Design, synthesis and cytotoxic activity of sulfonylated derivatives of camptothecin.

With the intention of advancing our research on diverse C-20 derivatives of camptothecin (CPT), 38 CPT derivatives bearing sulphonamide and sulfonylurea chemical scaffolds and different substituent groups have been designed, synthesised and evaluated in vitro for cytotoxicity against four tumour cell lines, A-549 (lung carcinoma), KB (nasopharyngeal carcinoma), MDA-MB-231 (triple-negative breast cancer) and KBvin (an MDR KB subiline). As a result, all the synthesised compounds showed promising in vitro cytotoxic activity against the four cancer cell lines tested, and were more potent than irinotecan. Importantly, compounds 12b, 12f, 12j and 13 l possessed better antiproliferative activity against all tested tumour cell lines with IC50 values of 0.0118 - 0.5478 µM, and resulted approximately 3 to 4 times more cytotoxic than topotecan against multidrug-resistant KBvin subline. Convincing evidences are achieved that incorporation of sulphonamide and sulfonylurea motifs into position-20 of camptothecin confers markedly enhanced cytotoxic activity against cancer cell lines.

Effectiveness and safety of early lens extraction during par plana vitrectomy for proliferative diabetes retinopathy with mild cataract: a randomized clinical trial.

AIM: To evaluate the effectiveness and safety of early lens extraction during pars plana vitrectomy (PPV) for proliferative diabetic retinopathy (PDR) compared to those of PPV with subsequent cataract surgery. METHODS: This multicenter randomized controlled trial was conducted in three Chinese hospitals on patients with PDR, aged >45y, with mild cataracts. The participants were randomly assigned to the combined (PPV combined with simultaneously cataract surgery, i.e., phacovitrectomy) or subsequent (PPV with subsequent cataract surgery 6mo later) group and followed up for 12mo. The primary outcome was the change in best-corrected visual acuity (BCVA) from baseline to 6mo, and the secondary outcomes included complication rates and medical expenses. RESULTS: In total, 129 patients with PDR were recruited and equally randomized (66 and 63 in the combined and subsequent groups respectively). The change in BCVA in the combined group [mean, 36.90 letters; 95% confidence interval (CI), 30.35-43.45] was significantly better (adjusted difference, 16.43; 95%CI, 8.77-24.08; P<0.001) than in the subsequent group (mean, 22.40 letters; 95%CI, 15.55-29.24) 6mo after the PPV, with no significant difference between the two groups at 12mo. The overall surgical risk of two sequential surgeries was significantly higher than that of the combined surgery for neovascular glaucoma (17.65% vs 3.77%, P=0.005). No significant differences were found in the photocoagulation spots, surgical time, and economic expenses between two groups. In the subsequent group, the duration of work incapacity (22.54±9.11d) was significantly longer (P<0.001) than that of the combined group (12.44±6.48d). CONCLUSION: PDR patients aged over 45y with mild cataract can also benefit from early lens extraction during PPV with gratifying effectiveness, safety and convenience, compared to sequential surgeries.

Application and Mechanism of Cryptolepine and Neocryptolepine Derivatives as T3SS Inhibitors for Control of Bacterial Leaf Blight on Rice.

Bacterial leaf blight (BLB) caused by Xanthomonas oryzae pv oryzae (Xoo) is extremely harmful to rice production. The traditional control approach is to use bactericides that target key bacterial growth factors, but the selection pressure on the pathogen makes resistant strains the dominant bacterial strains, leading to a decline in bactericidal efficacy. Type III secretion system (T3SS) is a conserved and critical virulence factor in most Gram-negative bacteria, and its expression or absence does not affect bacterial growth, rendering it an ideal target for creating drugs against Gram-negative pathogens. In this work, we synthesized a range of derivatives from cryptolepine and neocryptolepine. We found that compound Z-8 could inhibit the expression of Xoo T3SS-related genes without affecting the growth of bacteria. an in vivo bioassay showed that compound Z-8 could effectively reduce the hypersensitive response (HR) induced by Xoo in tobacco and reduce the pathogenicity of Xoo in rice. Furthermore, it exhibited synergy in control of bacterial leaf blight when combined with the quorum quenching bacterial F20.

Improved anti-tumor activity of fluorinated camptothecin derivatives 9-fluorocamptothecin and 7-ethyl-9-fluorocamptothecin on hepatocellular carcinoma by targeting topoisomerase I.

