Small Molecule Derivatives Research Articles

Novel PDE4 inhibitors derived from Chinese medicine forsythia.

Cyclic adenosine monophosphate (cAMP) is a crucial intracellular second messenger molecule that converts extracellular molecules to intracellular signal transduction pathways generating cell- and stimulus-specific effects. Importantly, specific phosphodiesterase (PDE) subtypes control the amplitude and duration of cAMP-induced physiological processes and are therefore a prominent pharmacological target currently used in a variety of fields. Here we tested the extracts from traditional Chinese medicine, Forsythia suspense seeds, which have been used for more than 2000 years to relieve respiratory symptoms. Using structural-functional analysis we found its major lignin, Forsynthin, acted as an immunosuppressant by inhibiting PDE4 in inflammatory and immune cell. Moreover, several novel, selective small molecule derivatives of Forsythin were tested in vitro and in murine models of viral and bacterial pneumonia, sepsis and cytokine-driven systemic inflammation. Thus, pharmacological targeting of PDE4 may be a promising strategy for immune-related disorders characterized by amplified host inflammatory response.

Chemical derivatives of a small molecule deubiquitinase inhibitor have antiviral activity against several RNA viruses.

Most antiviral treatment options target the invading pathogen and unavoidably encounter loss of efficacy as the pathogen mutates to overcome replication restrictions. A good strategy for circumventing drug resistance, or for pathogens without treatment options, is to target host cell proteins that are utilized by viruses during infection. The small molecule WP1130 is a selective deubiquitinase inhibitor shown previously to successfully reduce replication of noroviruses and some other RNA viruses. In this study, we screened a library of 31 small molecule derivatives of WP1130 to identify compounds that retained the broad-spectrum antiviral activity of the parent compound in vitro but exhibited improved drug-like properties, particularly increased aqueous solubility. Seventeen compounds significantly reduced murine norovirus infection in murine macrophage RAW 264.7 cells, with four causing decreases in viral titers that were similar or slightly better than WP1130 (1.9 to 2.6 log scale). Antiviral activity was observed following pre-treatment and up to 1 hour postinfection in RAW 264.7 cells as well as in primary bone marrow-derived macrophages. Treatment of the human norovirus replicon system cell line with the same four compounds also decreased levels of Norwalk virus RNA. No significant cytotoxicity was observed at the working concentration of 5 µM for all compounds tested. In addition, the WP1130 derivatives maintained their broad-spectrum antiviral activity against other RNA viruses, Sindbis virus, LaCrosse virus, encephalomyocarditis virus, and Tulane virus. Thus, altering structural characteristics of WP1130 can maintain effective broad-spectrum antiviral activity while increasing aqueous solubility.

Biodegradable dendritic polymersomes as modular, high-relaxivity MRI contrast agents

A modular approach combining nanoscale components that each contribute to an enhancement in Gd(III) relaxivity is described here. Small molecule and dendritic alkyne derivatives of a Gd(III) complex were conjugated to the surfaces of biodegradable polymersomes resulting in ionic relaxivities of 10.6 mM−1 s−1 and 26.1 mM−1 s−1 respectively.

Synthesis of a quinazoline derivative: A new α1-adrenoceptor ligand for conjugation to quantum dots to study α1-adrenoceptors in living cells

Quantum dots (QDs) that are conjugated to small molecule derivatives of drugs and endogenous ligands may be useful tools to study the distribution and dynamic of membrane bound receptors, ion channels and transporters in live cells. In order to use these tools, it is necessary to functionalize QDs with bioactive ligands. In this paper, we successfully synthesized a ligand of α(1)-adrenoceptor that could be conjugated to QDs. In addition, the conjugation of the ligands to QDs and their biological activity were evaluated through binding assay with 30 nM QD conjugates in living human embryonic kidney 293 cells.

Abstract 3562: Characterization of a novel small molecule inhibitor with potent anticancer activity

Abstract A series of isoquinolineamine small molecule derivatives were synthesized and screened as potential anticancer agents. Among them, we identified one isoquinolineamine analogue with potential anticancer activity. This compound inhibited the proliferation of a variety of cancer cells derived from many human solid tumors with IC50 values ranging from 14 nM to 71 nM. The compound also was more effective against gemcitabine and cisplatin-resistant cancer cell lines when compared to the original cytotoxic cancer drugs. In mice bearing tumor xenografts, treatment with the compound significantly inhibited the growth of tumors, enhanced tumor regression, and also prevented the growth of tumors in a paclitaxel-resistant xenograft model. This compound is well tolerated and had no effects on body weight compared to control animals. Mechanistic studies showed that cancer cells treated with this compound resulted in the elevation of cytochrome c in the cytosol, the decrease of Bcl-2 and the activation of Caspase 9. Further studies showed inhibition of the expression of several signaling molecules important for cell proliferation (p-Erk, p-p38 and p-Akt) and also decreased protein levels of p-GSK3α/β and β-catenin. Therefore, our result suggests that this compound could be a promising antitumor agent. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3562.

Universal polyethylene glycol linkers for attaching receptor ligands to quantum dots

Biologically active small molecule derivatives that can be conjugated to quantum dots have the promise of revolutionizing fluorescent imaging in biology. In order to achieve this several technical hurdles have to be surmounted, one of which is non-specific adsorption of quantum dots to cell membranes. Pegylating quantum dots has been shown to eliminate non-specific binding. Consequently it is necessary to develop a universal synthetic methodology to attach small molecule ligands to polyethylene glycol. These pegylated small molecules may then be conjugated to the surfaces of quantum dots. Ideally this universal strategy should be adaptable and be applicable to PEG chains of varying lengths. This paper describes the development of one such methodology and the synthesis of a pegylated derivative of the known 5HT 2 agonist 1-(2-aminopropyl)-2,5-dimethoxy benzene. This compound was tested and found to be an agonist for the 5HT 2A and 5HT 2C receptor having EC 50 values of 250 and 50 nM, respectively.

