Synthesis and Antibacterial Evaluation of Novel 3-Substituted Ocotillol-Type Derivatives as Leads.

Due to the rapidly growing bacterial antibiotic-resistance and the scarcity of novel agents in development, bacterial infection is still a global problem. Therefore, new types of antibacterial agents, which are effective both alone and in combination with traditional antibiotics, are urgently needed. In this paper, a series of antibacterial ocotillol-type C-24 epimers modified from natural 20(S)-protopanaxadiol were synthesized and evaluated for their antibacterial activity. According to the screening results of Gram-positive bacteria (B. subtilis 168 and MRSA USA300) and Gram-negative bacteria (P. aer PAO1 and A. baum ATCC19606) in vitro, the derivatives exhibited good antibacterial activity, particularly against Gram-positive bacteria with an minimum inhibitory concentrations (MIC) value of 2-16 µg/mL. The subsequent synergistic antibacterial assay showed that derivatives 5c and 6c enhanced the susceptibility of B. subtilis 168 and MRSA USA300 to chloramphenicol (CHL) and kanamycin (KAN) (FICI < 0.5). Our data showed that ocotillol-type derivatives with long-chain amino acid substituents at C-3 were good leads against antibiotic-resistant pathogens MRSA USA300, which could improve the ability of KAN and CHL to exhibit antibacterial activity at much lower concentrations with reduced toxicity.

Design, synthesis and in vitro NO-releasing activities of ocotillol-type furoxans.

A series of novel ocotillol-type furoxan derivatives was synthesized by coupling various furoxans to 3-OH of 6-deoxy ocotillol, and their in vitro nitric oxide (NO) releasing capability was studied. The discharge of NO was examined after 30 min at two different concentrations, the results showed that all of the compounds tested could release NO in a dose-dependent manner. All of the synthesized compounds released similar amounts of NO at 100 µM, whereas at 500 µM these compounds showed more difference, in which compound II1, II3, II4, III2 displayed higher potency in releasing NO at this concentration. Analysis of the in vitro data showed that the derivatives bearing the same furoxan group on different ocotillol cores possessed various NO releasing capacity, suggesting that the structure of carrier of NO releasing groups may affect the NO release. Indeed, except compound II2, 24(S)-6-deoxy ocotillol derivatives from compound 6 with different furoxan substitutions at 3-OH and III2 displayed enhanced NO releasing capacity, compared to other compounds derived from compounds 5 and 9. The results illustrated that the functional group and the stereochemistry on the ocotillol structure may affect the NO release of furoxans.

Dual Stimuli-Responsive Micelles for Imaging-Guided Mitochondrion-Targeted Photothermal/Photodynamic/Chemo Combination Therapy-Induced Immunogenic Cell Death.

Introduction: As the special modality of cell death, immunogenic cell death (ICD) could activate immune response. Phototherapy in combination with chemotherapy (CT) is a particularly efficient tumor ICD inducing method that could overcome the defects of monotherapies. Methods: In this study, new dual stimuli-responsive micelles were designed and prepared for imaging-guided mitochondrion-targeted photothermal/photodynamic/CT combination therapy through inducing ICD. A dual-sensitive methoxy-polyethylene glycol-SS-poly(L-γ-glutamylglutamine)-SS-IR780 (mPEG-SS-PGG-SS-IR780) polymer was synthesized by grafting IR780 with biodegradable di-carboxyl PGG as the backbone, and mPEG-SS-PGG-SS-IR780/paclitaxel micelles (mPEG-SS-PGG-SS-IR780/PTXL MCs) were synthesized by encapsulating PTXL in the hydrophobic core. Results: In-vivo and -vitro results demonstrated that the three-mode combination micelles inhibited tumor growth and enhanced the therapeutic efficacy of immunotherapy. The dual stimuli-responsive mPEG-SS-PGG-SS-IR780/PTXL MCs were able to facilitate tumor cell endocytosis of nanoparticles. They were also capable of promoting micelles disintegration and accelerating PTXL release. The mPEG-SS-PGG-SS-IR780/PTXL MCs induced mitochondrial dysfunction by directly targeting the mitochondria, considering the thermo- and reactive oxygen species (ROS) sensitivity of the mitochondria. Furthermore, the mPEG-SS-PGG-SS-IR780/PTXL MCs could play the diagnostic and therapeutic roles via imaging capabilities. Conclusion: In summary, this study formulated a high-efficiency nanoscale platform with great potential in combined therapy for tumors through ICD.