Primary liver cancer is one of the most common malignant cancers of the digestive system that lacks effective chemotherapeutic drugs in clinical settings. Camptothecin (CPT) and its derivatives have been approved for cancer treatment; however, their application is limited by their systemic toxicity. For lead optimization in new drug discovery stages, fluorination is an effective and robust approach to increase the bioavailability and optimize the pharmacokinetics of candidate compounds, thereby improving their efficacy. To obtain new and highly active CPT derivatives, we designed, synthesized, and evaluated two new fluorinated CPT derivatives, 9-fluorocamptothecin (A1) and 7-ethyl-9-fluorocamptothecin (A2), in this study. In vitro, A1 and A2 exhibited more robust anti-tumor activity than topotecan (TPT) in various cancer cells, particularly hepatocellular carcinoma (HCC) cells. In vivo, A1 and A2 exhibited greater anti-tumor activity than TPT in both AKT/Met induced primary HCC mouse models and implanted HepG2 cell xenografts. Acute toxicity tests revealed that A1 and A2 were not lethal and did not cause significant body weight loss at high doses. Moreover, A1 and A2 exhibited no significant toxicity in the mouse liver, heart, lung, spleen, kidney, and hematopoietic systems at therapeutic doses. Mechanistically, A1 and A2 blocked HCC cell proliferation by inhibiting the enzymatic activity of Topo I, subsequently inducing DNA damage, cell cycle arrest, and apoptosis. In summary, our results indicate that fluorination improves the anti-tumor activity of CPT while decreasing its toxicity and highlight the application potential of fluorination products A1 and A2 in clinical settings.

Tuning Surface Plasmonic Resonance and Surface Wettability of Au/CrN Films Using Nitrogen-Containing Gas.

The surface plasmonic resonance, surface wettability, and related mechanical nanohardness and of face-centered-cubic (fcc) chromium nitride (CrN) films have been successfully manipulated via the simple method of tuning nitrogen-containing gas with different nitrogen-to-argon ratios, varying from 3.5 (N35), to 4.0 (N40), to 4.5 (N45), which is directly proportional to argon. All of the obtained CrN films showed that the surface wettability was due to hydrophilicity. All of the characteristics were mainly confirmed and explained by using X-ray diffraction (XRD) patterns, including plan-view and cross-section SEM images, with calculations of the average grain size performed via histograms accompanied by different preferred grain orientations. In the present work, not only the surface plasmonic resonance, but also the surface wettability and the related mechanical nanohardness of CrN films were found to be tunable via a simple method of introducing adjustable nitrogen-reactive-containing gas during the deposition process, while the authors suggest that the crystal orientation transition from the (111) to the (200) crystalline plane changed significantly with the nitrogen-containing gas. So the transition of the preferred orientation of CrN's cubic close-packed from (111) to (200) varied at this composite, caused and found by the nitrogen-containing gas, which can be tuned by the nitrogen-to-argon ratio. The surface plasmonic resonance and photoluminescence quenching effects were coupled photon and electron oscillations, which could be observed, and which existed at the interface between the CrN and Au metals in the designed heterostructures.

Design and synthesis of novel 7-ethyl-10-fluoro-20-O-(cinnamic acid ester)-camptothecin derivatives as potential high selectivity and low toxicity topoisomerase I inhibitors for hepatocellular carcinoma.

A series of new 7-ethyl-10-fluoro-20-O-(cinnamic acid ester)-camptothecin derivatives were synthesized and evaluated for cytotoxicity against four human tumor cell lines including HepG2 (hepatocellular carcinoma), SW480 (colorectal cancer), A2780 (ovarian cancer), and Hucct1 (intrahepatic cholangiocarcinoma). The results of cytotoxic activities in vitro showed that most of the camptothecin derivatives harbor promising cytotoxic activity against tested tumor cell lines. Among them, compound XJS-11 exhibited broad-spectrum inhibitory activities against HepG2, SW480, A2780, and Hucct1 cell lines with IC50 values of 0.03, 0.09, 0.22, and 0.32 µM, respectively. Further investigation demonstrated that compound XJS-11 exhibited more effective growth inhibition against a variety of human hepatoma cells (Sk-hep-1, Hep3B and Huh7) and lower cytotoxicity against immortalized normal human liver cell line L02 than the positive control topotecan. Especially, XJS-11 showed higher selective toxicity in two kinds of human hepatoma cells and immortalized normal human liver cell line (IC50(L-02)/IC50(HepG2) = 113.20; IC50(L-02)/IC50(Hep3B) = 85.60) than topotecan (IC50(L-02)/IC50(HepG2) = 9.45; IC50(L-02)/IC50(Hep3B) = 8.52). Mechanistically, XJS-11 induced cell cycle arrest and cell apoptosis in HepG2 and Hep3B cells by inhibiting Top I activity in a manner similar to that of topotecan. Meanwhile, XJS-11 could attenuate the tumor growth in both xenograft and primary HCC mouse models. In addition, the acute toxicity assay showed that XJS-11 did not cause lethality or significant body weight loss with a single intraperitoneal dose at 100 mg/kg or with an intraperitoneal dose at 25 mg/kg for 7 days. Moreover, unlike topotecan, XJS-11 had no apparent toxicity to the mouse liver, kidney, and hemopoietic system of the C57BL/6 mice. Taken together, XJS-11 merits further development as a new generation of the camptothecin-derived drug candidate.

