Design, synthesis and biological evaluation of novel 9-N-substituted-13-alkylberberine derivatives from Chinese medicine as anti-hepatocellular carcinoma agents.

A series of novel 9-N-substituted-13-alkylberberine derivatives from Chinese medicine were designed and synthesized with improved anti-hepatocellular carcinoma (HCC) activities. The optimal compound 4d showed strong activities against HepG2, Sk-Hep-1, Huh-7 and Hep3B cells with IC50 values of 0.58-1.15 µM, which were superior to positive reference cisplatin. Interestingly, 4d exhibited over 40-fold more potent activity against cisplatin-resistant HepG2/DPP cells while showing lower cytotoxicity in normal LX-2 cells. The mechanism studies revealed 4d greatly stabilized G-quadruplex DNA leading to intracellular c-MYC expression downregulation, blocked G2/M-phase cell cycle by affecting related p-cdc25c, cdc2 and cyclin B1 expressions, and induced apoptosis by a ROS-promoted PI3K/Akt-mitochondrial pathway. Furthermore, 4d possessed good pharmacokinetic properties and significantly inhibited the tumor growth in the H22 liver cancer xenograft mouse model without obvious toxicity. Altogether, the remarkably biological profiles of 4d both in vitro and in vivo would make it a promising candidate for HCC therapy.

Design, synthesis, and biological evaluation of novel protopanoxadiol derivatives based PROTACs technology for the treatment of lung cancer.

Protopanoxadiol is a key active ingredient derived from Panax ginseng that is well-known to exhibit anti-tumor activity. Previous research focused on the natural protopanaxadiol derivative AD-1 has demonstrated that it possesses broad spectrum anti-tumor activities in vitro and in vivo. However, its limited activity, selectivity, and cell permeability have impeded its therapeutic application. Herein, a series of novel AD-1 derivatives were designed and synthesized based on proteolysis-targeting chimera (PROTAC) technology by linking AD-1 at the C-3 and C-12 positions with pomalidomide through linkers of alkyl chain of differing lengths to achieve the goal of improving the efficacy of the parent compound. Among these synthesized PROTACs, the representative compound A05 exhibited the most potent anti-proliferative activity against A549 cells. Furthermore, mechanistic studies revealed that compound A05 was able to suppress MDM2 expression, disrupt interactions between p53 and MDM2 and readily induce apoptotic death via the mitochondrial apoptosis pathway. Moreover, the in vivo assays revealed that compound A05 exhibited both anti-proliferative and anti-metastatic activities in the zebrafish tumor xenograft model with A549 cells. Together, our findings suggest that AD-1 based PROTACs associated with the degradation of MDM2 may have promising effects for the treatment of lung cancer and this work provide a foundation for future efforts to develop novel anti-tumor agents from natural products.

Synthesis, biological evaluation and mechanism studies of C-3 substituted nitrogenous heterocyclic 23-Hydroxybetulinic acid derivatives as anticancer agents.

A series of novel nitrogenous heterocycle substituted 23-Hydroxybetulinic acid (23-HBA) derivatives with amide linkages at the C-3 position were designed, synthesized and evaluated for their antitumor activities. The biological screening results showed that most of the derivatives exhibited more potent antiproliferative activities than 23-HBA. In particular compound II-9 exhibited the most potent activities with IC50 values ranging from 1.96 µM to 6.20 µM against five cancer cell lines (B16, HepG2, A2780, MCF-7 and A549). The preliminary mechanism study showed that compound II-9 caused cell cycle arrest at G1 phase, induced cell apoptosis and depolarized mitochondria of B16 cells in a dose dependent manner. Moreover, western blot analysis indicated that compound II-9 down-regulated the expression of anti-apoptotic protein Bcl-2, up-regulated the expression of pro-apoptotic protein Bad, and activated cytochrome C and caspase 3 to cause cell apoptosis. In summary, II-9 may serve as a promising lead for the development of new natural product-based antitumor agents and deserve further investigation.

Development of a novel truncated deguelin derivative possessing nitric oxide donor as a potential anti-lung cancer agent.

