Bradykinin antagonists and thiazolidinone derivatives as new potential anti-cancer compounds

August 6, 2014, 1:58 am

≫ Next: Coumarin hybrids as novel therapeutic agents

≪ Previous: Development of potent antagonists for formyl peptide receptor 1 based on Boc-Phe-d-Leu-Phe-d-Leu-Phe-OH

Publication date: 1 August 2014
Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 15
Author(s): Stanislav Avdieiev , Lajos Gera , Dmytro Havrylyuk , Robert S. Hodges , Roman Lesyk , Vincent Ribrag , Yegor Vassetzky , Vadym Kavsan

Glioblastoma (GB), the most aggressive brain tumour, and mantle cell lymphoma (MCL), a rare but very aggressive type of lymphoma, are highly resistant to chemotherapy. GB and MCL chemotherapy gives very modest results, the vast majority of patients experience recurrent disease. To find out the new treatment modality for drug-resistant GB and MCL cells, combining of bradykinin (BK) antagonists with conventional temozolomide (TMZ) treatment, and screening of thiazolidinones derivatives were the main objectives of this work. As it was revealed here, BKM-570 was the lead compound among BK antagonists under investigation (IC50 was 3.3μM) in human GB cells. It strongly suppressed extracellular signal-regulated kinases 1/2 (ERK1/2) and protein kinase B (AKT) phosphorylation. BK antagonists did not decrease the viability of MCL cells, thus showing the cell-specific mode, while thiazolidinone derivatives, a novel group of promising anti-tumour compounds inhibited proliferation of MCL cells: IC50 of ID 4526 and ID 4527 compounds were 0.27μM and 0.16μM, correspondingly. However, single agents are often not effective in clinic due to activation of collateral pathways in tumour cells. We demonstrated a strong synergistic effect after combinatorial treatment by BKM-570 together with TMZ that drastically increased cytotoxic action of this drug in rat and human glioma cells. Small proportion of cells was still viable after such treatment that could be explained by presence of TMZ-resistant cells in the population.

It is possible to expect that the combined therapy aimed simultaneously at different elements of tumourigenesis will be more effective with lower drug concentrations than the first-line drug temozolomide used alone in clinics.

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Coumarin hybrids as novel therapeutic agents

August 6, 2014, 1:58 am

≫ Next: Graphical contents list

≪ Previous: Bradykinin antagonists and thiazolidinone derivatives as new potential anti-cancer compounds

Publication date: 1 August 2014
Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 15
Author(s): Sonali Sandhu , Yogita Bansal , Om Silakari , Gulshan Bansal

Naturally occurring coumarins, having wide spectrum of activities such as antioxidant, anti-inflammatory, anticancer, MAO-B inhibitory and antimicrobial, are frequently used by the researchers to develop novel synthetic and semisynthetic coumarin based therapeutic agents. Many of these agents are hybrid molecules, which are designed through concept of molecular hybridization and have shown multiple pharmacological activities. This multifunctional attribute of these hybrid compounds makes them potential drug candidates for the treatment of multifactorial diseases such as cancer, Alzheimer’s disease, metabolic syndromes, AIDS, malaria, and cardiovascular diseases. The present review compiles research reports on development of different coumarin hybrids, classify these on the basis of their therapeutic uses and propose structure–activity relationships. It is intended to help medicinal chemist in designing and synthesizing novel and potent hybrid compounds for the treatment of different disorders.

