A Carbon-Carbon Bond Cleavage-Based Prodrug Activation Strategy Applied to ß-Lapachone for Cancer-Specific Targeting.

Prodrugs are one of the most common strategies for the design of targeted anticancer agents. However, their application is often hampered by the modifiable groups available on parent drugs. Herein, a carbon-carbon (C-C) bond cleavage-based prodrug activation strategy is reported, which was successfully used to design prodrugs of ß-lapachone (ß-lap), an ortho-quinone natural product without traditional modifiable groups for the construction of C-N/C-O bond cleavage-based prodrugs. The designed ß-lap prodrug with a reactive oxygen species-specific trigger was quickly activated, releasing ß-lap. It exerted anticancer efficacy via NAD(P)H:quinone oxidoreductase 1 (NQO1)-mediated futile redox cycling, resulting in potent cytotoxicity that was highly selective for NQO1-rich cancer cells over normal cells both in vitro and in vivo. This significantly amplified the therapeutic window of ß-lap. This study provides a practical strategy for the design of prodrugs for parent drugs that do not contain traditional modifiable groups.

Effect of gamma globulin combined with creatine phosphate on viral myocarditis.

OBJECTIVE: This study aimed to investigate the effect of gamma globulin (IVIG) and creatine phosphate (CP) on viral myocarditis (VMC). METHODS: We enrolled 121 young patients with VMC who were admitted in our hospital from February 2017 to September 2018, and divided them into two groups as follows: study group (62 patients, IVIG + CP + routine treatment), and control group (59 patients, conventional treatment). Patient's baseline data, including gender, age, disease course, etiology, cardiac function classification, and severity, were collected. Ejection fraction (EF), fractional shortening (FS), and mitral ratio of peak early to late diastolic filling velocity (E/A ratio) before and after treatment were recorded. These changes include the lactate dehydrogenase, creatine kinase (CK), aspartate aminotransferase, creatine kinase isoenzyme (CK-MB), and cardiac troponin I (CTnI). Furthermore, the changes in immune factors such as CD3+, CD4+, and CD8+ before and after the treatment were determined. RESULTS: The study group had a significantly higher response rate than the control group (P < 0.05). After treatment, the ejection fraction, fractional shortening, and mitral ratio of peak early-to-late diastolic filling velocity were more significantly improved in the study group than in the control group (P < 0.05). The electrocardiogram (ECG) results of the study group were also significantly better than those of the control group (P < 0.05). The levels of lactate dehydrogenase (LDH), creatine kinase (CK), aspartate aminotransferase (AST), creatine kinase isoenzyme (CK-MB), and cardiac troponin I (CTnI) in the study group were all significantly better than those in the control group (P < 0.05). Symptom recuperation, cardiac function recovery, and ECG and myocardial enzyme normalization were significantly faster in the study group than those in the control group (P < 0.05). The immune factor levels in the study group also significantly improved compared with those before the treatment (P < 0.05). Meanwhile, the adverse reactions in both groups showed no differences (P < 0.05). CONCLUSION: IVIG combined with CP exhibited better clinical effects and effectively boosted the immune system of patients with VMC.

Discovery of Nonquinone Substrates for NAD(P)H: Quinone Oxidoreductase 1 (NQO1) as Effective Intracellular ROS Generators for the Treatment of Drug-Resistant Non-Small-Cell Lung Cancer.

The elevation of oxidative stress preferentially in cancer cells by efficient NQO1 substrates, which promote ROS generation through redox cycling, has emerged as an effective strategy for cancer therapy, even for treating drug-resistant cancers. Here, we described the identification and structural optimization studies of the hit compound 1, a new chemotype of nonquinone substrate for NQO1 as an efficient ROS generator. Further structure-activity relationship studies resulted in the most active compound 20k, a tricyclic 2,3-dicyano indenopyrazinone, which selectively inhibited the proliferation of NQO1-overexpressing A549 and A549/Taxol cancer cells. Furthermore, 20k dramatically elevated the intracellular ROS levels through NQO1-catalyzed redox cycling and induced PARP-1-mediated cell apoptosis in A549/Taxol cells. In addition, 20k significantly suppressed the growth of A549/Taxol xenograft tumors in mice with no apparent toxicity observed in vivo. Together, 20k acts as an efficient NQO1 substrate and may be a new option for the treatment of NQO1-overexpresssing drug-resistant NSCLC.

An NAD(P)H:Quinone Oxidoreductase 1 Responsive and Self-Immolative Prodrug of 5-Fluorouracil for Safe and Effective Cancer Therapy.

