Multitarget-Directed Benzylideneindanone Derivatives: Anti-β-Amyloid (Aβ) Aggregation, Antioxidant, Metal Chelation, and Monoamine Oxidase B (MAO-B) Inhibition Properties against Alzheimer’s Disease

A novel series of benzylideneindanone derivatives were designed, synthesized, and evaluated as multitarget-directed ligands against Alzheimer’s disease. The in vitro studies showed that most of the molecules exhibited a significant ability to inhibit self-induced β-amyloid (Aβ_1–42) aggregation (10.5–80.1%, 20 μM) and MAO-B activity (IC₅₀ of 7.5–40.5 μM), to act as potential antioxidants (ORAC-FL value of 2.75–9.37), and to function as metal chelators. In particular, compound <b>41</b> had the greatest ability to inhibit Aβ_1–42 aggregation (80.1%), and MAO-B (IC₅₀ = 7.5 μM) was also an excellent antioxidant and metal chelator. Moreover, it is capable of inhibiting Cu­(II)-induced Aβ_1–42 aggregation and disassembling the well-structured Aβ fibrils. These results indicated that compound <b>41</b> is an excellent multifunctional agent for the treatment of AD

Structure Elucidation and Biological Activity of Two New Trichothecenes from an Endophyte, <i>Myrothecium roridum</i>

Worldwide, many different grains are infected by various fungi that may produce trichothecene mycotoxins. Fungi that produce trichothecenes, as well as the trichothecenes themselves, are potential problems for public health. On the other hand, trichothecenes possess multiple biological activities. Reduced toxicity may result in their applications in the pharmaceutical field. Two new trichothecenes along with seven known trichothecenes were isolated from an endophyte of the herb plant <i>Ajuga decumbens</i>. Their structures were deduced from 1D and 2D NMR data. The results of MTT assays revealed that new trichothecene 2′,3′-epoxymyrothecine A, <b>1</b>, and myrothecine A, <b>3</b>, exhibited much lower toxicity compared to other trichothecenes. New trichothecene 2′,3′-epoxymyrothecine A, <b>1</b>, could induce phosphorylation of JNK (c-Jun N-terminal protein kinase) protein and the PARP (poly ADP-ribose polymerase) cleavage, and eventually induce apoptosis in cancer cells. These results point out the possibility for application of trichothecenes as chemotherapeutic agent

A Natural Product from <i>Polygonum cuspidatum</i> Sieb. Et Zucc. Promotes Tat-Dependent HIV Latency Reversal through Triggering P-TEFb’s Release from 7SK snRNP

<div><p>The latent reservoirs of HIV represent a major impediment to eradication of HIV/AIDS. To overcome this problem, agents that can activate latent HIV proviruses have been actively sought after, as they can potentially be used in combination with the highly active antiretroviral therapy (HAART) to eliminate the latent reservoirs. Although several chemical compounds have been shown to activate latency, they are of limited use due to high toxicity and poor clinical outcomes. In an attempt to identify natural products as effective latency activators from traditional Chinese medicinal herbs that have long been widely used in human population, we have isolated procyanidin C-13,3',3"-tri-O-gallate (named as REJ-C1G3) from <i>Polygonum cuspidatum</i> Sieb. et Zucc., that can activate HIV in latently infected Jurkat T cells. REJ-C1G3 preferentially stimulates HIV transcription in a process that depends on the viral encoded Tat protein and acts synergistically with prostratin (an activator of the NF-κB pathway) or JQ1 (an inhibitor of Brd4) to activate HIV latency. Our mechanistic analyses further show that REJ-C1G3 accomplishes these tasks by inducing the release of P-TEFb, a host cofactor essential for Tat-activation of HIV transcription, from the cellular P-TEFb reservoir 7SK snRNP.</p></div

REJ-C1G3 triggers the release of P-TEFb from 7SK snRNP.

<p><b>(A and B)</b> WCE of J-Lat A2 (A) HeLa cells (B) that were either untreated (-) or treated (+) with REJ-C1G3 (20 μM) were analyzed by Western blotting for the indicated proteins (left panels). Anti-CDK9 immunoprecipitates (IP) derived from WCE were tested by Western blotting for presence of the indicated proteins (right panels). The amounts of the CDK9-bound proteins were quantified by densitometry and shown at the bottom. CDK9 in untreated cells (lane 1) was artifically set at 100%.</p

Determination of the purity and structure of REJ-C1G3 and its impact on cell viability.

<p><b>(A)</b> High performance liquid chromatography (HPLC) was performed to confirm the purity of REJ-C1G3. <b>(B)</b> Chemical tructure of REJ-C1G3. <b>(C and D)</b> J-Lat A2 (C) and HeLa cells (D) were exposed to REJ-C1G3 (20 μM) for 5 days and then assayed for cell viability. The error bars represent mean ± SD from three independent experiments.</p

Extracts of <i>Polygonum cuspidatum</i> Sieb. et Zucc. contain an activity that promotes HIV-1 LTR-driven EGFP expression.

<p><b>(A)</b> A flow chart depicting the purification of the active product REJ-C1G3 from the extracts of <i>Polygonum cuspidatum</i> Sieb. et Zucc.. <b>(B-E)</b> During the purification of REJ-C1G3, individual fractions obtained after each chromotography step were tested for their abilities to activate EGFP expression in J-Lat A2 cells. The indicated concentrations of these fractions or 2.5 μM prostratin as a positive control were incubated with J-Lat A2 cells for 12 hr, and the EGFP-positive cells detected by flow cytometry. The percentages of EGFP-expressing cells in the entire viable cell population were shown, with the error bars in all panels indicating mean ± SD from three independent experiments.</p

REJ-C1G3 preferentially stimulates the Tat-dependent HIV transcription.

<p><b>(A)</b> The HeLa-based based NH1 and NH2 cells were treated with REJ-C1G3 or DMSO as indicated. WCE were prepared and tested for luciferase activities (top panel) and the celluar tubulin levels detected by Western blotting (bottom panel). The activity detected in cells treated with DMSO was set to 1. The error bars represent mean ± SD from three independent experiments. <b>(B)</b> NH1 cells were transciently transfected with an empty vector (-) or the Tat-expressing construct (+; 10 ng/well) and then treated with REJ-C1G3 or DMSO (-) as indicated. WCE were prepared and tested for luciferase activities as in A. (C) mRNAs transcribed from the integrated HIV-1 LTR-luciferase reporter gene were analyzed by qRT-PCR with primers that hybridize to the three marked locations along the DNA template and then normalized to the levels of GAPDH mRNA. The error bars represent the mean ± SD from three independent measurements.</p

REJ-C1G3 synergizes with prostratin or JQ1 to reactivate latent HIV.

<p><b>(A and B)</b> J-Lat A2 cells were treated with REJ-C1G3 (20 μM) alone or in combination with prostratin (0.25 μM) or JQ1 (1 μM) for 12 hr and then analyzed by flow cytometry for the percentages of EGFP-positive cells in the total cell population. DMSO was used as a negative control. The error bars represent mean ± SD from three independent experiments.</p