2 β-3,4-Unsaturated sialic acid derivatives: Synthesis optimization, and biological evaluation as Newcastle disease virus hemagglutinin-neuraminidase inhibitors.
2β-3,4-Unsaturated sialic acid derivatives: Synthesis optimization, and biological evaluation as Newcastle disease virus hemagglutinin-neuraminidase inhibitors. Bioorg Med Chem. 2020 Jul 15;28(14):115563 Authors: La Rocca P, Rota P, Piccoli M, Cirillo F, Ghiroldi A, Franco V, Allevi P, Anastasia L Abstract The optimization of the synthetic protocol to obtain the 3,4-unsaturated sialic acid derivatives, through the fine-tuning of both the Ferrier glycosylation conditions and the subsequent hydrolysis work-up, is herein reported. The accomplishment of the desired β-anomers and some selected &a...
Source: Bioorganic and Medicinal Chemistry - July 5, 2020 Category: Chemistry Authors: La Rocca P, Rota P, Piccoli M, Cirillo F, Ghiroldi A, Franco V, Allevi P, Anastasia L Tags: Bioorg Med Chem Source Type: research

Yohimbine as a Starting Point to Access Diverse Natural Product-Like Agents with Re-programmed Activities against Cancer-Relevant GPCR Targets.
Abstract G protein-coupled receptors (GPCRs) constitute the largest protein superfamily in the human genome. GPCRs play key roles in mediating a wide variety of physiological events including proliferation and cancer metastasis. Given the major roles that GPCRs play in mediating cancer growth, they present promising targets for small molecule therapeutics. One of the principal goals of our lab is to identify complex natural products (NPs) suitable for ring distortion, or the dramatic altering of the inherently complex architectures of NPs, to rapidly generate an array of compounds with diverse molecular skeletal s...
Source: Bioorganic and Medicinal Chemistry - July 5, 2020 Category: Chemistry Authors: Paciaroni NG, Norwood VM, Ratnayake R, Luesch H, Huigens RW Tags: Bioorg Med Chem Source Type: research

Bisphosphonate esters interact with HMG-CoA reductase membrane domain to induce its degradation.
In this study, we developed a potent photoaffinity probe of the bisphosphonate esters through preliminary structure-activity relationship study and demonstrated binding of the bisphosphonate esters to the HMGCR membrane domain. These results provide an important clue to understand the elusive mechanism of the SR12813-mediated HMGCR degradation and serve as a basis to develop more potent HMGCR degraders that target the non-catalytic, membrane domain of the enzyme. PMID: 32616181 [PubMed - in process] (Source: Bioorganic and Medicinal Chemistry)
Source: Bioorganic and Medicinal Chemistry - July 5, 2020 Category: Chemistry Authors: Toyota Y, Yoshioka H, Sagimori I, Hashimoto Y, Ohgane K Tags: Bioorg Med Chem Source Type: research

N1-Substituted benzimidazole scaffold for farnesoid  X receptor (FXR) agonists accompanying prominent selectivity against vitamin D receptor (VDR).
N1-Substituted benzimidazole scaffold for farnesoid X receptor (FXR) agonists accompanying prominent selectivity against vitamin D receptor (VDR). Bioorg Med Chem. 2020 Jul 15;28(14):115512 Authors: Masuda A, Gohda K, Iguchi Y, Fujimori K, Yamashita Y, Oda K, Une M, Teno N Abstract As a cellular bile acid sensor, farnesoid X receptor (FXR) participates in regulation of bile acid, lipid and glucose homeostasis, and liver protection. With respect to the bone metabolism, FXR positively regulates bone metabolism through both bone formation and resorption of the bone remodeling pathways...
Source: Bioorganic and Medicinal Chemistry - July 5, 2020 Category: Chemistry Authors: Masuda A, Gohda K, Iguchi Y, Fujimori K, Yamashita Y, Oda K, Une M, Teno N Tags: Bioorg Med Chem Source Type: research