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Graphical contents list

August 6, 2014, 1:58 am

≫ Next: Editorial board

≪ Previous: Coumarin hybrids as novel therapeutic agents

Publication date: 1 August 2014
Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 15

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Editorial board

August 6, 2014, 1:58 am

≫ Next: Semi-synthesis of biologically active nisin hybrids composed of the native lanthionine ABC-fragment and a cross-stapled synthetic DE-fragment

≪ Previous: Graphical contents list

Publication date: 1 August 2014
Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 15

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Semi-synthesis of biologically active nisin hybrids composed of the native lanthionine ABC-fragment and a cross-stapled synthetic DE-fragment

August 6, 2014, 1:58 am

≫ Next: Design, synthesis and in vitro pharmacology of GluK1 and GluK3 antagonists. Studies towards the design of subtype-selective antagonists through 2-carboxyethyl-phenylalanines with substituents interacting with non-conserved residues in the GluK binding sites

≪ Previous: Editorial board

Publication date: Available online 2 August 2014
Source:Bioorganic & Medicinal Chemistry
Author(s): Jack C. Slootweg , Nienke Peters , H (Linda). C. Quarles van Ufford , Eefjan Breukink , Rob M.J. Liskamp , Dirk T.S. Rijkers

The antimicrobial peptide nisin is a promising template for designing novel peptide-based antibiotics to improve its drug-like properties. First steps in that direction represent the synthesis of hybrid nisin derivatives that contain a native nisin ABC-part and synthesized cross-stapled DE-ring fragments and described here. The biological activity of the newly synthesized nisin derivatives was evaluated in order to compare the bioactivity of the synthetic DE-ring containing mimic and native lanthionine-bridged DE-ring containing nisin. The native nisin ABC-ring system was obtained via chymotrypsin digestion of full-length nisin, and was subsequently functionalized at the C-terminal carboxylate with two different amino-alkyne moieties. Next, nisin hybrids were successfully prepared using Cu(I)-catalyzed azide alkyne cycloaddition ‘click’ chemistry by chemo-selective ligation of the ABC-alkyne with the N-terminal azido functionalized dicarba-DE ring mimic. The newly synthesized compounds were active as potent lipid II binders and retained antimicrobial activity in a growth inhibition assay. However, pore formation was not observed, possibly either due to the different character of the ‘staples’ as compared to the parent sulfides, or due to the triazole moiety as a sub-optimal amide bond isostere.

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Design, synthesis and in vitro pharmacology of GluK1 and GluK3 antagonists. Studies towards the design of subtype-selective antagonists through 2-carboxyethyl-phenylalanines with substituents interacting with non-conserved residues in the GluK binding sites

August 6, 2014, 1:58 am

≫ Next: Development of novel membrane active lipidated peptidomimetics active against drug resistant clinical isolates

≪ Previous: Semi-synthesis of biologically active nisin hybrids composed of the native lanthionine ABC-fragment and a cross-stapled synthetic DE-fragment

Publication date: Available online 2 August 2014
Source:Bioorganic & Medicinal Chemistry
Author(s): Niklas Sköld , Birgitte Nielsen , Jacob Olsen , Liwei Han , Lars Olsen , Ulf Madsen , Jesper L. Kristensen , Darryl S. Pickering , Tommy N. Johansen

In order to identify compounds selective for the GluK1 and GluK3 subtypes of kainate receptors we have designed and synthesized a series of (S)-2-amino-3-((2-carboxyethyl)phenyl)propanoic acid analogues with hydrogen bond donating and accepting substituents on the aromatic ring. Based on crystal structures of GluK1 in complex with related ligands, the compounds were designed to explore possible interactions with non-conserved residues outside the glutamate ligand binding site and challenge the water binding network. Apart from obtaining GluK1 selective antagonists one analogue with a phenyl-substituted urea (compound 31) showed some preference for GluK3 over GluK1-receptors. Docking studies indicate that this preference may be attributed to contacts between the NH of the urea substituent and non-conserved Ser741 and Ser761 residues.

