak inhibitory effects on PTP1B, with IC50 values ranging from 5.7 ± 0.5 to 61.0 ± 4.8 μM.

(+)- and (−)-Mangelonoids A and B, two pairs of novel macrocyclic diterpenoid enantiomers featuring an unprecedented bicyclo[9.3.1]pentadecane core and a rare bridgehead double bond, were isolated from Croton mangelong. Their structures were unambiguously established using spectroscopic data, X-ray crystallography, and electronic circular dichroism analysis. A plausible biosynthesis pathway for these compounds was proposed. (−)-Mangelonoid A exhibited NF-κB inhibition with an IC50 value of 7.27 ± 1.30 μM.

Hongkonoids A-D (1-4), the first example of ascorbylated terpenoids featuring a unique 5,5,5-fused tricyclic spiroketal butyrolactone moiety and diterpenoid-derived long chain, were isolated from Dysoxylum hongkongense. Their structures were unambiguously assigned by a combination of spectroscopic data, chemical degradation, X-ray crystallography, CD analysis, and total synthesis. The total syntheses of compounds 1-4 were effectively accomplished by a convergent strategy with the longest linear sequences of 12-14 steps and overall yields of 5.4-9.6%. Notably, we exploited a bioinspired one-pot method to construct the key intermediate 14 from an easily made compound 12 by involving the cascade reactions of an elaborate Claisen rearrangement, deprotections, and a 5-exo-trig cyclization. The desired major epimer 14a was then transformed to the main building block 21. Assembly of 21 and the long chain vinyl iodide 7 was made by an NHK coupling reaction to furnish the framework of 1-4. Some of the hongkonoids and/or synthetic analogs showed significant to moderate inhibitory activities against NF-κB, 11β-HSD1, and sterol synthesis. The most active NF-κB inhibitor 34 exhibited distinct inhibition on the LPS-induced inflammatory responses in RAW 246.7 and primary BMDM cells.

Chemical investigation into the alkaloidal constituents of the Nepalese Daphniphyllum himalense has returned two new compounds, himalensines A (1) and B (2), with unprecedented carbon skeletons. Structures of the two alkaloids have been characterized on the basis of spectroscopic methods, especially via 2D NMR data analysis. Himalensine B (2) showed marginal inhibitory activities against two kinases, PTP1B and IKK-β.

An efficient method for the soluble polymer-supported synthesis of 5-arylidene thiazolidinones and pyrimidinones using aniline as a traceless linker was described. Aldehyde substrates were attached to the polyethylene glycol (PEG)-bound aniline via an imine linkage, and after the subsequent PEG-promoted Suzuki coupling reaction for the diversification, Knoevenagel condensation was readily employed as the cleavage strategy.

A series of pyridine-2-carboxylic acid derivatives were synthesized according to the leads from the screening, and potent inhibitors have been obtained by structural modification. They have shown submicromolar inhibition of the enzymes (for example, for 9n, IC(50) = 130 nM for EcMetAP1 and IC(50) = 380 nM for ScMetAP1). They represent small-molecule MetAP inhibitors with novel structures different from alkylating fumagillin derivatives and peptidic bestatin-based MetAP inhibitor.

The synthesis and matrix metalloproteinase (MMP) inhibitory activity of a series of gamma-keto carboxylic acids are described. Among nine MMP isozymes tested, compound 1j displays selective inhibition of MMP-2, -9, and -12 with IC(50) values between 0.20 and 1.51 microuM, and in male golden Syrian hamsters, it shows protection against PPE-induced emphysema.