Down-expression of TaPIN1s Increases the Tiller Number and Grain Yield in Wheat.

BACKGROUND: Tiller number is a factor determining panicle number and grain yield in wheat (Triticum aestivum). Auxin plays an important role in the regulation of branch production. PIN-FORMED 1 (PIN1), an auxin efflux carrier, plays a role in the regulation of tiller number in rice (Oryza sativa); however, little is known on the roles of PIN1 in wheat. RESULTS: Nine homologs of TaPIN1 genes were identified in wheat, of which TaPIN1-6 genes showed higher expression in the stem apex and young leaf in wheat, and the TaPIN1-6a protein was localized in the plasma membrane. The down-expression of TaPIN1s increased the tiller number in TaPIN1-RNA interference (TaPIN1-RNAi) transgenic wheat plants, indicating that auxin might mediate the axillary bud production. By contrast, the spikelet number, grain number per panicle, and the 1000-grain weight were decreased in the TaPIN1-RNAi transgenic wheat plants compared with those in the wild type. In summary, a reduction of TaPIN1s expression increased the tiller number and grain yield per plant of wheat. CONCLUSIONS: Phylogenetic analysis and protein structure of nine TaPIN1 proteins were analyzed, and subcellular localization of TaPIN1-6a was located in the plasma membrane. Knock-down expression of TaPIN1 genes increased the tiller number of transgenic wheat lines. Our study suggests that TaPIN1s is required for the regulation of grain yield in wheat.

[Genetic diversity analysis of Andrographis paniculata in China based on SRAP and SNP].

In order to reveal genetic diversity of domestic Andrographis paniculata and its impact on quality, genetic backgrounds of 103 samples from 7 provinces in China were analyzed using SRAP marker and SNP marker. Genetic structures of the A. paniculata populations were estimated with Powermarker V 3.25 and Mega 6.0 software, and polymorphic SNPs were identified with CodonCode Aligner software. The results showed that the genetic distances of domestic A. paniculata germplasm ranged from 0. 01 to 0.09, and no polymorphic SNPs were discovered in coding sequence fragments of ent-copalyl diphosphate synthase. A. paniculata germplasm from various regions in China had poor genetic diversity. This phenomenon was closely related to strict self-fertilization and earlier introduction from the same origin. Therefore, genetic background had little impact on variable qualities of A. paniculata in domestic market. Mutation breeding, polyploid breeding and molecular breeding were proposed as promising strategies in germplasm innovation.

Ligustrazine derivatives. Part 3: Design, synthesis and evaluation of novel acylpiperazinyl derivatives as potential cerebrocardiac vascular agents.

A series of novel acylpiperazinyl Ligustrazine derivatives was designed, synthesized, and their protective effects on damaged ECV-304 cells and antiplatelet aggregation activities were evaluated. The results showed that compound E33 displayed most potential protective effects on the ECV-304 cells damaged by hydrogen peroxide, and compound E1 was found to be the most active antiplatelet aggregation agent. Structure-activity relationships were briefly discussed.

Connexin 43, a new therapeutic target for cardiovascular diseases.

Junctional channels (JC) play essential roles in the normal function of the cardiovascular system, mediating the spread of the electrical impulse that triggers synchronized contraction of the cardiac chambers and contributing to the coordination of activities between cells of the arterial wall. In mammalian hearts, cells most prominently express JC built of Connexin40 (Cx40), Cx43 and Cx45, of which Cx43 is the predominant intercellular gap junction protein. Changes in cardiovascular Cx gene expression during development or in response to (patho)physiological signals are expected to be a crucial factor in normal cardiac development and functions, and several cardiac diseases, such as atrial fibrillation, hypertrophy, heart failure, atherosclerosis, etc. Although the underlying molecular mechanisms have not yet been elucidated, recent research has found a variety of novel potential therapies related to Cx43 that can help to learn more about the mechanism of those cardiovascular diseases and the signaling pathway.