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Development of novel membrane active lipidated peptidomimetics active against drug resistant clinical isolates

August 6, 2014, 1:58 am

≫ Next: Optimization of Physicochemical Properties and Safety Profile of Novel Bacterial Topoisomerase Type II Inhibitors (NBTIs) with activity against Pseudomonas aeruginosa

≪ Previous: Design, synthesis and in vitro pharmacology of GluK1 and GluK3 antagonists. Studies towards the design of subtype-selective antagonists through 2-carboxyethyl-phenylalanines with substituents interacting with non-conserved residues in the GluK binding sites

Publication date: Available online 4 August 2014
Source:Bioorganic & Medicinal Chemistry
Author(s): Sandeep Lohan , Arneesh kalanta , Praveen Sonkusre , Swaranjit Singh Cameotra , Gopal Singh Bisht

A new series of small cationic lipidated peptidomimetics have been synthesized and found to be highly active against several susceptible as well as drug resistant clinical isolates of bacteria and fungi. All lipidated peptidomimetics do not cause significant lysis of human erythrocytes (HC50 > 200 μg/mL). Calcein dye leakage experiment revealed membranolytic effect of LPEP08 which was further confirmed by scanning electron microscopy (SEM). The involvement of intracellular targets as an alternate mode of action was precluded by DNA retardation assay. Additionally, LPEP08 exhibit high proteolytic stability and dose not elicit resistance against drug resistant clinical isolate of S. aureus, even after 16 rounds of passaging. These results demonstrate the potential of lipidated peptidomimetics as biocompatible anti-infective therapeutics.

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Optimization of Physicochemical Properties and Safety Profile of Novel Bacterial Topoisomerase Type II Inhibitors (NBTIs) with activity against Pseudomonas aeruginosa

August 6, 2014, 1:58 am

≫ Next: Novel fluorinated pyrrolo[1,2-a]pyrazine-2,6-dione derivatives: synthesis and anticonvulsant evaluation in animal models of epilepsy

≪ Previous: Development of novel membrane active lipidated peptidomimetics active against drug resistant clinical isolates

Publication date: Available online 4 August 2014
Source:Bioorganic & Medicinal Chemistry
Author(s): Folkert Reck , David E. Ehmann , Thomas J. Dougherty , Joseph V. Newman , Sussie Hopkins , Gregory Stone , Nikunj Agrawal , Paul Ciaccio , John McNulty , Herbert Barthlow , Jennifer O’Donnell , Kosalaram Goteti , John Breen , Janelle Comita-Prevoir , Mark Cornebise , Mark Cronin , Charles J. Eyermann , Bolin Geng , Greg R. Carr , Lakshmipathi Pandarinathan , Xuejun Tang , Andrew Cottone , Liang Zhao , Natascha Bezdenejnih-Snyder

Type II bacterial topoisomerases are well validated targets for antimicrobial chemotherapy. Novel bacterial type II topoisomerase inhibitors (NBTIs) of these targets are of interest for the development of new antibacterial agents that are not impacted by target-mediated cross-resistance with fluoroquinolones. We now disclose the optimization of a class of NBTIs towards Gram-negative pathogens, especially against drug-resistant Pseudomonas aeruginosa. Physicochemical properties (pKa and logD) were optimized for activity against P. aeruginosa and for reduced inhibition of the hERG channel. The optimized analogs 9g and 9i displayed potent antibacterial activity against P. aeruginosa, and a significantly improved hERG profile over previously reported analogs. 9g showed an improved QT profile in in vivo models and lower clearance in rat over earlier compounds. The compounds show promise for the development of new antimicrobial agents against drug-resistant Pseudomonas aeruginosa.

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Novel fluorinated pyrrolo[1,2-a]pyrazine-2,6-dione derivatives: synthesis and anticonvulsant evaluation in animal models of epilepsy

August 6, 2014, 1:58 am

≫ Next: Design, synthesis and evaluation of 2-aminothiazole derivatives as sphingosine kinase inhibitors

≪ Previous: Optimization of Physicochemical Properties and Safety Profile of Novel Bacterial Topoisomerase Type II Inhibitors (NBTIs) with activity against Pseudomonas aeruginosa

Publication date: Available online 4 August 2014
Source:Bioorganic & Medicinal Chemistry
Author(s): Maciej Dawidowski , Justyna Choińska , Weronika Mika , Jadwiga Turło

