T7 peptide-mediated co-delivery platform overcoming multidrug-resistant breast cancer: In vitro and in vivo evaluation.

P-glycoprotein (P-gp) overexpressed mutidrug resistance (MDR) is currently a key factor limiting the effectiveness of breast cancer chemotherapy. Systemic administration based on P-gp-associated mechanism leads to severe toxic side effects. Here, we designed a T7 peptide-modified mixed liposome (T7-MLP@DTX/SchB) that, by active targeting co-delivering chemotherapeutic agents and P-gp inhibitors, harnessed synergistic effects to improve the treatment of MDR breast cancer. This study established drug-resistant cell models and animal models. Subsequently, comprehensive evaluations involving cell uptake, cell apoptosis, cellular toxicity assays, in vivo tumor-targeting capability, and anti-tumor activity assays were conducted to assess the drug resistance reversal effects of T7-MLP@DTX/SchB. Additionally, a systematic assessment of the biosafety profile of T7-MLP@DTX/SchB was executed, including blood profiles, biochemical markers, and histopathological examination. It was found that this co-delivery strategy successfully exerted the synergistic effects, since there was a significant tumor growth inhibitory effect on multidrug-resistant breast cancer. Targeted modification with T7 peptide enhanced the therapeutic efficacy remarkably, while vastly ameliorating the biocompatibility compared to free drugs. The intriguing results supported the promising potential use of T7-MLP@DTX/SchB in overcoming MDR breast cancer treatment.

A naphthimide-based ratiometric fluorescent probe for selective and visual detection of phosgene in solution and the gas phase.

As a colorless, highly toxic and widely used chemical reagent, phosgene poses a potentially serious threat to public health and environmental safety. Therefore, there is an urgent need to develop a simple and sensitive method for detecting phosgene. In this work, a ratiometric fluorescent probe (NED) for phosgene was developed by utilizing 4-substituted 1,8-naphthimide unit as the fluorophore and ethylenediamine as the recognition moiety. The probe NED undergoes intramolecular cyclization reaction with phosgene, resulting in a remarkable ratiometric fluorescence response. The probe NED displays high sensitivity (LOD = 4.9 nM), excellent ratiometric fluorescence signal, and high selectivity toward phosgene over other relevant analytes. In addition, paper test strip capable of visually detecting gaseous phosgene has also been fabricated.

Indole derivatives as tubulin polymerization inhibitors for the development of promising anticancer agents.

The α- and ß-tubulins are the major polypeptide components of microtubules (MTs), which are attractive targets for anticancer drug development. Indole derivatives display a variety of biological activities including antitumor activity. In recent years, a great number of indole derivatives as tubulin polymerization inhibitors have sprung up, which encourages medicinal chemists to pursue promising inhibitors with improved antitumor activities, excellent physicochemical, pharmacokinetic and pharmacodynamic properties. In this review, the recent progress from 2010 to present in the development of indole derivatives as tubulin polymerization inhibitors was summarized and reviewed, which would provide useful clues and inspirations for further design of outstanding tubulin polymerization inhibitors.

Virtual Screening and Optimization of Novel mTOR Inhibitors for Radiosensitization of Hepatocellular Carcinoma.

BACKGROUND: Radiotherapy has an ameliorative effect on a wide variety of tumors, but hepatocellular carcinoma (HCC) is insensitive to this treatment. Overactivated mammalian target of rapamycin (mTOR) plays an important part in the resistance of HCC to radiotherapy; thus, mTOR inhibitors have potential as novel radiosensitizers to enhance the efficacy of radiotherapy for HCC. METHODS: A lead compound was found based on pharmacophore modeling and molecular docking, and optimized according to the differences between the ATP-binding pockets of mTOR and PI3K. The radiosensitizing effect of the optimized compound (2a) was confirmed by colony formation assays and DNA double-strand break assays in vitro. The discovery and preclinical characteristics of this compound are described. RESULTS: The key amino acid residues in mTOR were identified, and a precise virtual screening model was constructed. Compound 2a, with a 4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidine scaffold, exhibited promising potency against mTOR (mTOR IC50=7.1 nmol/L (nM)) with 126-fold selectivity over PI3Kα. Moreover, 2a significantly enhanced the sensitivity of HCC to radiotherapy in vitro in a dose-dependent manner. CONCLUSION: A new class of selective mTOR inhibitors was developed and their radiosensitization effects were confirmed. This study also provides a basis for developing mTOR-specific inhibitors for use as radiosensitizers for HCC radiotherapy.