Conformational restriction: an effective tactic in 'follow-on'-based drug discovery.

The conformational restriction (rigidification) of a flexible ligand has often been a commonly used strategy in drug design, as it can minimize the entropic loss associated with the ligand adopting a preferred conformation for binding, which leads to enhanced potency for a given physiological target, improved selectivity for isoforms and reduced the possibility of drug metabolism. Therefore, the application of conformational restriction strategy is a core aspect of drug discovery and development that is widely practiced by medicinal chemists either deliberately or subliminally. The present review will highlight current representative examples and a brief overview on the rational design of conformationally restricted agents as well as discuss its advantages over the flexible counterparts.

Recent advances in the structure-based rational design of TNKSIs.

Human tankyrases 1 and 2 (TNKS1/2) are attractive pharmacological biotargets, especially for the treatment of specific types of cancer. This article provides a fairly comprehensive overview of the structural biology of the TNKS-inhibitor complex and the current medicinal chemistry strategies being used in the structure-based rational design of tankyrase-specific inhibitors.

"Old Dogs with New Tricks": exploiting alternative mechanisms of action and new drug design strategies for clinically validated HIV targets.

HIV-1 reverse transcriptase, protease and integrase have been recognized as clinically validated but still underexploited targets for antiretroviral treatment. Although a large number of inhibitors have been used in clinical trials, the rapid emergence of multiple drug-resistant strains requires the identification of not only novel classes of antiretroviral drugs that act via the unprecedented mechanism of action but also innovative drug discovery strategies towards these three important targets. This review summarizes and discusses current endeavours towards the discovery and development of novel inhibitors with alternative mechanisms of action, and also provides examples illustrating new methodologies in medicinal chemistry that contribute to the identification of novel antiretroviral agents.

Recent advances in the discovery and development of novel HIV-1 NNRTI platforms (Part II): 2009-2013 update.

The long-term usage of HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs) eventually leads to rapid emergence of drug-resistant viruses and severe side effect. Therefore, it is imperative to seek the additional NNRTIs with potent and broad spectrum anti-mutant activities, and excellent pharmacokinetic profiles. The discovery of etravirine, rilpivirine and other successful examples has influenced the NNRTIs design strategy profoundly. Sustained efforts in this area have led to the identification of many promising NNRTIs hits, leads and candidates for the last few years. Hence, this review aims to highlight recent prominent advances in this field as well as contributions from our laboratory toward the discovery of novel potent NNRTIs from 2009 to 2013 (by May).

Novel HIV-1 non-nucleoside reverse transcriptase inhibitors: a patent review (2011-2014).

INTRODUCTION: There is a continuous need for next-generation non-nucleoside RT inhibitors (NNRTIs) with different resistance profiles, improved safety, excellent tolerability, and favorable physicochemical properties. AREAS COVERED: In this review we intend to narrate a general and cutting-edge overview of current state of NNRTI patents during the 2011-2014 (June) period and future perspectives. Particular focus is placed on the highlighting of some emerging medicinal chemistry principles and insights in the discovery and development of NNRTIs. EXPERT OPINION: The development of effective NNRTIs is moving on from trial-and-error approaches to sophisticated subconscious strategies. Several newly emerging structure-based virtual screening methodologies (such as Monte Carlo free energy perturbation calculations) or new drug design insights, such as taking full use of the specific noncovalent reverse transcriptase/NNRTIs interactions, stereochemical diversity-oriented conformational restriction, novel strategies to enhance solubility and early absorption, distribution, metabolism, excretion, and toxicity (ADMET) assessment, will continue to evolve to complement the classical NNRTIs discovery approaches (structure-based core-refining and substituents-decorating).

Discovery and characterization of novel imidazopyridine derivative CHEQ-2 as a potent CDC25 inhibitor and promising anticancer drug candidate.

