Unprecedented sesquiterpene-polycyclic polyprenylated acylphloroglucinol adduct against acute myeloid leukemia via inhibiting mitochondrial complex Ⅴ

Monosescinol A(1),the first example of sesquiterpene–polycyclic polyprenylated acylphloroglucinol(PPAP)adduct,which represented a new subclass of PPAP-type natural products,along with two new congeners with normal spiro 6/6/5 tricyclic architecture,were isolated from Hypericum longistylum.Monosescinol A possessed an unprecedented 6/5/5/6/6 pentacyclic carbon skeleton that might be assembled from the 6/6/5 carbon skeleton,via the splitting decomposition of C-3/C-14,and the attack from the C-3 in the PPAP core to C-28 in sesquiterpene section.In addition,we have firstly confirmed that 24R configuration was existed in sec–Bu containing PPAPs by single crystal diffraction data analysis of monosescinol B(2),that might provide an enlightenment in the configurational determination of sec–Bu containing PPAPs.Significantly,further pharmacological research has found that compound 1 exhibited remarkable pharmacological effects against acute myeloid leukemia(AML)cell lines,with direct inhibition of mitochondrial complex V and an increase in mitochondrial membrane potential,and led to an induction of oxidative stress,endogenous inflammation,and apoptosis of AML cells.

Spirohypertones A and B as potent antipsoriatics:Tumor necrosis factor-αinhibitors with unprecedented chemical architectures

Tumor necrosis factor-α(TNF-α)is a promising target for inflammatory and autoimmune diseases.Spirohypertones A(1)and B(2),two unprecedented polycyclic polyprenylated acylphloroglucinols with highly rearranged skeletons,were isolated from Hypericum patulum.The structures of 1 and 2 were confirmed through comprehensive spectroscopic analysis,single-crystal X-ray diffraction and electronic circular dichroism calculations.Importantly,2 showed remarkable TNF-αinhibitory activity,which could protect L929 cells from death induced by co-incubation with TNF-αand actinomycin D.It also demonstrated the ability to suppress the inflammatory response in HaCaT cells stimulated with TNF-α.Notably,in an imiquimod-induced psoriasis murine model,2 restrained symptoms of epidermal hyperplasia associated with psoriasis,presenting anti-inflammatory and antiproliferative effects.This discovery positions 2 as a potent TNF-αinhibitor,providing a promising lead compound for developing an antipsoriatic agent.

Polyaspers A and B,the First Ergosterol-Polyether Adducts with Unprecedented 6/6/6/5/5/6/6/6/6 Nonacyclic Architecture from Aspergillus sp.TJ507

Psoriasis is a chronic immune-mediated inflammatory skin disease and the TNF-αis an important therapeutic target of this disease.In our continuous study of bioactive natural products from fungi,the first ergosterol-polyether adducts,polyaspers A(1)and B(2),along with two known ergosterols,(36,5α,6α,22E)-5,6-epoxy-3-hydroxyergosta-8,22-dien-7-one(3)and calvasterol B(4),were iso-lated from Aspergillus sp.TJ507.Structure elucidation was accomplished by extensive spectroscopic analysis and single-crystal X-ray diffraction tests.Polyaspers A and B possessing an unequalled 6/6/6/5/5/6/6/6/6 nonacyclic system,and their biosynthetic path-ways were proposed to include intermolecular cyclization and Diels-Alder reactions.Activity screen of these isolates showed that 1-3 could improve the cell viability in an actinomycin D/TNF-αinduced L929 cells death model,with the EC50 values of 49.85,46.75 and 4.99μmol/L,respectively,and the activity of 3 was even comparable with that of the positive control SPD304.Further bioactive investigations discovered 3 could suppress the inflammatory response simulated with TNF-αin HaCaT cells.In an imiquimod-induced psoriasis murine model,3 significantly restrained the development of psoriasis symptoms and reduced the expression of IL-17 and IL-23,presenting an anti-psoriatic effect.As such,those ergosterol derivatives,might serve as lead compounds for the development of novel TNF-αinhibitory agents in the clinical treatment of psoriasis.