Design and synthesis of Aza-boeravinone derivatives as potential novel topoisomerase I inhibitors.

Based on the structural skeleton of natural products boeravinones, two types of 6H-chromeno[3,4-b]quinoline derivatives were designed and synthesized by nitrogen atom substitution strategy. Then, their cytotoxic activities were evaluated against six human tumor cell lines including HepG2 (hepatocellular carcinoma), A2780 (ovarian cancer), Hela (cervical cancer), HCT116 (colorectal cancer), SW1990 (pancreatic cancer), and MCF7 (breast cancer). The results showed that compounds ZML-8 and ZML-14 exhibited robust inhibitory activities against HepG2 cells with IC50 values of 0.58 and 1.94 µM, respectively. In addition, ZML-8 and ZML-14 showed higher selectivity against HepG2 and L-02 cells than Topotecan. Mechanistically, ZML-8 and ZML-14 not only induced cell cycle arrest in the G2/M phase and cell apoptosis, but also dose-dependently inhibited topoisomerase I activity and induced DNA damage in HepG2 cells. Molecular docking showed that ZML-8 and ZML-14 could interact with topoisomerase I-DNA complex with a similar binding mode to Topotecan. Inhibitory activities of these two compounds on topoisomerase I were then confirmed in both cell-free systems and in whole-cell lysates. Taken together, compounds ZML-8 and ZML-14 merit further development as a new generation of non-camptothecin topoisomerase I inhibitors for the treatment of cancer.

Antifungal Activity and Action Mechanism Study of Coumarins from Cnidium monnieri Fruit and Structurally Related Compounds.

The increasing resistance of plant diseases caused by phytopathogenic fungi highlights the need for highly effective and environmentally benign agents. The antifungal activities of Cnidium monnieri fruit extracts and five isolated compounds as well as structurally related coumarins against five plant pathogenic fungi were evaluated. The acetone extract, which contained the highest amount of five coumarins, showed strongest antifungal activity. Among the coumarin compounds, we found that 4-methoxycoumarin exhibited stronger and broader antifungal activity against five phytopathogenic fungi, and was more potent than osthol. Especially, it could significantly inhibit the growth of Rhizoctonia solani mycelium with an EC50 value of 21 µg mL-1 . Further studies showed that 4-methoxycoumarin affected the structure and function of peroxisomes, inhibited the ß-oxidation of fatty acids, decreased the production of ATP and acetyl coenzyme A, and then accumulated ROS by damaging MMP and the mitochondrial function to cause the cell death of R. solani mycelia. 4-Methoxycoumarin presented antifungal efficacy in a concentration- dependent manner in vivo and could be used to prevent the potato black scurf. This study laid the foundation for the future development of 4-methoxycournamin as an alternative and friendly biofungicide.

The Antifungal Mechanism of Isoxanthohumol from Humulus lupulus Linn.

Humulus lupulus Linn. is a traditional medicinal and edible plant with several biological properties. The aims of this work were: (1) to evaluate the in vitro antifungal activity of H. lupulus ethanolic extract; (2) to study the in vitro and in vivo antifungal activity of isoxanthohumol, an isoprene flavonoid from H. lupulus, against Botrytis cinerea; and (3) to explore the antifungal mechanism of isoxanthohumol on B. cinerea. The present data revealed that the ethanolic extract of H. lupulus exhibited moderate antifungal activity against the five tested phytopathogenic fungi in vitro, and isoxanthohumol showed highly significant antifungal activity against B. cinerea, with an EC50 value of 4.32 µg/mL. Meanwhile, it exhibited moderate to excellent protective and curative efficacies in vivo. The results of morphologic observation, RNA-seq, and physiological indicators revealed that the antifungal mechanism of isoxanthohumol is mainly related to metabolism; it affected the carbohydrate metabolic process, destroyed the tricarboxylic acid (TCA) cycle, and hindered the generation of ATP by inhibiting respiration. Further studies indicated that isoxanthohumol caused membrane lipid peroxidation, thus accelerating the death of B. cinerea. This study demonstrates that isoxanthohumol can be used as a potential botanical fungicide for the management of phytopathogenic fungi.