Lung cancer is the leading cause of cancer death in the world. Natural product deguelin and its truncated analogs have been reported to be potential therapeutic agents for lung cancer. In order to improve the potency, a novel truncated deguelin derivative (4) possessing nitric oxide (NO) donor was designed and synthesized. The biological evaluation showed that hybrid 4 exerted potent activity with an IC50 value of 0.41 µM in H1299 cells. Mechanism studies showed that it arrested the cell cycle at G2/M phase and suppressed Hsp90 function. In addition, hybrid 4 demonstrated potent inhibitory activity on the migration and invasion of lung cancer cells. Together, the promising results warrant further development of hybrid 4 as a potential anticancer agent for the treatment of lung cancer.

Novel hybrids of natural ß-elemene bearing isopropanolamine moieties: Synthesis, enhanced anticancer profile, and improved aqueous solubility.

A series of novel ß-elemene isopropanolamine derivatives were synthesized and evaluated for their antitumor activity. The results indicated that all of the compounds showed stronger antiproliferative activities than ß-elemene as well as improved aqueous solubility. In particular dimer 6q showed the strongest cytotoxicity against four tumor cell lines (SGC-7901, HeLa, U87 and A549) with IC50 values ranging from 4.37 to 10.20µM. Moreover, combination of 6q with cisplatin exhibited a synergistic effect on these cell lines with IC50 values ranging from 1.21 to 2.94µM, and reversed the resistance of A549/DPP cells with an IC50 value of 2.52µM. The mechanism study revealed that 6q caused cell cycle arrest at the G2 phase and induced apoptosis of SGC-7901 cells through a mitochondrial-dependent apoptotic pathway. Further in vivo study in H22 liver cancer xenograft mouse model validated the antitumor activity of 6q with a tumor inhibitory ratio (TIR) of 60.3%, which was higher than that of ß-elemene (TIR, 49.1%) at a dose of 60mg/kg. Altogether, the potent antitumor activity of 6qin vitro and in vivo warranted further preclinical investigation for potential anticancer chemotherapy.

Synthesis and anti-hepatocellular carcinoma activity of novel O2-vinyl diazeniumdiolate-based nitric oxide-releasing derivatives of oleanolic acid.

Considering that high levels of nitric oxide (NO) exert anti-cancer effect and the derivatives of oleanolic acid (OA) have shown potent anti-cancer activity, new O2-vinyl diazeniumdiolate-based NO releasing derivatives (5a-l, 11a-l) of OA were designed, synthesized, and biologically evaluated in the present study. These derivatives could release different amounts of NO in liver cells. Among them, 5d, 5i, 5j, 11g, 11h, and 11j released more NO in SMMC-7721 cells and displayed stronger proliferative inhibition against SMMC-7721 and HepG2 cells than OA and other tested compounds. The most active compound 5j showed almost 20-fold better solubility than OA in aqueous solution, released larger amounts of NO in liver cancer cells than that in normal ones, and exhibited potent anti-hepatocellular carcinoma activity but little effect on the normal liver cells. The inhibitory activity against the cancer cells was significantly diminished upon addition of an NO scavenger, suggesting that NO may contribute, at least in part, to the activity of 5j.

Total synthesis, structural elucidation and anti-inflammatory activity evaluation of 2-deoxy-3,6-anhydro hexofuranoside derivatives isolated from Sauropus rostratus.

The first total synthesis of four 2-deoxy-3,6-anhydro hexofuranoside derivatives, namely sauropunols (A-D), isolated from the traditional Chinese medicinal plant Sauropus rostratus was accomplished. Structures of sauropunols A and B were clearly elucidated and reassigned. The anti-inflammatory activities of sauropunols (A-D) as well as the synthetic intermediates were evaluated, which is valuable for further structure-activity relationship (SAR) studies on this class of natural products.

Antitumor and Antibacterial Derivatives of Oridonin: A Main Composition of Dong-Ling-Cao.

Isodon rubescens has been used as a traditional green tea for more than 1000 years and many medicinal functions of I. rubescens are also very useful, such as its well-known antitumor and antibacterial activities. Oridonin, a bioactive ent-kaurane diterpenoid, is the major ingredient of this medicinal tea. Herein, 22 novel oridonin derivatives were designed and synthesized. The antibacterial activity was evaluated for the first time. Compound 12 was the most promising one with MIC of 2.0 µg/mL against B. subtilis, which was nearly 3-fold stronger than positive control chloromycetin. The antiproliferative property was also assayed and compound 19 showed stronger activity than taxol. The apoptosis-inducing ability, cell cycle arrest effect at S phase and influence of mitochondrial membrane potential by 19 in CaEs-17 cancer cells were first disclosed. Based on the above results, the cell apoptosis induced by compound 19 in CaEs-17 cells was most probably involved in the intrinsic apoptotic pathway.