Cell division cycle (CDC) 25 proteins are key phosphatases regulating cell cycle transition and proliferation via the interactions with CDK/Cyclin complexes. Overexpression of CDC25 proteins is frequently observed in cancer and is related to aggressiveness, high-grade tumors and poor prognosis. Thus, inhibiting CDC25 activity in cancer treatment appears a good therapeutic strategy. In this article, refinement of the initial hit XDW-1 by synthesis and screening of a focused compound library led to the identification of a novel set of imidazopyridine derivatives as potent CDC25 inhibitors. Among them, the most potent molecule was CHEQ-2, which could efficiently inhibit the activities of CDC25A/B enzymes as well as the proliferation of various different types of cancer cell lines in vitro assay. Moreover, CHEQ-2 triggered S-phase cell cycle arrest in MCF-7, HepG2 and HT-29 cell lines, accompanied by generation of ROS, mitochondrial dysfunction and apoptosis. Besides, oral administration of CHEQ-2 (10 mg/kg) significantly inhibited xenografted human liver tumor growth in nude mice, while demonstrated extremely low toxicity (LD50 > 2000 mg/kg). These findings make CHEQ-2 a good starting point for further investigation and structure modification.

"Old friends in new guise": exploiting privileged structures for scaffold re-evolution/refining.

The attempts to increase novel drug productivity through creative discovery technologies have fallen short of producing the satisfactory results. For these reasons, evolved from the concept of drug repositioning, "privileged structure"-guided scaffold re-evolution/refining is a primary strategy to identify structurally novel chemotypes by modifying the central core structure and the side-chain of the existing active compounds, or to exploit undescribed bioactivites by making full use of readily derivatized motifs with well-established synthetic protocols. Herein, we review the basic tricks of exploiting privileged structures for scaffold re-evolution/refining. The power of this strategy is exemplified in the discovery of other new therapeutic applications by refining privileged structures in anti-viral agents.

Heterocycle-thioacetic acid motif: a privileged molecular scaffold with potent, broad-ranging pharmacological activities.

Privileged structures can bind to multiple targets with high affinity, thus aiding the discovery of novel bioactive agents. Heterocycle- thioacetic acid derivatives, a group of molecules containing a heterocycle core linked with a thioacetic acid-derived fragment, represent an important type of "privileged scaffold" possessing a wide spectrum of biological properties. Numerous encouraging investigations demonstrated that this privileged structure should be extensively exploited for the therapeutic benefits. In view of its predominance, and on the basis of our research interest involved in this scaffold, an updated and detailed account of the pharmacological properties of heterocycle-thioacetic acid derivatives is described in this article.

Privileged scaffolds or promiscuous binders: a glance of pyrrolo[2,1-f][1,2,4]triazines and related bridgehead nitrogen heterocycles in medicinal chemistry.

Pyrrolo[2,1-f][1,2,4]triazine template, a unique bridgehead nitrogen heterocycle, certainly deserves the title of "privileged scaffold" in the drug discovery field because of the versatility and potential to yield derivatives with a wide range of biological activities, such as anti-anaplastic lymphoma kinase (ALK), Janus kinase 2 (JAK2), VEGFR-2, EGFR and/or HER2, Met kinase, p38α mitogen-activated protein (MAP) kinase and insulin-like growth factor receptor (IGF-1R) kinase activities, etc. These different biological properties of pyrrolo[2,1-f][1,2,4]triazine derivatives have motivated new studies in searching for novel derivatives with improved activity and also other applications in pharmaceutical field. However, no systematic review is available in the literature on the pyrrolo[2,1- f][1,2,4]triazine derivatives concerning the design of potent drug-like compounds. Owing to the importance of this heterocyclic system, the present paper is an attempt to the pharmacological activities, structural modifications and the structure-activity relationship (SAR) reported for bridgehead nitrogen heterocycles in the current literature, making an effort to highlight the importance and therapeutic potentials of the pyrrolo[2,1-f][1,2,4]triazine scaffold and its bridgehead nitrogen bioisosters as heterocyclic privileged medicinal scaffolds.

Multivalent agents: a novel concept and preliminary practice in Anti-HIV drug discovery.