A series of fluorinated analogs of the potent investigative anticonvulsant agent (4S,8aS)-4-phenylperhydropyrrolo[1,2-a]pyrazine-2,6-dione 1 was prepared and characterized by IR, ¹H, ¹³C NMR and mass spectral data. The compounds have been evaluated in the in vivo rodent models of epilepsy. They displayed high activity in the ‘classical’ maximal electroshock seizure (MES) and subcutaneous Metrazole (scMET) tests as well as in the 6Hz model of pharmacoresistant limbic seizures. The results showed that incorporating fluorine atoms into the phenyl ring of 1 can be beneficial for the anticonvulsant potency. The most promising meta-trifluoromethyl and meta-trifluoromethoxy derivatives (4S ,8aS )-5h and (4S ,8aS )-5l, respectively, displayed very broad spectra of activity across the preclinical seizure models.

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Design, synthesis and evaluation of 2-aminothiazole derivatives as sphingosine kinase inhibitors

August 6, 2014, 1:58 am

≫ Next: Synthetic (+)-terrein suppresses interleukin-6/soluble intereleukin-6 receptor induced-secretion of vascular endothelial growth factor in human gingival fibroblasts

≪ Previous: Novel fluorinated pyrrolo[1,2-a]pyrazine-2,6-dione derivatives: synthesis and anticonvulsant evaluation in animal models of epilepsy

Publication date: Available online 5 August 2014
Source:Bioorganic & Medicinal Chemistry
Author(s): Dominik Vogt , Julia Weber , Katja Ihlefeld , Astrid Brüggerhoff , Ewgenij Proschak , Holger Stark

Sphingosine kinases (SphK1, SphK2) are main regulators of sphingosine-1-phosphate (S1P), which is a pleiotropic lipid mediator involved in numerous physiological and pathophysiological functions. SphKs are targets for novel anti-cancer and anti-inflammatory agents that can promote cell apoptosis and modulate autoimmune diseases. Herein, we describe the design, synthesis and evaluation of an aminothiazole class of SphK inhibitors. Potent inhibitors have been discovered through a series of modifications using the known SKI-II scaffold to define structure-activity relationships. We identified N-(4-methylthiazol-2-yl)-(2,4’-bithiazol)-2’-amine (24, ST-1803; IC50 values: 7.3 μM (SphK1), 6.5 μM (SphK2)) as a promising candidate for further in vivo investigations and structural development.

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Synthetic (+)-terrein suppresses interleukin-6/soluble intereleukin-6 receptor induced-secretion of vascular endothelial growth factor in human gingival fibroblasts

August 7, 2014, 1:59 am

≫ Next: Sulfonamide inhibition study of the carbonic anhydrases from the bacterial pathogen Porphyromonas gingivalis: The β-class (PgiCAb) versus the γ-class (PgiCA) enzymes

≪ Previous: Design, synthesis and evaluation of 2-aminothiazole derivatives as sphingosine kinase inhibitors

Publication date: Available online 7 August 2014
Source:Bioorganic & Medicinal Chemistry
Author(s): Hiroki Mandai , Kazuhiro Omori , Daisuke Yamamoto , Toki Tsumura , Kyouta Murota , Satoshi Yamamoto , Koichi Mitsudo , Soichiro Ibaragi , Akira Sasaki , Hiroshi Maeda , Shogo Takashiba , Seiji Suga

Interleukin (IL)-6 is a proinflammatory cytokine that performs a wide variety of biological functions, including important roles in the progression of chronic inflammatory diseases such as periodontal disease. (+)-Terrein, a secondary bioactive fungal metabolite isolated from Aspergillus terreus, has various biological activities; however, its anti-inflammatory effects are still unknown. The purpose of this study was to examine the effect of synthetic (+)-terrein on IL-6 signaling and related protein production in human gingival fibroblasts. To our knowledge, this study is the first to report that synthetic (+)-terrein is not cytotoxic at concentrations less than 20 μM and suppresses IL-6/soluble IL-6 receptor (sIL-6R)-induced phosphorylation of signal transducer and activator of transcription-3, extracellular signal-regulated kinase 1/2, and c-jun N-terminal kinase 1/2—signaling proteins that are downstream of IL-6 signaling. In addition, synthetic (+)-terrein suppresses IL-6/sIL-6R-induced vascular endothelial growth factor (VEGF) secretion in a concentration-dependent manner (p < 0.01). These data suggest that synthetic (+)-terrein has potential anti-IL-6 signaling activity and suppresses VEGF-associated inflammatory disease progression.

