Discovery of xanthone-based nitric oxide donors targeting biofilm clearance.

Bacteria biofilm infection seriously challenges clinical drug therapy. Nitric oxide (NO) was reported to disperse biofilm, eliminate bacteria resistance and kill bacteria. In this study, on the basis of membrane targeting of α-mangostin (α-MG) and the dispersion effect of NO on bacteria biofilms, we designed and synthesized 30 NO donors that α-MG was conjugated with a nitrobenzene or a nitrate and other four representative reference derivatives.

A novel α-mangostin derivative synergistic to antibiotics against MRSA with unique mechanisms.

Methicillin-resistant (MRSA) remains a leading cause of hospital-acquired infections, often linked to complicated treatments, increased mortality risk, and significant cost burdens. Several antibacterial agents have been developed to address MRSA resistance. In this study, potential agents to combat MRSA resistance were explored, with the antibacterial activity of synthesized α-mangostin (α-MG) derivatives being evaluated alongside investigations into their cellular mechanisms against MRSA2.

Synthesis and evaluation of novel tetrahydroisoquinoline-benzo[h]chromen-4-one conjugates as dual ABCB1/CYP1B1 inhibitors for overcoming MDR in cancer.

The emergence of multidrug resistance (MDR) in malignant tumors is one of the major threats encountered currently by many chemotherapeutic agents. Among the various mechanisms involved in drug resistance, P-glycoprotein (P-gp, ABCB1), a member of the ABC transporter family that significantly increases the efflux of various anticancer drugs from tumor cells, and the metabolic enzyme CYP1B1 are widely considered to be two critical targets for overcoming MDR. Unfortunately, no MDR modulator has been approved by the FDA to date.

Joint Screening and Identification of Potential Targets of Nitazoxanide by Affinity Chromatography and Label-Free Techniques.

Background: Nitazoxanide not only exhibits a broad spectrum of activities against various pathogens infecting animals and humans but also induces cellular autophagy. Currently, the pattern of action and subcellular targets of nitazoxanide-induced cellular autophagy are still unclear.

Methods: To identify potential targets of nitazoxanide in mammalian cells, we developed an af-finity chromatography system using tizoxanide, a deacetyl derivative of nitazoxanide, as a ligand.

Nitazoxanide synergizes polymyxin B against by depleting cellular energy.

The rapid expansion of antibiotic-resistant bacterial diseases is a global burden on public health. It makes sense to repurpose and reposition already-approved medications for use as supplementary agents in synergistic combinations with existing antibiotics. Here, we demonstrate that the anthelmintic drug nitazoxanide (NTZ) synergistically enhances the effectiveness of the lipopeptide antibiotic polymyxin B in inhibiting gram-negative bacteria, including those resistant to polymyxin B.

Design, synthesis and biological evaluation of the positional isomers of the galactose conjugates able to target hepatocellular carcinoma cells via ASGPR-mediated cellular uptake and cytotoxicity.

Galactose as a recognizing motif for asialoglycoprotein receptor (ASGPR) is a widely accepted vector to deliver cytotoxic agents in the therapy of hepatocellular carcinoma (HCC), however, the individual hydroxyl group of galactose (Gal) contributed to recognizing ASGPR is obscure and remains largely unanswered in the design of glycoconjugates. Herein, we designed and synthesized five positional isomers of Gal-anthocyanin Cy5.0 conjugates and three Gal-doxorubicin (Dox) isomers, respectively.

The SAR and action mechanisms of autophagy inhibitors that eliminate drug resistance.

Autophagy is an essential homeostatic and catabolic process crucial for the degradation or recycling of proteins and cellular components. Drug resistance has been demonstrated to be closely implicated in increased autophagy. Autophagy inhibition to reverse drug resistance involves in the five stages of autophagy, including phagophore initiation, vesicle nucleation, vesicle elongation, vesicle fusion and cargo degradation.

A gulose moiety contributes to the belomycin (BLM) disaccharide selective targeting to lung cancer cells.

Eight mono- or disaccharide analogues derived from BLM disaccharide, along with the corresponding carbohydate-dye conjugates have been designed and synthesized in this study, aiming at exploring the effect of a gulose residue on the cellular binding/uptake of BLM disaccharide and it possible uptake mechanism. Our evidence is presented indicating that, for the cellular binding/uptake of BLM disaccharide, a gulose residue is an essential subunit but unrelated to its chemical nature. Interestingly, d-gulose-dye conjugate is able to selectively target A549 cancer cells, but l-gulose-dye conjugate fails.

α-naphthoflavone-derived cytochrome P450 (CYP)1B1 degraders specific for sensitizing CYP1B1-mediated drug resistance to prostate cancer DU145: Structure activity relationship.

We previously discovered extrahepatic cytochrome P450 1B1 (CYP1B1) degraders able to overcome drug resistance toward docetaxel using a PROTACs technology, however, the underexplored structure activity relationships and poor water solubility posed a major hurdle in the development of CYP1B1 degraders. Herein, continuous efforts are made to develop more promising α-naphthoflavone (ANF)-derived chimeras for degrading CYP1B1. Guided by the strongest ANF-derived CYP1B1 degrader 3a we ever reported, 17 ANF analogues are designed and synthesized to evaluate the CYP1B1 degradation and resultant resistance reversal.

Discovery of degradable niclosamide derivatives able to specially inhibit small cell lung cancer (SCLC).

Small cell lung cancer (SCLC) is exceedingly tough to treat and easy to develop resistance upon long use of the first-line drug carboplatin or radiotherapy. Novel medicines effective and specific against SCLC are greatly needed. Herein, we focused on the discovery of such a medicine by exploring a drug niclosamide with repurposing strategy.

Oligosaccharide-camptothecin conjugates as potential antineoplastic drugs: Design, synthesis and biological evaluation.

Thirty novel 20 (S)-O-linked camptothecin (CPT) glycoconjugates were synthesized. They showed more potent in vitro cytotoxicities over irinotecan, but very weak direct topoisomerase I (Topo I) inhibition was observed at 100.0 μM.

Antitumor activity and structure-activity relationship of heparanase inhibitors: Recent advances.

Heparanase (HPSE)-directed tumor progression plays a crucial role in mediating tumor-host crosstalk and priming the tumor microenvironment, leading to tumor growth, metastasis and chemo-resistance. HPSE-mediated breakdown of structural heparan sulfate (HS) networks in the extracellular matrix (ECM) and basement membranes (BM) directly facilitates tumor growth and metastasis. Lysosome HPSE also induces multi-drug resistance via enhanced autophagy.

Design and synthesis of α-naphthoflavone chimera derivatives able to eliminate cytochrome P450 (CYP)1B1-mediated drug resistance via targeted CYP1B1 degradation.

Extrahepatic cytochrome P450 1B1 (CYP1B1), which is highly expressed in various tumors, is an attractive and potential target for cancer prevention, therapy, and reversal of drug resistance. CYP1B1 inhibition is the current predominant therapeutic paradigm to treating CYP1B1-mediated malignancy, but therapeutic effect has little success. Herein, we reported CYP1B1 degradation in place of CYP1B1 inhibition for reversing drug resistance toward docetaxel in CYP1B1-overexpressing prostate cancer cell line DU145 using a PROTAC strategy.