The Dark-Purple Tea Cultivar 'Ziyan' Accumulates a Large Amount of Delphinidin-Related Anthocyanins.

Recently, we developed a novel tea cultivar 'Ziyan' with distinct purple leaves. There was a significant correlation between leaf color and anthocyanin pigment content in the leaves. A distinct allocation of metabolic flow for B-ring trihydroxylated anthocyanins and catechins in 'Ziyan' was observed. Delphinidin, cyanidin, and pelargonidin (88.15 mg/100 g FW in total) but no other anthocyanin pigments were detected in 'Ziyan', and delphinidin (70.76 mg/100 g FW) was particularly predominant. An analysis of the catechin content in 'Ziyan' and eight other cultivars indicated that 'Ziyan' exhibits a preference for synthesizing B-ring trihydroxylated catechins (with a proportion of 74%). The full-length cDNA sequences of flavonoid pathway genes were isolated by RNA-Seq coupled with conventional TA cloning, and their expression patterns were characterized. Purple-leaved cultivars had lower amounts of total catechins, polyphenols, and water extract than ordinary non-anthocyanin cultivars but similar levels of caffeine. Because dark-purple-leaved Camellia species are rare in nature, this study provides new insights into the interplay between the accumulations of anthocyanins and other bioactive components in tea leaves.

Current natural products with antihypertensive activity.

Natural products have been an important source of new drugs, which also played a dominant role in the discovery and research of new drugs for the treatment of hypertension. This review article reviews the recent progress in the research and development of natural lead compounds with antihypertensive activity, including alkaloids, diterpenes, coumarins, flavonoids, and peptides. We summarized their structures, sources, as well as the antihypertensive mechanisms. These information provides instructive reference for the following structural modifications and optimization.

Synthesis of 13-ß-elemene ester derivatives and evaluation of their antioxidant activity in human umbilical vein endothelial cells.

In the present study, a series of 13-ß-elemene ester derivatives were designed and prepared, and their antioxidant activity was investigated in the H2O2-treated human umbilical vein endothelial cells (HUVECs). Among the test compounds, the dimer compounds 5v and 5w exhibited the most potent antioxidant activity with significant ROS suppression being observed. Both compounds markedly inhibited the H2O2-induced changes in various biochemical substances, such as superoxide dismutase (SOD), malonyldialdehyde (MDA), nitric oxide (NO), and lactic dehydrogenase (LDH), which were superior to that of the positive control vitamin E. Further more, they did not produce any obvious cytotoxicity, but increased the viability of HUVECs injured by H2O2 in a dose-dependent manner. Additionally, compound 5w, designed as a prodrug-like compound, showed improved stability relative to compound 4 in vitro.

Insights into drug discovery from natural products through structural modification.

Natural products (NPs) have played a key role in drug discovery and are still a prolific source of novel lead compounds or pharmacophores for medicinal chemistry. Pharmacological activity and druggability are two indispensable components advancing NPs from leads to drugs. Although naturally active substances are usually good lead compounds, most of them can hardly satisfy the demands for druggability. Hence, these structural phenotypes have to be modified and optimized to overcome existing deficiencies and shortcomings. This review illustrates druggability optimization of NPs through structural modification with some successful examples.

Synthesis and biological evaluation of ambradiolic acid as an inhibitor of glycogen phosphorylase.

Ambradiolic acid (3) with oleanane skeleton is a natural pentacyclictriterpene. The first synthesis of 3 starting from 23-hydroxybetulinic acid (2) has been accomplished in 12-steps with a total yield of 18.1% in our study. Compound 3 was further biologically evaluated and found to exhibit significant inhibitory activity against rabbit muscle glycogen phosphorylase (GP) with an IC50 value of 12.4 µM, suggesting it could be a potential lead compound for the development of hypoglycemic drugs.