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Sulfonamide inhibition study of the carbonic anhydrases from the bacterial pathogen Porphyromonas gingivalis: The β-class (PgiCAb) versus the γ-class (PgiCA) enzymes

August 7, 2014, 1:59 am

≫ Next: Design, Synthesis and SAR Exploration of Tri-substituted 1,2,4-Triazoles as Inhibitors of the Annexin A2-S100A10 Protein Interaction

≪ Previous: Synthetic (+)-terrein suppresses interleukin-6/soluble intereleukin-6 receptor induced-secretion of vascular endothelial growth factor in human gingival fibroblasts

Publication date: Available online 7 August 2014
Source:Bioorganic & Medicinal Chemistry
Author(s): Sonia Del Prete , Daniela Vullo , Sameh M. Osman , Andrea Scozzafava , Zeid AlOthman , Clemente Capasso , Claudiu T. Supuran

The oral pathogenic bacterium Porphyromonas gingivalis, encodes for two carbonic anhydrases (CAs, EC 4.2.1.1) one belonging to the γ-class (PgiCA) and another one to the β-class (PgiCAb). This last enzyme has been cloned and characterized here for its inhibition profile with the main class of CA inhibitors, the sulfonamides. Many of the clinically used sulfonamides as well as simple aromatic/heterocyclic sulfonamides were ineffective as PgiCAb inhibitors whereas better inhibition was observed with simple derivatives such as sulfanilamide, metanilamide, 4-aminoalkylbenzenesulfonamides (KIs of 364-475 nM). The halogenosulfanilamides incorporating heavy halogens, 4-hydroxy- and 4-hydroxyalkyl-benzenesulfonamides, were also micromolar, ineffective PgiCAb inhibitors. The best inhibitors of the β-class enzyme were acetazolamide and ethoxzolamide, with KIs of 214-280 nM. Interestingly, the γ-class enzyme was much more sensitive to sulfonamide inhibitors compared to the β-class one, PgiCAb. Identification of potent and possibly selective inhibitors of PgiCAb/PgiCA may lead to pharmacological tools useful for understanding the physiological role(s) of these enzymes, since this bacterium is the main causative agent of periodontitis and few treatment options are presently available.

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Design, Synthesis and SAR Exploration of Tri-substituted 1,2,4-Triazoles as Inhibitors of the Annexin A2-S100A10 Protein Interaction

August 7, 2014, 1:59 am

≫ Next: Shogaol–huprine hybrids: dual antioxidant and anticholinesterase agents with β-amyloid and tau anti-aggregating properties

≪ Previous: Sulfonamide inhibition study of the carbonic anhydrases from the bacterial pathogen Porphyromonas gingivalis: The β-class (PgiCAb) versus the γ-class (PgiCA) enzymes

Publication date: Available online 7 August 2014
Source:Bioorganic & Medicinal Chemistry
Author(s): Tummala R.K. Reddy , Chan Li , Xiaoxia Guo , Peter M. Fischer , Lodewijk.V. Dekker

Recent target validation studies have shown that inhibition of the protein interaction between annexin A2 and the S100A10 protein may have potential therapeutic benefits in cancer. Virtual screening identified certain 3,4,5-trisubstituted 4H-1,2,4-triazoles as moderately potent inhibitors of this interaction. A series of analogues were synthesized based on the 1,2,4-triazole scaffold and were evaluated for inhibition of the annexin A2–S100A10 protein interaction in competitive binding assays. 2-[(5-{[(4,6-Dimethylpyrimidin-2-yl)sulfanyl]methyl}-4-(furan-2-ylmethyl)-4H-1,2,4-triazol-3-yl)sulfanyl]-N-[4-(propan-2-yl)phenyl]acetamide (36) showed improved potency and was shown to disrupt the native complex between annexin A2 and S100A10.

