Biologically active isoquinoline alkaloids covering 2014-2018.

Isoquinoline alkaloids, an important class of N-based heterocyclic compounds, have attracted considerable attention from researchers worldwide since the early 19th century. Over the past 200 years, many compounds from this class were isolated, and most of them and their analogs possess various bioactivities. In this review, we survey the updated literature on bioactive alkaloids and highlight research achievements of this alkaloid class during the period of 2014-2018. We reviewed over 400 molecules with a broad range of bioactivities, including antitumor, antidiabetic and its complications, antibacterial, antifungal, antiviral, antiparasitic, insecticidal, anti-inflammatory, antioxidant, neuroprotective, and other activities. This review should provide new indications or directions for the discovery of new and better drugs from the original naturally occurring isoquinoline alkaloids.

Design, synthesis and antifungal activity evaluation of isocryptolepine derivatives.

In this paper, the nitrogen atom was inserted into the anthracycline system of the isocryptolepine nucleus to obtain the "Aza"-type structure benzo[4,5]imidazo[1,2-c] quinazoline. A series of "Aza"-type derivatives were designed, synthesized and evaluated for their antifungal activity against six plant fungi in vitro. Among all derivatives, compounds A-0, B-1 and B-2 showed significant antifungal activity against B. cinerea with the EC50 values of 2.72 µg/mL, 5.90 µg/mL and 4.00 µg/mL, respectively. Compound A-2 had the highest activity against M. oryzae with the EC50 values of 8.81 µg/mL, and compound A-1 demonstrated the most control efficacy against R. solani (EC50, 6.27 µg/mL). Moreover, compound A-0 was selected to investigate the in vivo tests against B. cinerea and the results indicated that the preventative efficacy of it up to 72.80% at 100 µg/mL. Preliminary mechanism studies revealed that after treatment with A-0 at 5 µg/mL, the B. cinerea mycelia appeared curved, collapsed and the cell membrane integrity may be damaged. The reactive oxygen species production, mitochondrial membrane potential and nuclear morphometry of mycelia have been changed, and the membrane function and cell proliferation of mycelia were destroyed. Compounds A-0, A-1, B-1 and B-2 presented weaker toxicities against two cells lines than isocryptolepine. This study lays the foundation for the future development of isocryptolepine derivatives as environmentally friendly and safe agricultural fungicides.

Anti-phytopathogenic activity and the possible mechanisms of action of isoquinoline alkaloid sanguinarine.

Isoquinoline alkaloids possess broad pharmacological activities. In this study, the antifungal activity of twelve isoquinoline alkaloids, including berberine (1), jatrorrhizine (2), coptisine (3), corydaline (4), tetrahydroberberine (5), chelidonine (6), dihydrosanguinarine (7), chelerythrine (8), sanguinarine (9), palmatine (10), tetrahydropalmatine (11) and columbamine (12) were evaluated against eight plant pathogenic fungi in vitro. All the tested compounds showed varying degrees of inhibition against the eight tested plant fungi. Among them, sanguinarine exhibited high antifungal activity (EC50 ranging from 6.96-59.36 µg/mL). It displayed the best inhibitory activity against Magnaporthe oryzae (EC50 = 6.96 µg/mL), compared with azoxystrobin (EC50 = 12.04 µg/mL), and significantly suppressed spore germination of M. oryzae with the inhibition rate reaching 100% (50 µg/mL). The optical microscopy and scanning electron microscopy observations revealed that after treating M. oryzae mycelia with sanguinarine at 10 µg/mL, the mycelia appeared curved, collapsed and the cell membrane integrity was eventually damaged. Furthermore, the reactive oxygen species production, mitochondrial membrane potential and nuclear morphometry of mycelia had been changed, and the membrane function and cell proliferation of mycelia were destroyed. These results will enrich our insights into action mechanisms of antifungal activity of sanguinarine against M. oryzae.

Biologically active quinoline and quinazoline alkaloids part I.

Quinoline and quinazoline alkaloids, two important classes of N-based heterocyclic compounds, have attracted tremendous attention from researchers worldwide since the 19th century. Over the past 200 years, many compounds from these two classes were isolated from natural sources, and most of them and their modified analogs possess significant bioactivities. Quinine and camptothecin are two of the most famous and important quinoline alkaloids, and their discoveries opened new areas in antimalarial and anticancer drug development, respectively. In this review, we survey the literature on bioactive alkaloids from these two classes and highlight research achievements prior to the year 2008 (Part I). Over 200 molecules with a broad range of bioactivities, including antitumor, antimalarial, antibacterial and antifungal, antiparasitic and insecticidal, antiviral, antiplatelet, anti-inflammatory, herbicidal, antioxidant and other activities, were reviewed. This survey should provide new clues or possibilities for the discovery of new and better drugs from the original naturally occurring quinoline and quinazoline alkaloids.

Biologically active quinoline and quinazoline alkaloids part II.