Synthesis and evaluation of new 1-oxa-8-azaspiro[4.5]decane derivatives as candidate radioligands for sigma-1 receptors.
We report the design, synthesis, and evaluation of a series of 1-oxa-8-azaspiro[4.5]decane and 1,5-dioxa-9-azaspiro[5.5]undecane derivatives as selective σ1 receptor ligands. All seven ligands exhibited nanomolar affinity for σ1 receptors (Ki(σ1) = 0.47 - 12.1 nM) and moderate selectivity over σ2 receptors (Ki(σ2)/ Ki(σ1) = 2 - 44). Compound 8, with the best selectivity among these ligands, was selected for radiolabeling and further evaluation. Radioligand [18F]8 was prepared via nucleophilic 18F-substitution of the corresponding tosylate precursor, with an overa...
Source: Bioorganic and Medicinal Chemistry - July 5, 2020 Category: Chemistry Authors: Tian J, He Y, Deuther-Conrad W, Fu H, Xie F, Zhang Y, Wang T, Zhang X, Zhang J, Brust P, Huang Y, Jia H Tags: Bioorg Med Chem Source Type: research

Fibroblast growth factor receptor modulators employing diamines with reduced phospholipidosis-inducing potential.
Abstract SUN13837 (1), a fibroblast growth factor receptor modulator, has been an attractive candidate for treating neurodegenerative diseases. However, one of its metabolites, N-benzyl-4-(methylamino)piperidine (BMP), turned out to possess phospholipidosis-inducing potential (PLIP) in vitro. To obtain SUN13837 analogs with reduced phospholipidosis risk, we replaced BMP with other diamines possessing low PLIP. Our effort led to the discovery of compound 6 with increased efficacy. Further structural modifications to reduce hydrogen bond donors afforded 17 with improved brain exposure. Oral administration of 17 at 1...
Source: Bioorganic and Medicinal Chemistry - July 5, 2020 Category: Chemistry Authors: Sakai H, Inoue H, Murata K, Toba T, Shimmyo Y, Narii N, Ueno SY, Igawa Y, Takemoto N Tags: Bioorg Med Chem Source Type: research

Design, synthesis and evaluation of carbamate-linked uridyl-based inhibitors of human ST6Gal I.
Abstract Sialic acid at the terminus of cell surface glycoconjugates is a critical element in cell-cell recognition, receptor binding and immune responses. Sialyltransferases (ST), the enzymes responsible for the biosynthesis of sialylated glycans are highly upregulated in cancer and the resulting hypersialylation of the tumour cell surface correlates strongly with tumour growth, metastasis and drug resistance. Inhibitors of human STs, in particular human ST6Gal I, are thus expected to be valuable chemical tools for the discovery of novel anticancer drugs. Herein, we report on the computationally-guided design and...
Source: Bioorganic and Medicinal Chemistry - July 5, 2020 Category: Chemistry Authors: Montgomery AP, Dobie C, Szabo R, Hallam L, Ranson M, Yu H, Skropeta D Tags: Bioorg Med Chem Source Type: research

6,6'-Aryl trehalose analogs as potential Mincle ligands.
Abstract 6,6'-Aryl trehalose derivatives have been synthesized with a view towards identifying novel Th-17-inducing vaccine adjuvants based on the high affinity Mincle ligand Brartemicin. The initial structure-activity relationships of these novel trehalose-based compounds were investigated. All compounds have been evaluated for their ability to engage the Mincle receptor and induce a potential pro-Th17 cytokine profile from human peripheral blood mononuclear cells based on IL-6 production in human peripheral blood mononuclear cells. The preliminary biological characterization of the designed analogs presented in ...
Source: Bioorganic and Medicinal Chemistry - July 5, 2020 Category: Chemistry Authors: Rasheed OK, Ettenger G, Buhl C, Child R, Miller SM, Evans JT, Ryter KT Tags: Bioorg Med Chem Source Type: research