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Shogaol–huprine hybrids: dual antioxidant and anticholinesterase agents with β-amyloid and tau anti-aggregating properties

August 7, 2014, 1:59 am

≫ Next: Thieno[2,3-d]pyrimidine-2-carboxamides Bearing a Carboxybenzene Group at 5-Position: Highly Potent, Selective, and Orally Available MMP-13 Inhibitors Interacting with the S1” Binding Site

≪ Previous: Design, Synthesis and SAR Exploration of Tri-substituted 1,2,4-Triazoles as Inhibitors of the Annexin A2-S100A10 Protein Interaction

Publication date: Available online 7 August 2014
Source:Bioorganic & Medicinal Chemistry
Author(s): F. Javier Pérez-Areales , Ornella Di Pietro , Alba Espargaró , Anna Vallverdú-Queralt , Carles Galdeano , Ilaria M. Ragusa , Elisabet Viayna , Catherine Guillou , M. Victòria Clos , Belén Pérez , Raimon Sabaté , Rosa M. Lamuela-Raventós , F. Javier Luque , Diego Muñoz-Torrero

Multitarget compounds are increasingly being pursued for the effective treatment of complex diseases. Herein, we describe the design and synthesis of a novel class of shogaol–huprine hybrids, purported to hit several key targets involved in Alzheimer’s disease. The hybrids have been tested in vitro for their inhibitory activity against human acetylcholinesterase and butyrylcholinesterase and antioxidant activity (ABTS^.+, DPPH and Folin-Ciocalteu assays), and in intact Escherichia coli cells for their Aβ42 and tau anti-aggregating activity. Also, their brain penetration has been assessed (PAMPA-BBB assay). Even though the hybrids are not as potent AChE inhibitors or antioxidant agents as the parent huprine Y and [4]-shogaol, respectively, they still exhibit very potent anticholinesterase and antioxidant activities and are much more potent Aβ42 and tau anti-aggregating agents than the parent compounds. Overall, the shogaol–huprine hybrids emerge as interesting brain permeable multitarget anti-Alzheimer leads.

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Thieno[2,3-d]pyrimidine-2-carboxamides Bearing a Carboxybenzene Group at 5-Position: Highly Potent, Selective, and Orally Available MMP-13 Inhibitors Interacting with the S1” Binding Site

August 7, 2014, 1:59 am

≫ Next: Attachment of carbohydrates to methoxyaryl moieties leads to highly selective inhibitors of the cancer associated carbonic anhydrase isoforms IX and XII

≪ Previous: Shogaol–huprine hybrids: dual antioxidant and anticholinesterase agents with β-amyloid and tau anti-aggregating properties

Publication date: Available online 7 August 2014
Source:Bioorganic & Medicinal Chemistry
Author(s): Hiroshi Nara , Kenjiro Sato , Takako Naito , Hideyuki Mototani , Hideyuki Oki , Yoshio Yamamoto , Haruhiko Kuno , Takashi Santou , Naoyuki Kanzaki , Jun Terauchi , Osamu Uchikawa , Masakuni Kori

On the basis of X-ray co-crystal structures of matrix metalloproteinase-13 (MMP-13) in complex with its inhibitors, our structure-based drug design (SBDD) strategy was directed to achieving high affinity through optimal protein–ligand interaction with the unique S1˝ hydrophobic specificity pocket. This report details the optimization of lead compound 44 to highly potent and selective MMP-13 inhibitors based on fused pyrimidine scaffolds represented by the thienopyrimidin-4-one 26c. Furthermore, we have examined the release of collagen fragments from bovine nasal cartilage in response to a combination of IL-1 and oncostatin M.