Synthesis and antimycobacterial evaluation of natural oridonin and its enmein-type derivatives.

A series of enmein-type derivatives were synthesized and assayed for their antimycobacterial effects. The structures of the synthesized compounds were established by (1)H NMR, (13)C NMR and mass spectral analysis. All the compounds were screened for their antimycobacterial properties against Mycobacterium phlei, Mycobacterium smegmatis and Mycobacterium marinum. Compounds 2, 6g and 6i were found to exhibit potent antimycobacterial activity against M. phlei at a concentration of 0.5 µg/mL, which was comparable to that of positive drug streptomycin. Furthermore, five compounds were tested against Mycobacterium tuberculosis H37Rv based on the promising preliminary screening results. Among them, compound 10 showed potent activity with IC50 value of 17.1 µg/mL against M. tuberculosis H37Rv strain. Thus, compound 10 could emerge as a promising lead for further research work.

Novel 3-substituted ocotillol-type triterpenoid derivatives as antibacterial candidates.

Plant-derived triterpenoid saponins are involved in the plant defense system by targeting bacterial membranes. A series of ocotillol-type triterpenoid derivatives were synthesized starting from PPD, one of the main components of Panax ginseng and their antibacterial activity against several representative bacteria were evaluated. Compounds 5 and 11 exhibited excellent antibacterial activity with MIC values of 1 µg/mL against Staphylococcus aureus and 8 µg/mL and 4 µg/mL against Bacillus subtilis, respectively. Furthermore, when compounds 5 and 11 were combined with two commercial antibiotics kanamycin and chloramphenicol, they showed strong synergistic activity at sub-MIC levels against S. aureus USA300 and B. subtilis 168. Moreover, chloramphenicol turned from a bacteriostatic to a bactericidal agent when combined with compound 11 against B. subtilis 168.

Synthesis and ß-adrenergic blocking activity of oxime ether hybrids derived from a natural isochroman-4-one.

AIM: In a search for new cardiovascular drug candidates, a series of novel oxime ethers derived from a natural isochroman-4-one were synthesized. METHOD: Compounds 3 and 6, derived from the natural antihypertensive compound 7, 8-dihydroxy-3-methyl-isochroman-4-one (XJP), were designed and synthesized. Subsequently, a series of novel isochroman-4-one oxime ether hybrids were prepared by hybridizing various N-substituted isopropanolamine functionalities to isochroman-4-one oxime. Furthermore, ß1-adrenergic blocking activities of the synthesized compounds were assayed using the isolated rat left atria. RESULTS: Twenty target compounds were obtained, and the preliminary structure-activity relationships were deduced. The most promising compound Ic exhibited ß1-adrenoceptor blocking activity (inhibition: 52.2%) at 10(-7) mol·L(-1), which was superior to that of propranolol (inhibition: 49.7%). CONCLUSION: The results suggested that natural product XJP/isopropanolamine moiety hybrids may provide a promising approach for the discovery of novel cardiovascular drug candidates.

Transformation of strictosamide to vincoside lactam by acid catalysis.

AIM: To identify the structure of the acid-catalyzed product of strictosamide and explore the reaction mechanism. METHODS: The acid-catalyzed reaction process of strictosamide was monitored by HPLC, and a macroporous resin was used to purify the reaction solution. The structure of the product was confirmed by MS, NMR, and ROESY spectra. RESULTS: The acid-catalyzed transformation yield from strictosamide to vincoside lactam was 52%. CONCLUSION: The reaction mechanism of the transformation from strictosamide to vincoside lactam may be related to the stability of the three-dimensional configuration of the compound. These results offer a new way to obtain vincoside lactam from the widely distributed indole alkaloid strictosamide by acid-catalysis.

Total synthesis and antihypertensive activity of (+/-)7,8-dihydroxy-3-methyl-isochromanone-4.

This letter describes the total synthesis, preliminary biological evaluation and mechanism studies of a novel and structurally unique isochromanone, (+/-)7,8-dihydroxy-3-methyl-isochromanone-4 (1), a nature product contained in banana (Musa sapientum L.) peel. The bioassay showed that compound 1 displays potent antihypertensive activity in renal hypertensive rats and further mechanism studies revealed that it is an ACE inhibitor.