Semisynthetic Compounds Research Articles

Semisynthesis of N-acyl homoserinelactone derivatives and the antifeedant activity against Mythimna separata

Seven homoserine-lactone (HL) acylated derivatives (HL1-HL7) were synthesized to determine the differences in antifeedant affects. The differences between these derivatives and tutin against Mythimna separata were tested. The structural assignments of these semisynthetic compounds were examined based on their infrared radiaion (IR), electrospray ionization mass spectrometry (ESIMS), and 1H- and 13C-nuclear magnetic resonance (13C-NMR) spectral data. Compound HL1 (N-(4-nitrobenzoyl)-homoserinelactone) is the optimized insecticidal agent among these compounds. In addition, the antifeedant activities between homoserinelactone and 7-hydroxycoumarin, tutin derivatives with the same acidylated substitutions were compared, which could help design and synthesize stronger novel botanical insecticides.

Cytotoxic activity of semi-synthetic ingenol derived from Euphorbia tirucalli on a large panel of human cancer cell lines.

e13559 Background: The latex from Euphorbia tirucalli is used in Brazil as anticancer and other disease as folk treatment; however, little is known about its anticancer proprieties. We report in vitro activity of 3 semi-synthetic ingenol compounds derived from E. tirucalli, ingenol A (ingenol-3-trans-cinnamate), ingenol B (3-caproyl-ingenol) and ingenol C (ingenol-3-dodecanoate), against a large panel of human cancer cell lines. Methods: Anti-tumor effects of the 3 semi-synthetic compounds were assessed using MTS assays on 77 cancer lines from 13 tumor models, such as breast, colon, bladder, prostate, lung, pancreas, esophagus, glioblastoma, melanoma, head and neck and cervical cancer. Additionally, we evaluate the its potential combinatorial value with temozolomide (TMZ) in gliomas. Ongoing experiments will identify potential drug target(s) by assessing changes in global protein expression. Results: Ingenol A, B and C exhibited dose-dependent and time-dependent cytotoxic effects. Amongst the derived tested, ingenol C displayed the best activity across the tumor cell lines. In comparison with TMZ, ingenol C showed a median of 136 fold higher efficacy, range 15-511 fold, in the glioma cell lines analyzed. Conclusions: The semi-synthetic ingenol compounds, in particular the ingenol C, demonstrated a potent anti-tumor activity on all cancer cell lines evaluated. Our findings may provide insight into designing ingenol-based therapies for cancer patients. [Table: see text]

Antibiotics: present and future

The author discuss the up to date interpretation of the concept of antibiotics and antibiotic research, as well as the present role of various natural, semisynthetic and synthetic antibiotic compounds in various areas of the human therapy. The origin and the total number of all antibiotics and applied antibiotics in the practice, as well as the bioactive microbial metabolites (antibiotics) in other therapeutical, non-antibiotic fields (including agriculture) are also reviewed. The author discusses main problems, such as increasing (poly)resistance, virulence of pathogens and the non-scientific factors (such as a decline of research efforts and their sociological, economic, financial and regulatory reasons). A short summary of the history of Hungarian antibiotic research is also provided. The author briefly discusses the prospects in the future and the general advantages of the natural products over synthetic compounds. It is concluded that new approaches for the investigation of the unlimited possibilities of the living world are necessary. The discovery of new types or simply neglected (micro)organisms and their biosynthetic capabilities, the introduction of new biotechnological and genetic methods (genomics, metagenom, genome mining) are absolutely required in the future.