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Attachment of carbohydrates to methoxyaryl moieties leads to highly selective inhibitors of the cancer associated carbonic anhydrase isoforms IX and XII

August 7, 2014, 1:59 am

≫ Next: Development of p-carborane-based nonsteroidal progesterone receptor antagonists

≪ Previous: Thieno[2,3-d]pyrimidine-2-carboxamides Bearing a Carboxybenzene Group at 5-Position: Highly Potent, Selective, and Orally Available MMP-13 Inhibitors Interacting with the S1” Binding Site

Publication date: Available online 7 August 2014
Source:Bioorganic & Medicinal Chemistry
Author(s): Leonardo E. Riafrecha , Oscar M. Rodríguez , Daniela Vullo , Claudiu T. Supuran , Pedro A. Colinas

The transmembrane isoforms of carbonic anhydrase (hCA IX and XII) have been shown to be linked to carcinogenesis and their inhibition to arrest primary tumor and metastases growth. In this paper, we present a new class of C-glycosides incorporating the methoxyaryl moiety, that was designed to selectively target and inhibit the extracellular domains of the cancer-relevant CA isozymes. The glycosides have been prepared by aldol reaction of glycosyl ketones with the appropriate aromatic aldehydes. We also present the inhibition profile of our new glycomimetics, against four isozymes of carbonic anhydrase comprising hCAs I and II (cytosolic, ubiquitous isozymes) and hCAs IX and XII (tumor associated isozymes). In this study, per-O-acetylated glycoside 4, 6 and deprotected compounds 7,9,10 and 12 were identified as potent and highly selective inhibitors of hCA IX and XII. These results confirm that attaching carbohydrate moieties to CA methoxyaryl pharmacophore improves and enhances its inhibitory activity. These CA inhibitors have developmental potential to selectively target cancer cells, leading to cell death.

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Development of p-carborane-based nonsteroidal progesterone receptor antagonists

August 7, 2014, 1:59 am

≫ Next: The synthesis of 2′-methylseleno adenosine and guanosine 5′-triphosphates

≪ Previous: Attachment of carbohydrates to methoxyaryl moieties leads to highly selective inhibitors of the cancer associated carbonic anhydrase isoforms IX and XII

Publication date: Available online 7 August 2014
Source:Bioorganic & Medicinal Chemistry
Author(s): Shinya Fujii , Eiichi Nakano , Naoki Yanagida , Shuichi Mori , Hiroyuki Masuno , Hiroyuki Kagechika

Progesterone receptor (PR) regulates various physiological processes, including the female reproductive system, and development of nonsteroidal PR antagonists is considered desirable for clinical application, as they are expected to have reduced side effects. We have synthesized a series of nonsteroidal PR antagonists using a 4-cyanophenyl-p-carborane core structure. Among them, compound 14d exhibited potent PR-antagonistic activity (IC50: 27 nM). It showed high binding affinity for PR, but did not bind to androgen receptor or estrogen receptor. This PR-selective antagonist may be a promising lead compound for clinically applicable progesterone receptor modulators.

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The synthesis of 2′-methylseleno adenosine and guanosine 5′-triphosphates

August 7, 2014, 10:22 pm

≫ Next: Semisynthesis and antimicrobial activity of novel guttiferone-A derivatives

≪ Previous: Development of p-carborane-based nonsteroidal progesterone receptor antagonists

Publication date: 1 April 2012
Source:Bioorganic & Medicinal Chemistry, Volume 20, Issue 7
Author(s): Tobias Santner , Vanessa Siegmund , Andreas Marx , Ronald Micura

Modified nucleoside triphosphates (NTPs) represent powerful building blocks to generate nucleic acids with novel properties by enzymatic synthesis. We have recently demonstrated the access to 2′-SeCH3-uridine and 2′-SeCH3-cytidine derivatized RNAs for applications in RNA crystallography, using the corresponding nucleoside triphosphates and distinct mutants of T7 RNA polymerase. In the present note, we introduce the chemical synthesis of the novel 2′-methylseleno-2′-deoxyadenosine and -guanosine 5′-triphosphates (2′-SeCH3-ATP and 2′-SeCH3-GTP) that represent further candidates for the enzymatic RNA synthesis with engineered RNA polymerases.