To follow-up on our prior Part I review, this Part II review summarizes and provides updated literature on novel quinoline and quinazoline alkaloids isolated during the period of 2009-2016, together with the biological activity and the mechanisms of action of these classes of natural products. Over 200 molecules with a broad range of biological activities, including antitumor, antiparasitic and insecticidal, antibacterial and antifungal, cardioprotective, antiviral, anti-inflammatory, hepatoprotective, antioxidant, anti-asthma, antitussive, and other activities, are discussed. This survey should provide new clues or possibilities for the discovery of new and better drugs from the original naturally occurring quinoline and quinazoline alkaloids.

A clinical observational study on the application of enhanced recovery after laparoscopic pancreaticoduodenectomy.

Purpose: The safety and feasibility of enhanced recovery after surgery (ERAS) for laparoscopic pancreaticoduodenectomy (LPD) are unclear. The aim of this retrospective clinical study was to evaluate the impact of ERAS protocols for LPD. Patients and methods: Between March 2016 and December 2018, a total of 34 consecutive patients with ERAS for LPD were prospectively enrolled and compared with 68 consecutive patients previously treated for non-ERAS after LPD during an equal time frame. The intraoperative and postoperative data were collected and comparatively analyzed. Results: The mean length of postoperative hospital stay (15.8 ± 3.4 and 23.1 ± 5.1 days, P < 0.001) was reduced significantly in ER group than those in non-ER group. The operation time (462.7 ± 117.0 vs. 450.9 ± 109.8 min, P = 0.627) and intraoperative blood loss (523.5 ± 270.0 vs. 537.5 ± 241.8 ml, P = 0.800) were similar in the two groups. The complications (ER: 32.4% vs. non-ER: 35.3%, P > 0.05) and their severities (Clavien-Dindo grade ≥3 complications, 2 vs. 5 patients; P = 0.783) of patients with ERAS protocols were not increased. No difference in mortality and readmission rates was found. Finally, the total medical costs ($2.1 ± 0.7 × 104 and $2.3 ± 0.7 × 104, P = 0.017) in ER group were lower than those in non-ER group. Conclusion: the ERAS is safe and effective in the perioperative period of LPD. It could effectively reduce the length of postoperative stay and medical costs, and does not increase the incidence of postoperative complications.

Design and synthesis of novel 7-[(N-substituted-thioureidopiperazinyl)-methyl]-camptothecin derivatives as potential cytotoxic agents.

As part of continuing our research on diverse C-7 derivatives of camptothecin (CPT), 16 CPT derivatives bearing piperazinyl-thiourea chemical scaffold and different substituent groups have been designed, synthesized and evaluated in vitro for cytotoxicity against five tumor cell lines (A-549, MDA-MB-231, MCF-7, KB and KBvin). As a result, all the synthesized compounds showed promising in vitro cytotoxic activity against the five tumor cell lines tested, and were more potent than irinotecan. Importantly, compounds 13 g (IC50 = 0.514 µM) and 13o (IC50 = 0.275 µM) possessed similar or better antiproliferative activity against the multidrug-resistant (MDR) KBvin subline than that of topotecan (IC50 = 0.511 µM) and merit further development as anticancer candidates for clinical trail. With these results in hand, we have a reason to conclude that incorporating piperazinyl-thiourea motifs into position-7 of camptothecin confers well cytotoxic activity against cancer cell lines, probably resulting in new anticancer drugs.

Discovery of luotonin A analogues as potent fungicides and insecticides: Design, synthesis and biological evaluation inspired by natural alkaloid.

The prevention and control of plant diseases and insect pests is the most crucial issue facing crop protection. To discover novel pesticide candidates with diverse chemical structures from natural products, a series of luotonin A analogues were designed, synthesized and evaluated for their antifungal and insecticidal activities. Most of these compounds exhibited potent activity against Botrytis cinerea, Magnaporthe oryzae and Aphis craccivora. Among them, the antifungal activity of compound 10s against B. cinerea was comparable to azoxystrobin (EC50 = 0.09 mM) and against M. oryzae (EC50 = 0.19 mM) was slightly weaker than that of azoxystrobin (EC50 = 0.17 mM). Compounds 10k and 10o are the most active compounds against A. craccivora having identical mortality value of 42.05% at 50 µg/mL, respectively, which were slightly lower than pymetrozine (51.14%) at the same concentration. Revealed morphological changes of the fungal cell surface by scanning electron microscopy indicated that luotonin A analogues might exert their antifungal activity by destroying fungal cell membrane and cell wall. Furthermore, the results of the in vivo protective and curative activities of the compound 10s against S. sclerotiorum and B. cinerea showed that the curative effect was stronger than its protective effect and the curative effects reached 67.17% and 73.82% at 80 µg/mL respectively. The above results further demonstrated the potential of luotonin A analogues as novel fungicides and insecticides.

Acaricidal activity and enzyme inhibitory activity of active compounds of essential oils against Psoroptes cuniculi.