NDP-MSH inhibits neutrophil migration through nicotinic and adrenergic receptors in experimental peritonitis

Melanocortin is a potent anti-inflammatory molecule. However, little is known about the effect of melanocortin on acute inflammatory processes such as neutrophil migration. In the present study, we investigated the ability of [Nle4, D-Phe7]-melanocyte-stimulating hormone (NDP-MSH), a semisynthetic melanocortin compound, in the inhibition of neutrophil migration in carrageenin-induced peritonitis model. Herein, subcutaneous pretreatment with NDP-MSH decreased neutrophil trafficking in the peritoneal cavity in a dose-dependent manner. NDP-MSH inhibited vascular leakage, leukocyte rolling, and adhesion and reduced peritoneal macrophage inflammatory protein 2, but not TNF-alpha, IL-1beta, IL-10, and keratinocyte-derived chemokine production. In addition, the effect on neutrophil migration was reverted by the pretreatment with both propranolol (a nonselective beta-adrenergic antagonist) and mecamylamine (a nonselective nicotinic antagonist) but not by splenectomy surgery. Moreover, NDP-MSH intracerebroventricular administration inhibited neutrophil migration, indicating participation of the central nervous system. Our results propose that the NDP-MSH effect may be due to a spleen-independent neuro-immune pathway that efficiently regulates excessive neutrophil recruitment to tissues.

Anticancer steroids: linking natural and semi-synthetic compounds

Steroids, a widespread class of natural organic compounds occurring in animals, plants and fungi, have shown great therapeutic value for a broad array of pathologies. The present overview is focused on the anticancer activity of steroids, which is very representative of a rich structural molecular diversity and ability to interact with various biological targets and pathways. This review encompasses the most relevant discoveries on steroid anticancer drugs and leads through the last decade and comprises 668 references.

Temporary diplopia upon hyoscine-N-butyl bromide administration: case report

Hyoscine-N-butyl bromide is a widely used antispasmodic belonging to the belladonna alkaloid class of semisynthetic quaternary ammonium compounds. These compounds exert a spasmolytic action on the smooth muscles of the bile-gastrointestinal tract, genitourinary tract, salivary glands (xerostomia), and also on the visual apparatus - in particular, the irido-ciliary complex. As a consequence, they provoke collateral effects such as mydriasis and accommodation disturbances. We report the case of a 23-year-old woman who complained of not only “dry mouth” but also “cloudy vision” and a “diplopia”, both of temporary type, 2 hours after oral administration of hyoscine-N-butyl bromide.

A novel semisynthetic inhibitor of the FRB domain of mammalian target of rapamycin blocks proliferation and triggers apoptosis in chemoresistant prostate cancer cells.

The mammalian target of rapamycin (mTOR) is a key regulator of cell growth and its uncontrolled activation is a hallmark of cancer. Moreover, mTOR activation has been implicated in the resistance of cancer cells to many anticancer drugs, rendering this pathway a promising pharmacotherapeutic target. Here we explored the capability of a semisynthetic compound to intercept mTOR signaling. We synthesized and chemically characterized a novel, semisynthetic triterpenoid derivative, 3-cinnamoyl-11-keto-β-boswellic acid (C-KβBA). Its pharmacodynamic effects on mTOR and several other signaling pathways were assessed in a number of prostate and breast cancer cell lines as well as in normal prostate epithelial cells. C-KβBA exhibits specific antiproliferative and proapoptotic effects in cancer cell lines in vitro as well as in PC-3 prostate cancer xenografts in vivo. Mechanistically, the compound significantly inhibits the cap-dependent transition machinery, decreases expression of eukaryotic translation initiation factor 4E and cyclin D1, and induces G(1) cell-cycle arrest. In contrast to conventional mTOR inhibitors, C-KβBA downregulates the phosphorylation of p70 ribosomal S6 kinase, the major downstream target of mTOR complex 1, without concomitant activation of mTOR complex 2/Akt and extracellular signal-regulated kinase pathways, and independently of protein phosphatase 2A, liver kinase B1/AMP-activated protein kinase/tuberous sclerosis complex, and F12-protein binding. At the molecular level, the compound binds to the FKBP12-rapamycin-binding domain of mTOR with high affinity, thereby competing with the endogenous mTOR activator phosphatidic acid. C-KβBA represents a new type of proapoptotic mTOR inhibitor that, due to its special mechanistic profile, might overcome the therapeutic drawbacks of conventional mTOR inhibitors.

