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• Maintaining the geometry of B-ring is clearly crucial for bioactivity in the parent nucleus of lathyrane-type diterpenoid. • The acyloxy group at the 15-C position and the hydrophobic group at the 3-C are necessary for anti-inflammatory activity. • Compounds 15 and 17 demonstrated superior IL-1β-suppressed activation than other derivatives. • Compound 15 (EFL3) efficiently inhibits the IL-1β production related to the MSU-mediated inflammasome activation. Lathyrane-based diterpenoid is one of the critical bioactive elements of Euphorbia lathyris L., a widely used traditional Chinese medicine for the treatment of inflammation and infection. In this study, we introduced and evaluated seven synthetic or natural lathyrane-based diterpenoids with the same core structure but notable structural variations at specific positions, for their anti-inflammatory and gout-alleviating properties. There was no significant cytotoxicity below 10 μM among the initial test of the cell counting kit 8 of the seven candidate derivatives (compounds 13 to 19) in this work. Furthermore, maintaining the acyloxy group at 15-C position and the strongly hydrophobic aryl structure at 3-C and 5-C positions, compounds 15 (Euphorbia factor L3, EFL3) and 17 strikingly inhibited the production of IL-1β related to the actuation of the inflammasome in our study. The ELISA assay indicated that the anti-inflammatory effects of EFL3 were better associated with MSU stimulation than other second-line pathways triggered by inflammasome. Further examinations on the acute paw gout model in C57BL/6 mice showed that EFL3 had a significantly inflammatory retarding effect by intraperitoneal injection. It decreased swelling volume as well as the cleavage and activation of local IL-1β and casepas-1 in the paw. To conclude, our findings reveal several potential key structure–activity relationships that govern the anti-inflammatory effects of lathyrane-type diterpenoids, the dispensable acyl group at the 15-C position, the importance of maintaining the spatial structure of the B-ring, and the potential importance of hydrophobic substituents at the 3-C position. These insights may provide guidance for the structural design of lathyrane-type agents in the future; furthermore, we found that the lathyrane-based diterpenoid EFL3 is a potential agent for gout that is expected to provide a novel therapeutic strategy for inflammation intervention. [ABSTRACT FROM AUTHOR]

[Display omitted] • Trisarcglaboids A and B were new family lindenane sesquiterpenoid trimer. • Compound 1 was highly cytotoxic to five human cancer cell lines. • Compound 1 potentially induced apoptosis by blocking Akt phosphorylation. Trisarcglaboids A and B (1 and 2), representing the first example of lindenane sesquiterpenoid trimers repolymerized based on the classical [4 + 2] type dimer, together with known biogenic precursors chlorahololide D (3) and sarcandrolide A (4), were identified as chemical components of the root of Sarcandra glabra. The novel trimeric lindenane sesquiterpenoid skeletons, including their absolute configurations, were characterized using MS, NMR, ECD, and X-ray single crystal diffraction. The proposed Diels-Alder cycloaddition between Δ 2(3) of the tiglic acyl group of the classical [4 + 2] type dimer and Δ 15(4),5(6) of the third lindenane may serve as the key biogenic step. In addition, compound 1 exerted significant cytotoxicity against five human cancer cell lines with IC 50 values ranging from 1 to 7 μM, potentially through blocking Akt phosphorylation and activating the endogenous apoptosis pathway. [ABSTRACT FROM AUTHOR]