Design and synthesis of novel 20(S)-α-aminophosphonate derivatives of camptothecin as potent antitumor agents.

29 novel 20(S)-aminophosphonate derivatives of camptothecin were synthesized via a FeCl3 - catalyzed one-pot reaction. All of these compounds displayed similar or superior cytotoxic activity in comparison with that of Irinotecan against Hep3B, MCF-7, A-549, MDA-MB-231, KB, and multidrug-resistant (MDR) KB-vin cell lines. Out of them, compound B07 exhibited significant cytotoxicity and 10-fold improvement in activity compared to Irinotecan. Mechanistically, B07 not only induced cell apoptosis and cell cycle arrest in Hep3B and MCF-7 cells, but also inhibited Topoisomerase I activity in the cell and cell-free system in a manner similar to that of Irinotecan. In both xenograft and primary HCC mouse models, B07 showed significant anti-tumor activity and was more potent than Irinotecan. Additionally, the acute toxicity assay showed that B07 had no apparent toxicity to the mouse liver, kidney, and hemopoietic system of the FVB/N mice. Therefore, these findings indicate that compound B07 could be a potential Topoisomerase I poison drug candidate for further clinical trial.

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 antineoplastic activity of novel 20(S)-acylthiourea derivatives of camptothecin.

For the purpose of advancing our research on diverse C-20 decorated derivatives of camptothecin (CPT), 46 new CPT acylthiourea derivatives were synthesized and evaluated in vitro for their cytotoxicity. All the compounds showed promising in vitro cytotoxicity against six tumor cell lines (Hep3B, MCF7, A549, MDA-MB-231, KB and KB-vin). Out of them, compound c20 possesses remarkable in vitro cytotoxic activity and is more potent than topotecan. Mechanistically, c20 not only induces cell cycle arrest and cell apoptosis in A549 cells, but also inhibits Topo I activity in the cell and cell-free system in a manner similar to that of topotecan. In both xenograft and primary HCC mouse models, c20 displays significant in vivo anti-cancer activity and is more potent than topotecan. In addition, the acute toxicity assay showed that c20 has no apparent toxicity to mouse liver, kidney and hemopoietic system of the FVB/N mice. Take together, these results indicated that compound c20 could be a potential anti-cancer candidate for further clinical trial.

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.

Design, semisynthesis and potent cytotoxic activity of novel 10-fluorocamptothecin derivatives.

Fluorination is a well-known strategy for improving the bioavailability of bioactive molecules in the lead optimization phase of drug discovery projects. In an attempt to improve the antitumor activity of camptothecins (CPTs), novel 10-fluoro-CPT derivatives were designed, synthesized and evaluated for cytotoxicity against five human cancer cell lines (A-549, MDA-MB-231, KB, KB-VIN and MCF-7). All of the derivatives showed more potent in vitro cytotoxic activity than the clinical CPT-derived drug irinotecan against the tumor cell lines tested, and most of them showed comparable or superior potency to topotecan. Remarkably, compounds 16b (IC50, 67.0nM) and 19b (IC50, 99.2nM) displayed the highest cytotoxicity against the multidrug-resistant (MDR) KB-VIN cell line and merit further development as preclinical drug candidates for treating cancer, including MDR phenotype. Our study suggested that incorporation of a fluorine atom into position 10 of CPT is an effective method for discovering new potent CPT derivatives.

Design, synthesis, and cytotoxic activity of novel 7-substituted camptothecin derivatives incorporating piperazinyl-sulfonylamidine moieties.

In our continuing search for camptothecin (CPT)-derived antitumor drugs, novel 7-substituted CPT derivatives incorporating piperazinyl-sulfonylamidine moieties were designed, synthesized and evaluated for cytotoxicity against five tumor cell lines (A-549, MDA-MB-231, MCF-7, KB, and KB-VIN). All of the derivatives showed promising in vitro cytotoxic activity against the tested tumor cell lines, and were more potent than irinotecan. Remarkably, most of the compounds exhibited comparable cytotoxicity against the multidrug-resistant (MDR) KB-VIN and parental KB tumor cell lines, while irinotecan lost activity completely against KB-VIN. Especially, compounds 13r and 13p (IC50 0.38 and 0.85µM, respectively) displayed the greatest cytotoxicity against the MDR KB-VIN cell line and merit further development into preclinical and clinical drug candidates for treating cancer, including MDR phenotype.