Evaluation of Pseudopteroxazole and Pseudopterosin Derivatives against Mycobacterium tuberculosis and Other Pathogens

Pseudopterosins and pseudopteroxazole are intriguing marine natural products that possess notable antimicrobial activity with a commensurate lack of cytotoxicity. New semi-synthetic pseudopteroxazoles, pseudopteroquinoxalines and pseudopterosin congeners along with simple synthetic mimics of the terpene skeleton were synthesized. In order to build structure-activity relationships, a set of 29 new and previously reported compounds was assessed for in vitro antimicrobial and cytotoxic activities. A number of congeners exhibited antimicrobial activity against a range of Gram-positive bacteria including Mycobacterium tuberculosis H37Rv, with four displaying notable antitubercular activity against both replicating and non-replicating persistent forms of M. tuberculosis. One new semi-synthetic compound, 21-((1H-imidazol-5-yl)methyl)-pseudopteroxazole (7a), was more potent than the natural products pseudopterosin and pseudopteroxazole and exhibited equipotent activity against both replicating and non-replicating persistent forms of M. tuberculosis with a near absence of in vitro cytotoxicity. Pseudopteroxazole also exhibited activity against strains of M. tuberculosis H37Rv resistant to six clinically used antibiotics.

Trans-(−)-ε-Viniferin Increases Mitochondrial Sirtuin 3 (SIRT3), Activates AMP-activated Protein Kinase (AMPK), and Protects Cells in Models of Huntington Disease

Huntington disease (HD) is an inherited neurodegenerative disorder caused by an abnormal polyglutamine expansion in the protein Huntingtin (Htt). Currently, no cure is available for HD. The mechanisms by which mutant Htt causes neuronal dysfunction and degeneration remain to be fully elucidated. Nevertheless, mitochondrial dysfunction has been suggested as a key event mediating mutant Htt-induced neurotoxicity because neurons are energy-demanding and particularly susceptible to energy deficits and oxidative stress. SIRT3, a member of sirtuin family, is localized to mitochondria and has been implicated in energy metabolism. Notably, we found that cells expressing mutant Htt displayed reduced SIRT3 levels. trans-(-)-ε-Viniferin (viniferin), a natural product among our 22 collected naturally occurring and semisynthetic stilbenic compounds, significantly attenuated mutant Htt-induced depletion of SIRT3 and protected cells from mutant Htt. We demonstrate that viniferin decreases levels of reactive oxygen species and prevents loss of mitochondrial membrane potential in cells expressing mutant Htt. Expression of mutant Htt results in decreased deacetylase activity of SIRT3 and further leads to reduction in cellular NAD(+) levels and mitochondrial biogenesis in cells. Viniferin activates AMP-activated kinase and enhances mitochondrial biogenesis. Knockdown of SIRT3 significantly inhibited viniferin-mediated AMP-activated kinase activation and diminished the neuroprotective effects of viniferin, suggesting that SIRT3 mediates the neuroprotection of viniferin. In conclusion, we establish a novel role for mitochondrial SIRT3 in HD pathogenesis and discovered a natural product that has potent neuroprotection in HD models. Our results suggest that increasing mitochondrial SIRT3 might be considered as a new therapeutic approach to counteract HD, as well as other neurodegenerative diseases with similar mechanisms.

Improving on nature:The role of nanomedicine in the development of clinical natural drugs

It is astonishing to observe that in spite of the technical hitches encountered in natural product research, more than 50% of drug substances are natural products or inspired by natural compounds, covering a variety of therapeutic indications with a great range of chemical structures. Several latest reviews have tinted the tangible importance of natural products to the drug discovery process, being over a hundred natural product-derived compounds which are currently undergoing clinical trials [1]. Although these natural products represent a large source of potential drugs, mostly of them have limited clinical use due to chemical instability, low absorption and biodistribution, first pass metabolism, little accumulation in the organs of the body, inadequate efficacy or safety profiles [2,3]. These characteristics strongly influence the delivery of natural products using conventional dosage forms. Different strategies have been adopted to overcome these limitations, such as development of semisynthetic compounds or synthetic analogues, or the production of prodrugs but in mostly of the cases have not been satisfactory.