Plant essential oils and its chemical compositions are commonly applied in medicinal and other industries due to their broad advanced pharmacological activities. In the present study, we systematically evaluated the acaricidal activities of twelve compounds of essential oils against Psoroptes cuniculi in vitro and in vivo. In addition, to support the clinic uses, their toxicities against immortalized human keratinocytes (HaCaT) and human liver cells (HL-7702) and skin irritation were studied for evaluating the liver and skin safety. The possible mechanism of action of certain chemical were investigated by determining the inhibitory activities against cytochrome P450 (P450) acetylcholinesterase (AChE) and glutathione-S-transferase (GST). Among all tested compounds, eugenol exhibited the best acaricidal activity with LC50 value of 56.61 µg/ml in vitro. Meanwhile, after the treatment of eugenol for five times within 10 days, the P. cuniculi were eliminated in the naturally infested rabbits, no skin irritation was found in rabbits treated by eugenol. Moreover, eugenol presented no or weak cytotoxicity against HaCaT cells and HL-7702 cells with IC50 values of greater than 100 µg/ml. Furthermore, the moderate inhibitory activities of eugenol against mites P450 and AChE were demonstrated. Above results indicated that eugenol presented the promising acaricidal activity against P. cuniculi in vitro and in vivo, is safe for both humans and animals at the given doses. This work lays the foundation for the development of eugenol as an environmentally friendly acaricide agent.

Engineering of Peglayted Camptothecin Into Nanomicelles and Supramolecular Hydrogels for Pesticide Combination Control.

As a famous quinoline alkaloid, camptothecin (CPT) presented the significant anti-tumor activity, as well as the interesting insecticidal activities, but the low solubility, poor hydrophobicity and cuticular penetration of CPT have been severely limited the field application. In this study, we conjugated the camptothecin with polyethylene glycol, forming amphiphilic copolymer, mPEG-CPT, which could be self-assembled into micelles, or formed a hydrogel with α-CD by super-cross-linking to combine delivery with acetamiprid or nitenpyram. Results showed that the nitenpyram or acetamiprid loaded hydrogels showed dual phase release behavior, while the micelles displayed a synchronous and fast release profile. Moreover, these four nanopesticides showed potent or superior insecticidal activities and a synergetic effect against Brevicoryne brassicae, Tetranychus cinnabarinus, and Bursaphelenchus xylophilus. This finding indicated that micelles and hydrogels could be used as effective carriers for pesticide combination control.

Application of Sustainable Natural Resources in Agriculture: Acaricidal and Enzyme Inhibitory Activities of Naphthoquinones and Their Analogs against Psoroptes cuniculi.

As important secondary plant metabolites, naphthoquinones exhibit a wide range of biological activities. However, their potential as sustainable alternatives to synthetic acaricides has not been studied. This study for the first time investigates the acaricidal activity of naphthoquinones against Psoroptes cuniculi in vitro. Furthermore, the in vivo activity, the skin irritation effects, the cytotoxicity and the inhibitory activities against mite acetylcholinesterase (AChE) and glutathione S-transferase (GST) of the two compounds that displayed the best insecticidal activity in vitro were evaluated. Among fourteen naphthoquinones and their analogs, juglone and plumbagin were observed to possess the strongest acaricidal activities against P. cuniculi with LC50 values of 20.53 ppm and 17.96 ppm, respectively, at 24 h. After three treatments, these two chemicals completely cured naturally infested rabbits in vivo within 15 days, and no skin irritation was found in any of the treated rabbits. Compared to plumbagin, juglone presented no or weak cytotoxicity against HL-7702 cells. Moreover, these two chemicals significantly inhibited AChE and GST activity. These results indicate that juglone has promising toxicity against P. cuniculi, is safe for both humans and animals at certain doses, and could be used as a potential alternative bio-acaricide for controlling the development of psoroptic mange in agricultural applications.

[Identification of tumor-associated proteins in laryngeal squamous cell carcinoma by proteomics].

OBJECTIVE: To establish two-dimensional electrophoresis profiles from human laryngeal squamous cell carcinoma tissue and paired normal tumor-adjacent mucosa epithelia tissue, and to identify differential expression proteins. METHODS: The total proteins of human laryngeal squamous carcinoma tissue and paired normal tumor-adjacent mucosa epithelia tissue were separated by immobilized pH gradient-based two-dimensional gel electrophoresis (2-DE). The differential expression proteins were analyzed using image analysis software, then identified using mass spectrometry and database searching. RESULTS: Well-resolved, reproducible 2-DE patterns of laryngeal squamous cell carcinoma and adjacent normal mucosa epithelial were obtained. Differential protein spots were defined as spots in 2-DE gels. Thirteen proteins were preliminarily identified, naming which 10 proteins were upregulated in laryngeal cancer tissue. Such as cofilin-1, nuclear body protein SP140, GRP94, HSP 90, GSTP1-1, superoxide dismutase [Mn], cyclophilin A, proteasome activator complex subunit 2, apolipoprotein A-I precursor, CaM-like protein and so on. There were 3 proteins downregulated in laryngeal cancer tissue, which were fatty acid-binding protein, calgranulin A and calgranulin B. CONCLUSIONS: Thirteen proteins which are associated with the tumorigenesis of the laryngeal squamous cell carcinoma were characterized. These extensive protein variations indicate that multiple protein molecules should be simultaneously targeted as an effective strategy to counter the disease. It is better for understanding of the oncogenesis and pathogenesis in a global way, which in turn is a basis-for the rational designs of diagnostic and therapeutic methods.