The term multivalency (polyvalency) in the biological science is defined as the simultaneous binding of multiple ligands to one receptor (or multiple receptors to one ligand). The possibility of gaining potency and selectivity was significantly increased through the use of multivalent ligand as a homo- or hetero-dimer, thus multivalent ligands provided a more attractive strategy to design novel anti-HIV agents with therapeutic applications. Moreover, similar to phenomenon of multivalency, an alternative strategy is called the "mixed sites inhibitor", viz. a single molecule that possesses enough chemical space to maximize interactions with its complementary binding pocket, or to bind simultaneously in more than one regions in a target. Actually, the addition of a third heterocyclic nucleus to the parent compound resulted in "mixed sites" anti-HIV agents with broad spectrum of activities against the mutant HIV-1 strains. Based on current representative examples, the present article provided a brief review on the rationale for the design of different classes of multivalency anti-HIV agents and also discussed the advantages over their monomeric counterparts, providing a novel paradigm to facilitate the development of anti-HIV/AIDS therapeutic agents in treatment of HIV infected community.

Ligustrazine derivate DLJ14 reduces multidrug resistance of K562/A02 cells by modulating GSTπ activity.

Multidrug resistance (MDR) of tumor cells is a major obstacle in chemotherapeutic cancer treatment. Over-expression of glutathione S-transferase π (GSTπ) is one of the mechanisms contributing to MDR. In this study, we investigated the reversal of MDR by DLJ14, a ligustrazine derivate, in adriamycin (Adr) resistant human myelogenous leukemia (K562/A02) cells by modulating the expression of GSTπ and the activity of GST-related enzymes. In the MTT test, DLJ14 showed a weak inhibition on proliferation of both K562/A02 and K562 cells, while verapamil at the same concentration showed a much stronger inhibition. The sensitivity of K562/A02 cells to cytotoxic killing by Adr was enhanced by incubation with DLJ14 as a result of the increased intracellular accumulation of Adr. The accumulation of Adr induced by DLJ14 may due to down regulation of GST-related enzyme activity. Western blot analysis and RT-PCR showed that DLJ14 was able to inhibit the protein expression and mRNA expression of GSTπ in K562/A02 cells. Moreover, DLJ14 increased the expression of cellular c-Jun NH(2)-terminal kinase (JNK) in K562/A02 cells exposure to Adr. This is consistent with the inhibition of GSTπ. These results demonstrate that DLJ14 may be an attractive new agent for the chemosensitization of cancer cells.

Regulation and role of organic anion-transporting polypeptides (OATPs) in drug delivery at the choroid plexus.

The organic anion-transporting polypeptides (rodents: Oatps; human: OATPs) belong to the growing family of organic anion/prostaglandin transporters and are important components of the active efflux transport system at the choroid plexus epithelial cells. OATPs facilitate the elimination of xenobiotics and endogenous waste from the cerebrospinal fluid and prevent waste accumulation in the central nervous system (CNS). This review summarizes the structures, regulations and roles of Oatps/OATPs at the choroid plexus in drug delivery to the CNS.

Mmp-9, a potential target for cerebral ischemic treatment.

Matrix metalloproteinase-9 (MMP-9) which is a member of matrix metalloproteinases family that normally remodel the extracellular matrix, has been shown to play an important role in both animal models of cerebral ischemia and human stroke. The expression of MMP-9 is elevated after cerebral ischemia which is involved in accelerating matrix degradation, disrupting the blood-brain barrier, increasing the infarct size and relating to hemorrhagic transformation. Recently, many drugs, such as tetracycline derivatives, cyclooxygenase inhibitors, ACEI inhibitors and AT1 receptor blockers, etc., have been found to attenuate the elevated expression levels of MMP-9 after ischemia and to reduce the damage of cerebral ischemic. This article reviews the physiological features of MMP-9 and its important role in the genesis, propagation, and therapeutics of cerebral ischemic diseases.