Indazolyl-substituted piperidin-4-yl-aminopyrimidines as HIV-1 NNRTIs: Design, synthesis and biological activities.

A series of indazolyl-substituted piperidin-4-yl-aminopyrimidines (IPAPYs) were designed from two potent HIV-1 NNRTIs piperidin-4-yl-aminopyrimidine 3c and diaryl ether 4 as the lead compounds by molecular hybridization strategy. The target molecules 5a-q were synthesized and evaluated for their anti-HIV activities and cytotoxicities in MT-4 cells. 5a-q displayed moderate to excellent activities against wild-type (WT) HIV-1 with EC50 values ranging from 1.5 to 0.0064 µM. Among them, 5q was regarded as the most excellent compound against WT HIV-1 (EC50 = 6.4 nM, SI = 2500). And also, it displayed potent activities against K103 N (EC50 = 0.077 µM), Y181C (EC50 = 0.11 µM), E138K (EC50 = 0.057 µM), and moderate activity against double mutants RES056 (EC50 = 8.7 µM). Moreover, the structure-activity relationships (SARs) were summarized, and the molecular docking was performed to investigate the binding mode of IPAPYs and HIV-1 reverse transcriptase.

Recent progress in HIV-1 inhibitors targeting the entrance channel of HIV-1 non-nucleoside reverse transcriptase inhibitor binding pocket.

Since the entrance channel was proposed as a new binding site in non-nucleoside reverse transcriptase inhibitor binding pocket (NNIBP) of HIV-1 reverse transcriptase (RT) in 2012, a huge number of HIV-1 inhibitors acting on this target have sprung up, aiming to discover promising inhibitors with excellent antiviral activities, physicochemical properties, and so on. From 2012 to 2018, many noteworthy compounds have been continuously discovered. In this review, the recent progress in HIV-1 inhibitors targeting the entrance channel of HIV-1 NNIBP was summarized and reviewed, which would provide useful clues and inspiration for further design of HIV-1 inhibitors.

Advances in rationally designed dual inhibitors of HIV-1 reverse transcriptase and integrase.

Reverse transcriptase (RT) and integrase (IN) are two indispensable enzymes in human immunodeficiency virus type 1 (HIV-1) replication. RT is responsible for the transformation of the single-stranded RNA viral genome into double-stranded DNA, and IN catalyzes the integration of viral DNA into the host DNA. Although highly active antiretroviral therapy (HAART) combining nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs/NtRTIs) with nonnucleoside reverse transcriptase inhibitors (NNRTIs) or protease inhibitors (PIs) could suppress successfully HIV viral load and reduce evidently the mortality of HIV infected people, it involves the difficulty of perfect adherence, and other drawbacks such as viral rebound, toxicities and multi-drug resistances. Recently, rational drug design has become a dominant technique for the development of multi-target drugs. And the rationally designed dual inhibitors of HIV-1 RT and IN have become a hot topic of anti-HIV research. In this review, the advances in rationally designed dual inhibitors of HIV-1 RT and IN were summarized, including structurally diverse inhibitors, their structure-activity relationship (SAR) studies as well as binding mode analysis.

Structural modifications of quinolone-3-carboxylic acids with anti-HIV activity.

A series of new quinolone-3-carboxylic acids featuring a hydroxyl group at C-5 position were synthesized and evaluated for their in vitro activity against HIV in C8166 cell culture. All the compounds showed anti-HIV-1 activity with low micromolar to submicromolar EC(50) values. The most active compound 2k exhibited activity against wild-type HIV-1 with an EC(50) value of 0.13 µΜ. Preliminary structure-activity relationship of the newly synthesized quinolone analogues was also investigated. Further docking study revealed that the anti-HIV activity of these compounds might involve a two-metal chelating mechanism.