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Total Synthesis and Anti-Cancer Activity of Micrococcin P1 and Synthetic Fragments
Full text linkThiopeptides are a versatile group of natural products with a wealth of therapeutic potential. To expand the methods of syntheses of these compounds and more closely study their in vitro activity, we report the total synthesis of micrococcin P1 enabled by robust thiazole forming reactions. Never before used in the synthesis of thiopeptides, we were able to access decagram quantities of several thiazole containing fragments through the condensation of nitriles and aminothiols. These thiazole forming reactions are robustly scalable and we were able to produce nearly 200 mg of the natural product. Micrococcin and other synthetic precursors were used to probe structure-activity relationships in in vivo anti-cancer assays where micrococcin was not found to have significant anti-cancer activity, though several smaller fragments were found to have low micromolar to high nanomolar potency. Previously, only series B thiopeptides and their complex central piperidine fragments were known to have this activity. This finding shows that not only series B thiopeptides like thiostrepton and siomycin A have anti-cancer activity. That fragments of micrococcin P1, a series D thiopeptide, show comparable activity indicates a broader scope of activity in the family. Importantly, we have established a minimum scaffold for activity, and these fragments are more easily accessible with our shorter, higher yielding synthesis than that of previous fragments from thiostrepton. Following these discoveries, medicinal chemistry efforts to increase pharmacokinetic properties and potency of these fragments can be explored
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The Antibacterial Activity of Tricyclic Gyrase (GyrB/ParE) Inhibitor: A New Class of Antibacterial Agents
Full text linkGrowing antibiotics resistance and the limited amount of effective antibiotics against Gram-negative pathogens are the most alarming problems in clinic; therefore, the search for new board-spectrum antibacterial agents becomes an imminent task in the pharmaceutical industry. Researches have shown that Tricyclic Gyrase (GyrB/ParE) Inhibitors are a new class of board-spectrum antibacterial agents which are effective against multi-drug resistant bacteria strains. Pharmaceutical companies like Trius had synthesized such inhibitors but none of the inhibitors has made into clinical trials yet due to various safety issues and solubility problems. In this research, new tricyclic gyrase inhibitors were synthesized by modifying the functional groups. Minimum Inhibitory Concentration (MIC) Assays were used to examine their board-spectrum antibacterial potencies against nine total bacteria strains, including multi-drug resistant strains. The results showed that two of the synthesized compounds, D18 and Tri-1, have board-spectrum antibacterial activities and works against multi-drug resistant strains. Compounds Tri-2, Tri-3, and Tri-4 showed activity against Gram-positive bacteria only while compound Tri-5 showed poor antibacterial activity possible due to the 2-Methylpyrimmdin
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Synthesis of New Polyunsaturated Fatty Acid Ester of Hydroxyl Fatty Acid (FAHFA): Stearoyl Acid Ester of Leukotriene B4 (LTB4)
Full text linkFatty acid ester of hydroxyl fatty acid (FAHFA) is a molecule family of lipid ester. In recent years,some of them have showed function on anti-inflammation, anti-diabetes. Among them, a unique kind of
polyunsaturated FAHFA-13-HODE was discovered and found it reversed the original harmful effect as a
mediator in metabolism from its hydroxyl fatty acid part. Inspired by this phenomenon, Leukotriene B4 as
a mediator in cell leading to many harmful effects was chosen as the hydroxyl fatty acid part of new
FAHFAs and these FAHFAs were expected to have beneficial biological function. In this research, in order
to test this hypothesis, polyunsaturated FAHFAs--------5-stearoyl acid ester of LTB4 and 12-stearoyl acid
ester of LTB4 were synthesized, which consisted of hydroxyl fatty acid (HFA)-racemic leukotriene B4
analogies and fatty acid (FA)-stearoyl aci
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Total Synthesis of Eupalinilide E and Development of a Platform to Access Novel Thiopeptide Antibiotics
Full text linkControl of stem cell fate is a central goal of regenerative medicine. Hematopoieticstem cells (HSCs) are in high demand because they are routinely used in bone marrowtransplants. This has led to a shortage of clinically viable HSCs and there are no FDAapproved methods for the growth and maintenance of these cells ex vivo. The naturalproduct eupalinilide E (7) promotes the ex vivo self-renewal (expansion) of HSCs with a983-fold increase in growth after 14 days. The mode of action of eupalinilide E (7) remains unknown and appears to be independent of other known mechanism for HSC expansion. A synthetic route that can allow access to gram-scale quantities of eupalinilide E (7) has been developed.There remains a constant need for novel antibiotics to combat the ever growingproblem of antibiotic resistant infections. Thiopeptides are a well-studied family of naturalproducts with potent antibiotic activity against several contemporary antibiotic resistantbacterial strains. Although having low toxicity against human cell lines and in vivo animalmodels, thiopeptides have only been used in the agricultural industry due to their lowsolubility in water. En route to the total synthesis of the thiopeptide lactocillin (119), aplatform for the synthesis of novel thiopeptides has been developed. The route allows forrapid construction of the 29-membered macrocyclic core with synthetic handles for analog synthesis. Utilizing this route, derivative synthesis has begun with the intention ofultimately discovering novel thiopeptides with improved pharmacokinetics
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Synthesis of Tag-Pollutants Conjugates for Synthetically Evolved Receptors Screening
Full text linkFast on-site detection of organic pollutants using biosensors is developing rapidly. To select Nanobodies which have binding specificity to varies of pollutants to make the biosensors, the pollutants and tag conjugates was synthesized in lab and applied to cell culture. Our results demonstrated that the recombination of the naïve nanobody culture for generations does produces the nanobodies possessing high binding affinity towards organic pollutants
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The Synthesis and Structure-Activity Relationship of Covalent Inhibitors Targeting SCP1 and GNAS
