Structure-activity relationship and biological evaluation of berberine derivatives as PCSK9 down-regulating agents.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a secreted protein and its deficiency markedly enhanced the survival rate of patient with cardiovascular diseases (CVDs). Forty berberine (BBR) derivatives were synthesized and evaluated for their activities on down-regulating the transcription of PCSK9 in HepG2 cells, taking BBR as the lead. Structure-activity relationship (SAR) analysis revealed that 2,3-dimethoxy moiety might be beneficial for activity. Among them, 9k displayed the most potent activity with IC50 value of 9.5 ± 0.5 µM, better than that of BBR. Also, it significantly decreased PCSK9 protein level at cellular level, as well as in the liver and serum of mice in vivo. Furthermore, 9k markedly increased LDLR expression and LDL-C clearance via down-regulating PCSK9 protein. The mechanism of action of 9k is targeting HNF1α and/or Sp1 cluster modulation upstream of PCSK9, a different one from BBR. Therefore, 9k might have the potential to be a novel PCSK9 transcriptional inhibitor for the treatment of atherosclerosis, worthy for further investigation.

Evolution and Antibacterial Evaluation of 8-Hydroxy-cycloberberine Derivatives as a Novel Family of Antibacterial Agents Against MRSA.

Twenty-five new derivatives of 8-hydroxycycloberberine (1) were synthesized and evaluated for their activities against Gram-positive bacteria, taking 1 as the lead. Part of them displayed satisfactory antibacterial activities against methicillin-susceptible Staphylococcus aureus (MSSA) and methicillin-resistant Staphylococcus aureus (MRSA), as well as vancomycin-intermediate Staphylococcus aureus (VISA). Especially, compound 15a displayed an excellent anti-MRSA activity with MICs (minimum inhibitory concentrations) of 0.25⁻0.5 µg/mL, better than that of 1. It also displayed high stability in liver microsomes and whole blood, and the LD50 value of over 65.6 mg·kg-1 in mice via intravenous route, suggesting a good druglike feature. The mode of action showed that 15a could effectively suppress topo IV-mediated decatenation activity at the concentration of 7.5 µg/mL, through binding a different active pocket of bacterial topo IV from quinolones. Taken together, the derivatives of 1 constituted a promising kind of anti-MRSA agents with a unique chemical scaffold and a specific biological mechanism, and compound 15a has been chosen for the next investigation.

Synthesis and biological evaluation of 7-substituted cycloberberine derivatives as potent antibacterial agents against MRSA.

A series of new 7-substituted cycloberberine (CBBR) derivatives were synthesized and evaluated for their antibacterial activities against Gram-positive pathogens, taking CBBR as the lead. The SAR revealed that the introduction of a substituent at the C7 position resulted in a potency against both the reference Gram-positive bacteria and MDR clinical isolates, much higher than that of CBBR. Compound 1f with a 7-phenyl group exhibited higher activities against MRSA and VRE than that of vancomycin, with MIC values of 1-8 µg/mL. Its rapid bactericidal action against MRSA was further confirmed in time-kill study. The preliminary mechanism study indicated that 1f might target bacterial DNA Topo IV ParE subunit, indicating a mode of action distinct from the currently used antibacterial drugs such as quinolones. These results supplemented and enriched the SAR of its kind, and provided powerful information for developing these compounds into a novel class of antibacterial candidates against MRSA.

Synthesis and antibacterial evaluation of 13-substituted cycloberberine derivatives as a novel class of anti-MRSA agents.

A series of new 13-substituted cycloberberine (CBBR) derivatives were prepared and evaluated for their antibacterial activities against Gram-positive bacteria taking CBBR as the lead. Structure-activity relationship revealed that the introduction of a suitable electron-donating group at the 13-position in CBBR might be beneficial for the antibacterial potency. Among them, compounds 5b and 5w exhibited high potency against methicillin-sensitive (MSSA) and resistant strains of S. aureus (MRSA) with MIC values of 1-4 µg/mL. Both of them also displayed high stabilities in blood, and good in vivo safety profiles with LD50 values of 65.6 and 41.2 mg kg-1 in intravenous route respectively. Molecular docking analysis indicated that compound 5b might target FtsZ protein that could inhibit cell division, with the advantage of activity against multidrug resistant S. aureus. Therefore, we consider 13-substituted CBBR derivatives to be a novel class of anti-MRSA agents worthy of further investigation.

Synthesis and biological evaluation of new berberine derivatives as cancer immunotherapy agents through targeting IDO1.

To discover small-molecule cancer immunotherapy candidates through targeting Indoleamine 2,3-dioxygenase 1 (IDO1), twenty-five new berberine (BBR) derivatives defined with substituents on position 3 or 9 were synthesized and examined for repression of IFN-γ-induced IDO1 promoter activities. Structure-activity relationship (SAR) indicated that large volume groups at the 9-position might be beneficial for potency. Among them, compounds 2f, 2i, 2n, 2o and 8b exhibited increased activities, with inhibition rate of 71-90% compared with BBR. Their effects on IDO1 expression were further confirmed by protein level as well. Furthermore, compounds 2i and 2n exhibited anticancer activity by enhancing the specific lysis of NK cells to A549 through IDO1, but not cytotoxicity. Preliminary mechanism revealed that both of them inhibited IFN-γ-induced IDO1 expression through activating AMPK and subsequent inhibition of STAT1 phosphorylation. Therefore, compounds 2i and 2n have been selected as IDO1 modulators for small-molecule cancer immunotherapy for next investigation.