[Display omitted] • Novel HDACi were synthesized using a one-pot multi-component protocol as key step. • Compounds 8k and 8m were identified as highly selective HDAC6 inhibitors. • 8k and 8m showed significant inhibition of LPS-induced IL1B mRNA expression. Histone deacetylases (HDACs) are a class of enzymes that cleave acyl groups from lysine residues of histone and non-histone proteins. There are 18 human HDAC isoforms with different cellular targets and functions. Among them, HDAC6 was found to be overexpressed in different types of cancer. However, when used in monotherapy, HDAC6 inhibition by selective inhibitors fails to show pronounced anti-cancer effects. The HDAC6 enzyme also addresses non-histone proteins like α-tubulin and cortactin, making it important for cell migration and angiogenesis. Recently, the NLRP3 inflammasome was identified as an important regulator of inflammation and immune responses and, importantly, HDAC6 is critically involved the activation of the inflammasome. We herein report the design, synthesis and biological evaluation of a library of selective HDAC6 inhibitors. Starting from the previously published crystal structure of MAIP-032 in complex with CD2 of zHDAC6, we performed docking studies to evaluate additional possible interactions of the cap group with the L1-loop pocket. Based on the results we synthesized 13 novel HDAC6 inhibitors via the Groebke - Blackburn - Bienaymé three component reaction as the key step. Compounds 8k (HDAC1 IC 50 : 5.87 μM; HDAC6 IC 50 : 0.024 μM; selectivity factor (SF1/6): 245) and 8m (HDAC1 IC 50 : 3.07 μM; HDAC6 IC 50 : 0.026 μM; SF1/6: 118) emerged as the most potent and selective inhibitors of HDAC6 and outperformed the lead structure MAIP-032 (HDAC1 IC 50 : 2.20 μM; HDAC6 IC 50 : 0.058 μM; SF1/6: 38) both in terms of inhibitory potency and selectivity. Subsequent immunoblot analysis confirmed the high selectivity of 8k and 8m for HDAC6 in a cellular environment. While neither 8k and 8m nor the selectivity HDAC6 inhibitor tubastatin A showed antiproliferative effects in the U-87 MG glioblastoma cell line, compound 8m attenuated cell migration significantly in wound healing assays in U-87 MG cells. Moreover, in macrophages compounds 8k and 8m demonstrated significant inhibition of LPS-induced IL1B mRNA expression and TNF release. These findings suggest that our imidazo[1,2- a ]pyridine-capped HDAC6 inhibitors may serve as promising candidates for the development of drugs to effectively treat NLRP3 inflammasome-driven inflammatory diseases. [ABSTRACT FROM AUTHOR]

[Display omitted] • ALC67 belongs to a recently discovered family of novel antiproliferative agents. • A synthetic library of optically pure ferrocenyl analogs of ALC67 was prepared. • Two compounds (6c- cis and 6-d) showed similar cytotoxicity to ALC67 and cisplatin. • The cytotoxicity depended on the electrophilicity of the N -acyl side chain group. • Derivative 6c- cis also manifested a selective anti- Bacillus cereus activity. To improve the antiproliferative effect of ALC67 (diastereomeric mixture of ethyl 2-phenyl-3-propioloyl-1,3-thiazolidine-4-carboxylate), its structure was modified via (i) bioisosteric substitution of the phenyl ring by the ferrocene unit and (ii) replacing the propiolamide side-chain in ACL67 with other acyl groups having differing electrophilicities. In this way, a small library of methyl N -acyl-2-ferrocenyl-1,3-thiazolidine-4-carboxylates (13 compounds in total) was created and characterized by spectral and crystallographic means. The last N -acylation step was highly diastereoselective toward the cis -diastereomer. In solution, most of the obtained compounds existed as a mixture of two rotamers and displayed a preference for the syn -orientation around the C N bond. A twisted 5 T 4 envelope conformation was adopted by the derivative containing the N -phenoxyacetyl group in the crystalline state. Two derivatives with chloroacetyl and bromoacetyl groups in the N -3 side chain were cytotoxic to fibroblasts and hepatocellular cancer cells in the low micromolar range (IC 50 (MRC5) = 9.0 and 11.8 μM, respectively, and IC 50 (HepG2) = 10.6 and 18.4 μM, respectively) causing an effect similar to the lead compound (IC 50 (HepG2) = 10.0 μM) and cisplatin (IC 50 (MRC5) = 4.0 μM and IC 50 (HepG2) = 7.7 μM). Several derivatives also manifested modest antimicrobial effects against the studied microbial strains (MICs in the range from 0.44 to 4.0 μmol/mL). Our findings demonstrated that the introduction of a ferrocene core facilitated the preparation of optically pure analogs of ALC67 and that the cytotoxicity of compounds may be enhanced by adding proper electrophilic centers to the N -acyl side-chain. [ABSTRACT FROM AUTHOR]