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Semisynthesis and antimicrobial activity of novel guttiferone-A derivatives

August 7, 2014, 10:22 pm

≫ Next: Free radical scavenging and antiproliferative properties of Biginelli adducts

≪ Previous: The synthesis of 2′-methylseleno adenosine and guanosine 5′-triphosphates

Publication date: 15 April 2012
Source:Bioorganic & Medicinal Chemistry, Volume 20, Issue 8
Author(s): Kris S.T. Dias , Jaqueline P. Januário , Jéssica Lopes D’ Dego , Amanda L.T. Dias , Marcelo H. dos Santos , Ihosvany Camps , Luiz Felipe L. Coelho , Claudio Viegas Jr.

Six derivatives of guttiferone-A (LFQM-79, 80, 81, 82, 113 and 114) were synthesized and evaluated for their antimicrobial activity against the opportunistic or pathogenic fungi Candida albicans (ATCC 09548), Candida glabrata (ATCC 90030), Candida krusei (ATCC 6258), Candida parapsilosis (ATCC 69548), Candida tropicalis (ATCC 750), Cryptococcus neoformans (ATCC 90012), Trichophyton tonsurans, Microsporum gypseum and also against the opportunistic and pathogenic Gram-positive bacteria Staphylococcus aureus (ATCC 6538), Staphylococcus epidermidis (ATCC 12228), Bacillus cereus (ATCC 11778) and Gram-negative Escherichia coli (ATCC 25922), Pseudomonas aeruginosa (ATCC 9027), Salmonella typhimurium (ATCC 14028), Proteus mirabilis (ATCC 25933). The antimicrobial activities of derivatives were compared with guttiferone-A and they presented to be more potent than the original molecule and sometimes greater than standard drugs established in therapeutics. The current study showed that derivatives of guttiferone-A possess potent antimicrobial activity and are relatively non-cytotoxic, which reveal these new molecules as promising new drug prototype candidates, with innovative structural pattern.

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Free radical scavenging and antiproliferative properties of Biginelli adducts

August 7, 2014, 10:22 pm

≫ Next: Mapping pilicide anti-virulence effect in Escherichia coli, a comprehensive structure–activity study

≪ Previous: Semisynthesis and antimicrobial activity of novel guttiferone-A derivatives

Publication date: 15 April 2012
Source:Bioorganic & Medicinal Chemistry, Volume 20, Issue 8
Author(s): Daniel L. da Silva , Fabiano S. Reis , Dandara R. Muniz , Ana Lúcia T.G. Ruiz , João E. de Carvalho , Adão A. Sabino , Luzia V. Modolo , Ângelo de Fátima

A series of Biginelli adducts bearing different substituents at C-4 position were synthesized by using p-sulfonic acid calix[4]arene as a catalyst. The in vitro potential to scavenge reactive nitrogen/oxygen species (RNS and ROS) and the ability to inhibit cancer cells growth were then investigated. Four adducts were found to be potent scavengers of 2,2-diphenyl-1-picrylhydrazyl (RNS) and/or superoxide anion (ROS) radicals. The antiproliferative activity against cancer cells was disclosed for the first time for 16 monastrol analogs. The capacity of all compounds to inhibit cancer cells growth was dependent on the histological origin of cells, except for BA24, which was highly active against all cell lines. BA20 and BA33 were as potent as the reference drug doxorubicin against adriamycin-resistant ovarian and prostate cancer cells, respectively. These results highlight some monastrol analogs as lead compounds for the design of new free radical scavengers and anticancer agents.

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