Tripartite prodrug 1, composed of an NAD(P)H:quinone oxidoreductase 1 (NQO1)-responsive trigger group, a self-immolative linker, and the active drug 5-fluorouracil (5-FU), was designed and synthesized for site-specific cancer therapy. Upon bioreductive activation by NQO1, 1 can release the parent drug 5-FU specifically in NQO1-overexpressing cancer cells. This prodrug exerts comparable antitumor activity and a more favorable safety profile compared with 5-FU both in vitro and in vivo.

2-Substituted 3,7,8-trimethylnaphtho[1,2-b]furan-4,5-diones as specific L-shaped NQO1-mediated redox modulators for the treatment of non-small cell lung cancer.

Based on the scaffold of 3,7,8-trimethylnaphtho[1,2-b]furan-4,5-dione, a series of L-shaped derivatives with substituted side chains at the position of C2 were designed by analyzing the binding mode with NQO1. The drug-like compound 6q (named as DDO-7178) emerged as the most specific substrate of the two-electron oxidoreductase NQO1 and could hardly be reduced by one-electron oxidoreductases CPR (NQO1/CPR = 20.8). In addition, compound 6q showed much improved physicochemical properties such as water solubility than the control ß-lap. The follow-up studies indicated that 6q showed a NQO1-expressing cancer-cell-selective killing property. Preliminary mechanism studies on the anticancer effect indicated that 6q induced ROS production in an NQO1 dependent manner and activated Akt/MAPK pathways in a ROS-dependent fashion, thereby inducing apoptosis. In addition, emphasized compound 6q showed more significant antitumor efficacy than ß-lap without producing obvious toxic effects in vivo, which gave us a new tool for further investigation of NQO1-mediated redox modulators as anticancer drugs for the treatment of NQO1-overexpressed NSCLC.

Discovery of quinone-directed antitumor agents selectively bioactivated by NQO1 over CPR with improved safety profile.

In this work, we mainly focused on discovering compounds with good selectivity for NQO1 over CPR. The NQO1-mediated two-electron reduction of compounds would kill cancer cells selectively, while CPR-mediated one-electron reduction would induce potential hepatotoxicity. Several novel quinone-directed antitumor agents were discovered as specific NQO1 substrates through structure-activity relationship studies. Among them, compound 3,7,8-trimethylnaphtho[1,2-b]furan-4,5-dione (12b) emerged as the most specific substrate of the two-electron oxidoreductase NQO1 and could hardly be reduced by CPR. It afforded the highest selectivity between NQO1/CPR (selectivity ratio = 6.37), much higher than the control ß-lapachone (selectivity ratio = 1.36), indicated 12b may possess superior safety profile. The electrochemical studies provided a reasonable explanation to the good selectivity toward NQO1. Molecular docking studies supported that 12b was capable of forming additional C-H … π interactions with Trp105 and Phe178 residues compared to the control ß-lap. In addition, compound 12b was shown to kill cancer cells efficiently both in vitro and in vivo model. This work gave us a promising and novel scaffold for further investigation.

Synchronous slowing down in coupled logistic maps via random network topology.

The speed and paths of synchronization play a key role in the function of a system, which has not received enough attention up to now. In this work, we study the synchronization process of coupled logistic maps that reveals the common features of low-dimensional dissipative systems. A slowing down of synchronization process is observed, which is a novel phenomenon. The result shows that there are two typical kinds of transient process before the system reaches complete synchronization, which is demonstrated by both the coupled multiple-period maps and the coupled multiple-band chaotic maps. When the coupling is weak, the evolution of the system is governed mainly by the local dynamic, i.e., the node states are attracted by the stable orbits or chaotic attractors of the single map and evolve toward the synchronized orbit in a less coherent way. When the coupling is strong, the node states evolve in a high coherent way toward the stable orbit on the synchronized manifold, where the collective dynamics dominates the evolution. In a mediate coupling strength, the interplay between the two paths is responsible for the slowing down. The existence of different synchronization paths is also proven by the finite-time Lyapunov exponent and its distribution.

Affinity-Based Fluorescence Polarization Assay for High-Throughput Screening of Prolyl Hydroxylase 2 Inhibitors.

Prolyl hydroxylase domain 2 (PHD2) enzyme, a Fe(II) and 2-oxoglutarate (2-OG) dependent oxygenase, mediates key physiological responses to hypoxia by modulating the levels of hypoxia inducible factor 1-α (HIF1α). PHD2 has been shown to have the therapeutic potentials for conditions including anemia and ischemic disease. Currently, many activity-based assays have been developed for identifying PHD2 inhibitors. Here we report an affinity-based fluorescence polarization method using FITC-labeled HIF1α (556-574) peptide as a probe for quantitative and site-specific screening of small molecule PHD2 inhibitors.