Synthesis and cytotoxic activity evaluation of dihydrocucurbitacin B and cucurbitacin B derivatives

Two cucurbitacins, dihydrocucurbitacin B (1) and cucurbitacin B (2), which can be obtained in large amounts from the roots of Wilbrandia ebracteata and from the fruits of Luffa operculata, respectively, were used as starting materials for the preparation of a library of 29 semi-synthetic derivatives. The structural changes that were performed include the removal, modification or permutation of functional groups in rings A and B as well as in the side chain. All new semisynthetic compounds, as well as 1 and 2, were tested in vitro for their cytotoxic effects on non-small-cell lung cancer cells (A549 cells). Some of these compound displayed potent to moderate activity against A549 tumor cells, especially those cucurbitacin B derivatives which were modified at ring A.

Basic opioid pharmacology: an update.

Opioids are a group of analgesic agents commonly used in clinical practice. There are three classical opioid receptors (DOP, KOP and MOP), while the novel NOP receptor is considered to be a non-opioid branch of the opioid receptor family. Opioids can act at these receptors as agonists, antagonists or partial agonists. Opioid agonists bind to G-protein coupled receptors to cause cellular hyperpolarisation. Most clinically relevant opioid analgesics bind to MOP receptors in the central and peripheral nervous system in an agonist manner to elicit analgesia. Opioids may also be classified according to their mode of synthesis into alkaloids, semi-synthetic and synthetic compounds.

Supercritical Fluid Chromatography—Mass Spectrometry (SFC-MS) and MALDI-TOF-MS of Heterocyclic Compounds with Trivalent and Pentavalent Nitrogen in Cough Relief Medical Forms Tuxi and Cosylan

Alkaloids are natural, semisynthetic or synthetic organic compounds, normally polar with basic chemical properties and containing at least one nitrogen atom in a heterocyclic ring. Some synthetic or semisynthetic substances resemble the alkaloid architecture. Trivalent nitrogen in these substances is normal; however, some natural and semisynthetic alkaloids have pentavalent nitrogen. The drug pholcodine is a derivative of morphine. Pholcodine has very little addiction- developing effect. It is a semisynthetic alkaloid that was first synthesized in 1950 by Chabrier et al. Pholcodine possesses antitussive (cough relief) properties similar to codeine, morphine and ethylmorphine. The drug was used in liquid formulations as Tuxi and Tuxi Forte, and it is in present use in Tuxidrin as liquid mixture and in tablet form. Pholcodine is an Active Pharmacological Ingredient (API) in tablets and liquid mixtures. Leiras International and Weifa in Norway manufacture medical forms with pholcodine. Several impurities in pholcodine were described by J. Roe in 1997 and by Denk et al. in 2000 and 2002. In addition, several degradation products may be formed in liquid formulations under storage. Some of these products are related not to the original production of pholcodine but rather to its oxidation under storage. The appearance of degradation products strongly depends on the storage temperature and pH of the liquid phase. Pholcodine-N-oxide and pholcodine-N,N’-dioxide are among the degradation (oxidation) products; pholcodine can also degrade to morphine. There is little information about the toxicity of the N-oxide and no information on the N,N’-di- oxide of pholcodine. In this study, the fact that morphine is generated during the storage of formulations containing pholcodine is presented. Another antitussive mixture under the name Cosylan was analyzed to examine the oxidation of ethylmorphine to ethylmorphine-N-oxide. Ethylmorphine is the API in Cosylan.

Antifeedant activities of tutin and 7-hydroxycoumarin acylation derivatives against Mythimna separata

Seven 7-hydroxycoumarin (C) acylation derivatives (C1–C7) were synthesized to determine the differences in antifeedant effects between these derivatives and tutin against Mythimna separata. The structural assignments of these semisynthetic compounds were examined based on their IR, ESIMS, and 1H- and 13C-NMR spectral data. Compounds C2–C7, tutin, andrographolide and azadirachtin showed different antifeedant activities. Compared with tutin and andrographolide, the derivatives C3, C4, C5 and C7 presented greater antifeedant activities. It was concluded that the optimal insecticidal agent is C4 (7-methanesulfonyloxycoumarin).