Full text linkGlioblastoma (GBM) represents the most prevalent malignant tumor affecting the central nervous system. The current treatment regime consisting of surgery, chemotherapy, and radiation has remained the same for over two decades even though patients rarely live three years past treatment. Post-translational regulation of the repressor element-1 silencing transcription factor (REST) has been shown to be a successful method in reducing GBM derived tumors. Inhibition of REST’s regulatory protein small C-terminal domain phosphatase 1 (SCP1) is an effective strategy to modulate REST levels and therefore GBM. Guided by a structure-based drug design approach over 220 final compounds were synthesized and tested generating a broad understanding of their structure-activity relationship. To better understand the kinetics of the dually activated benzo[b]thiophene 1,1-dioxide warhead, an NMR based kinetic study was performed to generate half-life (t1/2) data and find the target zone of reactivity.The GNAS gene, responsible for encoding the Gαs subunit of heterotrimeric G proteins, exhibits the second highest mutation frequency in mucinous appendiceal adenocarcinoma. Despite being a druggable target, there are currently no commercially available inhibitors specifically targeting Gαs. Additionally, GNASR201 stands out as a target because it is the most cancer-causing mutation of all heterotrimeric G-proteins. As guanosine-5’-triphosphate (GTP) is the Gαs’s endogenous substrate the strategy was to synthesize GTP derivates that covalently bind the GNASR201C mutation allowing selectivity of the cancerous cells. Guanosine-epoxide (2.4) and a diastereomeric pair of its phosphoamidate prodrugs were synthesized and tested showing a proof of concept. Synthetic routes affording cyclic and acyclic covalent guanosine analogues were bottle necked by a phosphorylation step. Although optimization efforts resulted in parameters generating the desired product, reaction yields were insufficient to allow the generation of a diverse library
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
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Synthesis of vinaxanthone analogs
Full text linkSpinal cord injury is a debilitating injury that affects 12,000 people in the U.S. annually.1
Current treatment is limited; research in tissue engineering, biomaterials, and gene therapy have
dominated neuroregeneration studies. However, an inadequate amount of attention has been
dedicated to the development of small molecule therapeutics. Vinaxanthone (SM-345431) and
xanthofulvin (SM-216289) are two novel small molecule compounds co-isolated from
Penicillium sp. SPF-3059 that demonstrate axonal regenerative properties in both C. elegans and
adult rats. Initially, the molecules were thought to inhibit semaphorin 3A, a protein which
induces the collapse of neuronal growth cones. Knockout studies of semaphorin 3A indicate that
simply shutting off inhibitory signaling does not equate to the pronounced neuroregeneration
present from vinaxanthone and xanthofulvin administration, suggesting that the molecules
possess alternative modes of action. To uncover the mechanism of action for these two small
molecules, analogs of vinaxanthone and xanthofulvin are being developed for structure-activityrelationship
studies in C. elegans. Further research into the action of these analogs will provide
useful information regarding CNS inhibitory signaling in spinal cord injury models and potential
therapeutic options. Currently, the synthesis of vinaxanthone analogs is being pursued. Initial
data from G-protein coupled receptor assays (GPCR) indicates that various vinaxanthone analogs
have been found to possess either positive or negative allosteric modulation for the succinate
receptor 1 protein (SUCNR1 or GPR91). The synthesis of more vinaxanthone analogs will be
pursued (with an envisioned vinaxanthone library of 64 compounds) and their biological activity
tested.BiochemistryChemistr
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Studies toward the synthesis of celastrol and the late-stage hydroxylation of arenes mediated by 4,5-dichlorophthaloyl peroxide
Full text linktextThe natural product celastrol (1) possesses a wide array of promising biological activities related to diseases characterized by protein misfolding including those associated with neuronal degradation, inflammation, and cancer. Relevant to cancer, celastrol functions as a non-ATP-competitive inhibitor of heat shock protein-90, providing a potential lead for the development of new inhibitors with improved pharmacology. A laboratory preparation of the small molecule was undertaken to provide access to the unnatural enantiomer of celastrol. The lack of understanding of the chemistry and biology of the growing class of celastroids is attributed to the incompatibility of biologically inspired polyene cyclization strategies to assemble friedelin triterpenoids. As a result of these problems residing at the interface of chemistry and biology, a purely synthesis-based strategy for polyene cyclizations to rapidly construct the pentacyclic core of the friedelin and celastroid natural products has been developed. This efficient strategy is gram scalable culminating in the first total synthesis of wilforic acid (127) and an advanced intermediate capable of delivering celastrol (1) as well as numerous celastroid natural products. Phenols possess broad utility serving as key materials in all facets of chemical industries, especially the pharmaceutical industry. The ideal synthesis of a phenolic compound entails the direct oxidation of an aryl C-H bond remains to be a difficult synthetic challenge. Following our initial report describing the hydroxylation of arenes using phthaloyl peroxide, new peroxide derivatives were investigated to probe their reactivity in an effort to hydroxylate aromatics which were previously unreactive. Electronically poor to moderately rich arenes were successfully hydroxylated with a broad functional group tolerance using 4,5-dichlorophthaloyl peroxide. This protocol has been applied toward the rapid synthesis of phenolic analogs and metabolites of current pharmaceuticals as well as biocides. Mechanistic studies using kinetic isotope effect, competition, and benzylic oxidation experiments indicate that a novel diradical reverse-rebound mechanism is the likely pathway. Further examination of the transition-state using linear free energy relationships with sigma vs. sigma+ values established a linear trend with a low negative rho value (- 3.92) corresponding best using sigma values supporting a diradical reverse-rebound addition.Chemistr
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