Synthesis and biological evaluation of tricyclic matrinic derivatives as a class of novel anti-HCV agents.

BACKGROUND: 12N-benzyl matrinic acid analogues had been identified to be a novel scaffold of anti-HCV agents with a specific mechanism, and the representative compound 1 demonstrated a moderate anti-HCV activity. The intensive structure-activity relationship of this kind of compounds is explored so as to obtain anti-HCV candidates with good druglike nature. RESULTS: Taking compound 1 as the lead, 32 compounds (of which 27 were novel) with diverse structures on the 11-side chain, including methyl matrinate, matrinol, matrinic butane, (Z)-methyl Δßγ-matrinic crotonate derivatives were synthesized and evaluated for their anti-HCV activities. Among all the compounds, matrinol 7a demonstrated potential potency with a greatly improved SI value of 136. Pharmacokinetic studies of 7a showed the potential for oral administration that would allow further in vivo safety studies. The free hydroxyl arm in 7a made it possible to prepare pro-drugs for the potential in the treatment of HCV infection. CONCLUSIONS: 27 novel 12N-substituted matrinol derivatives were prepared. The SAR study indicated that the introduction of electron-donating substitutions on the benzene ring was helpful for the anti-HCV activity, and the unsaturated 11-side chain might not be favorable for the activity. This study provided powerful information on further strategic optimization and development of this kind of compounds into a novel family of anti-HCV agents. Graphical abstract Matrinol derivatives as a class of novel anti-HCV agents.

Synthesis and Identification of Novel Berberine Derivatives as Potent Inhibitors against TNF-α-Induced NF-κB Activation.

Twenty-three new berberine (BBR) analogues defined on substituents of ring D were synthesized and evaluated for their activity for suppression of tumor necrosis factor (TNF)-α-induced nuclear factor (NF)-κB activation. Structure-activity relationship (SAR) analysis indicated that suitable tertiary/quaternary carbon substitutions at the 9-position or rigid fragment at position 10 might be beneficial for enhancing their anti-inflammatory potency. Among them, compounds 2d, 2e, 2i and 2j exhibited satisfactory inhibitory potency against NF-κB activation, with an inhibitory rate of around 90% (5 µM), much better than BBR. A preliminary mechanism study revealed that all of them could inhibit TNF-α-induced NF-κB activation via impairing IκB kinase (IKK) phosphorylation as well as cytokines interleukin (IL)-6 and IL-8 induced by TNF-α. Therefore, the results provided powerful information on further structural modifications and development of BBR derivatives into a new class of anti-inflammatory candidates for the treatment of inflammatory diseases.

[Study on chemical constituents of Inula cappa].

Column chromatographies over silica gel, Sephadex LH-20, reverse phase C18, and MCI, and semi-preparative HPLC were used for separation and purification of constituents from Inula cappa. The 22 compounds were obtained and their strutures were determined by NMR and MS spectra data as nine flavonoids: luteolin (1), apigenin (2), chrysoeriol (3), artemetin (4), 2', 5-di- hydroxy-3, 6, 7, 4', 5'-pentamethoxyflavone (5), chrysosplenol C (6), apigenin-5-0-ß-D-glucopyranoside (7), luteolin-3-methyl, luteolin-3-methylether-4'-0-ß-D-glucopyranoside (8), luteolin-4'-0-ß-D-glucopyranoside (9); four triterpenes: darma-20, 24-dien- 3ß-0-acetate (10), darma-20, 24-dien-3ß-ol (11), epirfiedelanol (12), friedelin (13); three coumarins: scopoletin (14) , isosco- poletin (15) , scopolin(16) , and other types of compounds stigmasta-5, 22-dien-3ß-0-7-one (17), stigmasterol (18), palmitic acid (19), linoleic acid (20), linoleic acid methyl ester (21), (E) -9, 12, 13-trihydroxyoetadee-10-enoie acid (22). Compound 5 is a new natural product. Compounds 3-9, 15, 17, 21, and 22 were isolated from this genus for the first time.

Synthesis and the hepatoprotective activity of dibenzocyclooctadiene lignan derivatives.

The halogenated and oxidized derivatives (1a-1e, 1a'-1c', 2a-2d, 2a'-2b', 3a-3e, 3' and 3a'-3b') of schizandrin (1), schizandrin B (2) and schisanhenol (3) were synthesized. The hepatoprotective effects of these dibenzocyclooctadiene lignan analogues against CCl4-induced injury were preliminarily evaluated. Most of the analogues exhibited higher protective effects than the positive control biphenyldicarboxylate (DDB). Among these active analogues, dichloroschisanhenol (3a) exhibited the strongest protective activity (cell survival rate exceeding 98.0%).