Glionitrin B, a Cancer Invasion Inhibitory Diketopiperazine Produced by Microbial Coculture

A new diketopiperazine, glionitrin B (1), was produced using a microbial coculture of the fungus Aspergillus fumigatus KMC-901 and the bacterium Sphingomonas sp. KMK-001 that were isolated from acidic coal mine drainage. The structure of 1 was determined to be (3S,10aS)-dithiomethylglionitrin A. This structure was determined by the analyses of extensive NMR data and the circular dichroism spectra of the natural product and a semisynthetic compound derived from glionitrin A. In contrast to glionitrin A (2), glionitrin B (1) is not cytotoxic against the human prostate cancer cell line DU145. However, compound 1 caused suppression of DU145 cell invasion, producing 46% inhibition at 60 μM.

A Murine Model of Inflammatory Bladder Disease: Cathelicidin Peptide Induced Bladder Inflammation and Treatment With Sulfated Polysaccharides

Studies show that LL-37 is a naturally occurring urinary defensin peptide that is up-regulated during urinary tract infections. Although normal urinary LL-37 levels are antimicrobial, we propose that increased LL-37 may trigger bladder inflammation. We further suggest that anti-inflammatory sulfated polysaccharides known as semi-synthetic glycosaminoglycan ether compounds can treat/prevent LL-37 mediated bladder inflammation. C57BL/6 mice were catheterized/instilled with LL-37 (320 μM, 150 μl) for 45 minutes. Animals were sacrificed at 12 and 24 hours, and tissues were examined using hematoxylin and eosin. Separate experiments were performed for myeloperoxidase to quantify inflammation. GM-1111 semi-synthetic glycosaminoglycan ether treatments involved instillation of 10 mg/ml for 45 minutes directly before or after LL-37. Tissues were harvested at 24 hours. To compare semi-synthetic glycosaminoglycan ether efficacy, experiments were performed using 10 mg/ml heparin. Finally, tissue localization of semi-synthetic glycosaminoglycan ether was examined using a fluorescent GM-1111-Alexa Fluor® 633 conjugate. Profound bladder inflammation developed after LL-37. Greater tissue inflammation occurred after 24 hours compared to that at 12 hours. Myeloperoxidase assays revealed a 21 and 61-fold increase at 12 and 24 hours, respectively. Semi-synthetic glycosaminoglycan ether treatment after LL-37 showed mild attenuation of inflammation with myeloperoxidase 2.5-fold below that of untreated bladders. Semi-synthetic glycosaminoglycan ether treatment before LL-37 demonstrated almost complete attenuation of inflammation. Myeloperoxidase results mirrored those in controls. In heparin treated bladders minimal attenuation of inflammation occurred. Finally, instillation of GM-1111-Alexa Fluor 633 revealed urothelial coating, significant tissue penetration and binding to endovasculature. We developed what is to our knowledge a new model of inflammatory bladder disease by challenge with the naturally occurring urinary peptide LL-37. We also noted that a new class of anti-inflammatory sulfated polysaccharides prevents and mitigates bladder inflammation.

In vitro evaluation of the genotoxic and cytotoxic effects of artesunate, an antimalarial drug, in human lymphocytes

Artesunate is one of the main antimalarial drugs used in several countries. It is a semisynthetic compound derived from artemisinin, a substance extracted from the Chinese plant, Artemisia annua L. Despite the widespread use of artesunate as an antimalarial drug, there is a lack of data regarding its genotoxic effects in human lymphocytes. Therefore, in this study, we used the comet assay and micronucleus test to evaluate the possible genotoxic effects of artesunate in cultured human lymphocytes. In addition, cell death by necrosis and apoptosis was also assessed. Cells exposed to different concentrations of artesunate showed a significant concentration-dependent increase (P < 0.05) in DNA damage index and micronuclei frequency. A significant increase in the frequency of apoptotic and necrotic cells was also observed. Our results showed that artesunate is a genotoxic and cytotoxic compound in cultured human lymphocytes.