An HPLC/mass spectrometry platform for the development of multimodality contrast agents and targeted therapeutics: prostate‐specific membrane antigen small molecule derivatives

The production of disease-targeted agents requires the covalent conjugation of a targeting molecule with a contrast agent or therapeutic, followed by purification of the product to homogeneity. Typical targeting molecules, such as small molecules and peptides, often have high charge-to-mass ratios and/or hydrophobicity. Contrast agents and therapeutics themselves are also diverse, and include lanthanide chelates for MRI, (99m)Tc chelates for SPECT, (90)Y chelates for radiotherapy, (18)F derivatives for PET, and heptamethine indocyanines for near-infrared fluorescent optical imaging. We have constructed a general-purpose HPLC/mass spectrometry platform capable of purifying virtually any targeted agent for any modality. The analytical sub-system is composed of a single dual-head pump that directs mobile phase to either a hot cell for the purification of radioactive agents or to an ES-TOF MS for the purification of nonradioactive agents. Nonradioactive agents are also monitored during purification by ELSD, absorbance and fluorescence. The preparative sub-system is composed of columns and procedures that permit rapid scaling from the analytical system. To demonstrate the platform's utility, we describe the preparation of five small molecule derivatives specific for prostate-specific membrane antigen (PSMA): a gadolinium derivative for MRI, indium, rhenium and technetium derivatives for SPECT, and an yttrium derivative for radiotherapy. All five compounds are derived from a highly anionic targeting ligand engineered to have a single nucleophile for N-hydroxysuccinimide-based conjugation. We also describe optimized column/mobile phase combinations and mass spectrometry settings for each class of agent, and discuss strategies for purifying molecules with extreme charge and/or hydrophobicity. Taken together, our study should expedite the development of disease-targeted, multimodality diagnostic and therapeutic agents.

FILARIAL NEMATODE SECRETED PRODUCT ES‐62 IS AN ANTI‐INFLAMMATORY AGENT: THERAPEUTIC POTENTIAL OF SMALL MOLECULE DERIVATIVES AND ES‐62 PEPTIDE MIMETICS

1. The 'hygiene hypothesis' postulates that the recent increased incidence of allergic or autoimmune diseases (e.g. asthma, type I diabetes) in the West reflects an absence of appropriate priming of the immune response by infectious agents, such as parasitic worms, during childhood. 2. Consistent with this, it has long been recognized that several autoimmune disorders, such as rheumatoid arthritis (RA), a T helper (Th) 1-mediated autoimmune disease characterized by excess production of pro-inflammatory cytokines, such as tumour necrosis factor-alpha, exhibit reduced incidence and severity in geographical regions with high parasite load, suggesting that environmental factors may subtly alter disease progression. 3. Infection with worms also appears to suppress Th2-biased inflammatory disorders, such as asthma, because there also appears to be an inverse correlation between parasite load and atopy. This is perhaps more surprising, given that helminths often induce strong Th2-type immune responses characterized by release of specific cytokines, such as interleukin (IL)-4, IL-5 and IL-13. 4. Therefore, these findings suggest that the co-evolution of helminths with hosts, which has resulted in the ability of worms to modulate inflammatory responses in order to promote parasite survival, may also have generated a predisposition for the host to develop autoimmunity and allergy in the absence of infection. 5. The mechanisms underlying such immunomodulation are not clear, but appear to involve the release of parasite-derived molecules that allow the worms to modulate or evade the host immune response by a number of mechanisms, including skewing of cytokine responses and the induction of T regulatory cells. 6. In the present review we discuss the properties of one such filarial nematode-derived immunomodulatory molecule, namely ES-62, its anti-inflammatory action and the therapeutic potential of small molecule derivatives and peptides that mimic its action.

Discovery of Small Molecule Inhibitors of the Interaction of the Thyroid Hormone Receptor with Transcriptional Coregulators

Thyroid hormone (3,5,3'-triiodo-L-thyronine, T3) is an endocrine hormone that exerts homeostatic regulation of basal metabolic rate, heart rate and contractility, fat deposition, and other phenomena (1, 2). T3 binds to the thyroid hormone receptors (TRs) and controls their regulation of transcription of target genes. The binding of TRs to thyroid hormone induces a conformational change in TRs that regulates the composition of the transcriptional regulatory complex. Recruitment of the correct coregulators (CoR) is important for successful gene regulation. In principle, inhibition of the TR-CoR interaction can have a direct influence on gene transcription in the presence of thyroid hormones. Herein we report a high throughput screen for small molecules capable of inhibiting TR coactivator interactions. One class of inhibitors identified in this screen was aromatic beta-aminoketones, which exhibited IC50 values of approximately 2 microm. These compounds can undergo a deamination, generating unsaturated ketones capable of reacting with nucleophilic amino acids. Several experiments confirm the hypothesis that these inhibitors are covalently bound to TR. Optimization of these compounds produced leads that inhibited the TR-CoR interaction in vitro with potency of approximately 0.6 microm and thyroid signaling in cellular systems. These are the first small molecules irreversibly inhibiting the coactivator binding of a nuclear receptor and suppressing its transcriptional activity.