Multistage O2-producing liposome for MRI-guided synergistic chemodynamic/chemotherapy to reverse cancer multidrug resistance.

Reduced drug uptake and elevated drug efflux are two major mechanisms in cancer multidrug resistance (MDR). In the present study, a new multistage O2-producing liposome with NAG/R8-dual-ligand and stimuli-responsive dePEGylation was developed to address the abovementioned issues simultaneously. The designed C-NAG-R8-PTXL/MnO2-lip could also achieve magnetic resonance imaging (MRI)-guided synergistic chemodynamic/chemotherapy (CDT/CT). In vitro and in vivo studies showed that C-NAG-R8-PTXL/MnO2-lip enhanced circulation time by PEG and targeted the tumor site. After tumor accumulation, endogenous l-cysteine was administered, and the PEG-attached disulfide bond was broken, resulting in the dissociation of PEG shells. The previously hidden positively charged R8 by different lengths of PEG chains was exposed and mediated efficient internalization. In addition, the oxygen (O2) generated by C-NAG-R8-PTXL/MnO2-lip relieved the hypoxic environment within the tumor, thus reducing the efflux of chemotherapeutic drug. O2 was able to burst liposomes and triggered the release of PTXL. The toxic hydroxyl radical (·OH), which was produced by H2O2 and Mn2+, strengthened CDT/CT. C-NAG-R8-PTXL/MnO2-lip was also used as MRI contrast agent, which blazed the trail to rationally design theranostic agents for tumor imaging.

Nanoplatform-based natural products co-delivery system to surmount cancer multidrug-resistant.

The emergence of multidrug resistance (MDR) in malignant tumors is the primary reason for invalid chemotherapy. Antitumor drugs are often adversely affected by the MDR of tumor cells. Treatments using conventional drugs, which have specific drug targets, hardly regulate the complex signaling pathway of MDR cells because of the complex formation mechanism of MDR. However, natural products have positive advantages, such as high efficiency, low toxicity, and ability to target multiple mechanism pathways associated with MDR. Natural products, as MDR reversal agents, synergize with chemotherapeutics and enhance the sensitivity of tumor cells to chemotherapeutics, and the co-delivery of natural products and antitumor drugs with nanocarriers maximizes the synergistic effects against MDR in tumor cells. This review summarizes the molecular mechanisms of MDR, the advantages of natural products combined with chemotherapeutics in offsetting complicated MDR mechanisms, and the types and mechanisms of natural products that are potential MDR reversal modulators. Meanwhile, aiming at the low bioavailability of cocktail combined natural products and chemotherapeutic in vivo, the advantages of nanoplatform-based co-delivery system and recent research developments are illustrated on the basis of our previous research. Finally, prospective horizons are analyzed, which are expected to considerably improve the nano-co-delivery of natural products and chemotherapeutic systems for MDR reversal in cancer.

Integration of multiscale molecular modeling approaches with the design and discovery of fusidic acid derivatives.

Aim: Fusidic acid (FA) is an effective antibiotic against Staphylococcus aureus, but it is metabolically unstable. Methods & results: 14 derivatives were designed and synthesized by blocking the metabolic sites of FA (21-COOH and 3-OH) to maintain antibacterial activity and prolong the half-life. Six derivatives showed good antibacterial activity, and the pharmacokinetic experiments confirmed that two derivatives modified in 21-COOH released FA in vivo and showed longer half-lives than FA. Docking analysis and structure-activity relationships indicated that the 3-glycine derivatives with more hydrogen-bonding acceptor sites and positively charged surface areas were more likely to have good antibacterial activity. Conclusion: The results suggest that introducing groups that block the metabolic sites of FA could maintain antibacterial activity and prolong the half-lives.

Design and synthesis of 28-hydroxy protopanaxadiol as a novel probe template.

To explore the antitumour mechanism of 20(S)-protopanaxadiol (PPD) while maintaining its uncovered pharmacological active site 3-hydroxyl, 28-hydroxy protopanaxadiol (17), a small molecular probe template of PPD was first designed and synthesised based on the Baldwin's reaction. Thus, 28-hydroxyl of 17 was built successfully as a derivatized site of molecular probe's functional and report groups. The important intermediates and final product were confirmed by ESI-MS and nuclear magnetic resonance spectra with good yield. These studies provided a valuable basis for probe research of PPD.