A Potential Andrographolide Analogue against the Replication of Herpes Simplex Virus Type 1 in Vero Cells

Andrographolide (AD), and 14-deoxyandrographolide (DAD) isolated from Andrographis paniculata Nees, Acanthaceae, and 3,19-isopropylideneandrographolide (IPAD), a semi-synthetic compound of AD, were examined for anti-HSV-1 activity in vitro. The inhibitory effects of these compounds on viral entry and replication steps were determined using pre- and post-infection assays, respectively. All the three compounds exhibited less than 50% inhibitory act against viral entry. In the post-infection, IPAD displayed absolute inhibition, whereas AD and DAD gave moderate activity. IPAD was selected to determine for the stage of anti-replication by time-of-addition and time-of-removal assays. From the time of removal assay, IPAD activity began after 4 h and completed at 16 h post infection which corresponded to the early genes expression. Its ability to inhibit HSV-1 was confirmed by polymerase chain reaction and the expression of viral glycoproteins C and D by western blot analysis. No viral enveloped glycoproteins D and C expressions were found. IPAD exhibited anti-HSV-1 replication relating to the early step of replication. Structure-activity relationships of andrographolide against HSV-1 was proposed, it is the first report of this ent-labdane diterpene.

Cytotoxic oxasqualenoids from the red alga Laurencia viridis

Three new polyether squalene derivatives 15-dehydroxythyrsenol A ( 2), prethyrsenol A ( 3) and 13-hydroxyprethyrsenol A ( 4) have been isolated from the red alga Laurencia viridis. Their structures were determined through the interpretation of NMR spectroscopic data and chemical correlations. In addition, four semi-synthetic compounds modulating the solubility of the lead compound dehydrothyrsiferol ( 1) were prepared without loss of activity. The cytotoxicity of the new compounds exhibited low μM activities. In order to explain their biological properties, docking simulations of the natural and synthetic compounds onto the αvβ3 integrin binding region were carried out.

Abstract 5433: Analysis of the short-term and long-term in vitro cytotoxic effects of the anticancer drug Ukrain in breast cancer models

Abstract Ukrain is a semisynthetic compound derived from the extract of the plant Chelidonium majus L. Studies indicate that this anticancer drug exhibits cytostatic and cytolytic activity against several human cancer cell lines including colon, brain, ovarian, melanoma and lymphoma without adverse harmful side effects on healthy human cells. However, such activity has not been thoroughly investigated in a breast cancer model. In order to assess the in vitro cytotoxicity of Ukrain, we used mouse (4T07 and TUBO) and human (SKBR-3) breast cancer cell lines. 4T07 and TUBO are highly tumorigenic, nonmetastic tumor cell lines derived from spontaneous carcinomas in BALB/cfC3H and BALB-neuT mice, respectively. The TUBO and SKBR-3 cell lines constitutively express the HER-2/neu oncogene, which is overexpressed in 30% of human breast cancer patients. Tumor cells were trypsinized after reaching 90-95% confluency and plated with varying concentrations of Ukrain. Following 24, 48 and 72 hour treatment with Ukrain, cell number and viability was determined using the trypan blue exclusion method. To assess whether the tumor cells retained the capacity for unlimited proliferation, a clonogenic assay was conducted. Cells were seeded out in appropriate dilutions to form colonies within 2-3 weeks. Colonies were fixed and stained with crystal violet (0.5% w/v) and counted by microscopy. Lastly, to determine whether the cytotoxic effects of Ukrain are due to the induction of apoptosis, we carried out intracellular staining for active caspase-3. We observed a dose-dependent and time-dependent inhibition of tumor cell growth. As low as 50 υg/mL of Ukrain led to a significant decrease in tumor cell viability when compared to untreated cells. The clonogenic assay showed the inability of treated tumor cells to form colonies and regain their proliferative capacity whereas the untreated cells formed multiple colonies. We observed a several fold increase in caspase 3 activation of Ukrain treated cells compared to untreated cells confirming apoptosis as the cytotoxic mechanism of action. In conclusion, our data suggest that Ukrain could be effective as an anticancer drug for breast cancer due to its short-term and long-term inhibitory effects on tumor cell viability and proliferation. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5433. doi:10.1158/1538-7445.AM2011-5433