Synthesis and evaluation of heterocycle structures as potential inhibitors of Mycobacterium tuberculosis UGM.
This study made it possible to highlight an "oxazepino-indole" structure as a new inhibitor of UGM and of M. tuberculosis growth in vitro. PMID: 32546296 [PubMed - in process] (Source: Bioorganic and Medicinal Chemistry)
Source: Bioorganic and Medicinal Chemistry - June 18, 2020 Category: Chemistry Authors: Maaliki C, Fu J, Villaume S, Viljoen A, Raynaud C, Hammoud S, Thibonnet J, Kremer L, Vincent SP, Thiery E Tags: Bioorg Med Chem Source Type: research

Broad assessment of bioactivity of a collection of spiroindane pyrrolidines through "cell painting".
Broad assessment of bioactivity of a collection of spiroindane pyrrolidines through "cell painting". Bioorg Med Chem. 2020 Jul 01;28(13):115547 Authors: Singh M, Garza N, Pearson Z, Douglas J, Boskovic Z Abstract A collection of small molecules has been synthesized by composing photo-cycloaddition, C-H functionalization, and N-capping strategies. Multidimensional biological fingerprints of molecules comprising this collection have been recorded as changes in cell and organelle morphology. This untargeted, phenotypic approach allowed for a broad assessment of biological activity to be determi...
Source: Bioorganic and Medicinal Chemistry - June 18, 2020 Category: Chemistry Authors: Singh M, Garza N, Pearson Z, Douglas J, Boskovic Z Tags: Bioorg Med Chem Source Type: research

Synthesis, cytotoxicity, and in vivo antitumor activity study of parthenolide semicarbazones and thiosemicarbazones.
Abstract Parthenolide is an important sesquiterpene lactone with potent anticancer activities. In order to further improve its biological activity, a series of parthenolide semicarbazone or thiosemicarbazone derivatives was synthesized and evaluated for their anticancer activity. Derivatives were tested in vitro against 5 human tumor cell lines, and many of these showed higher cytotoxicity than parthenolide. Five compounds were further studied for their antitumor activity in mice. The in vivo result indicated that compound 4d showed both promising antitumor activity against mice colon tumor and small side effects ...
Source: Bioorganic and Medicinal Chemistry - June 18, 2020 Category: Chemistry Authors: Jia X, Liu Q, Wang S, Zeng B, Du G, Zhang C, Li Y Tags: Bioorg Med Chem Source Type: research

A critical update on the strategies towards modulators targeting androgen receptors.
Abstract Prostate cancer is the most common carcinoma of the male urinary system in developed countries. Androgen deprivation therapy has been commonly used in the treatment of prostate cancer for decades, but most patients will inevitably develop into more aggressive castration-resistant prostate cancer. Therefore, novel strategies are urgent to address this resistance mechanism. In this review, we discussed some new strategies for targeting androgen receptors through degradation pathways as potential treatments for prostate cancer. PMID: 32546299 [PubMed - in process] (Source: Bioorganic and Medicinal Chemistry)
Source: Bioorganic and Medicinal Chemistry - June 18, 2020 Category: Chemistry Authors: Luan H, Xu P, Meng Y, Li Z, Bian J Tags: Bioorg Med Chem Source Type: research

Investigation into the influence of an acrylic acid acceptor in organic D- π-A sensitizers against phototoxicity.
This study was an investigation into 1) the possibility of increasing phototoxicity by introducing another carboxyl group or by replacing a carboxyl group with a pyridinium group, and 2) the importance of an alkene in the acrylic acid acceptor for phototoxicity. A review of the design, synthesis, and evaluation of sensitizers revealed that neither dicarboxylic acid nor pyridinium photosensitizers enhance phototoxicity. An evaluation of a photosensitizer without an alkene in the acrylic acid moiety revealed that the alkene was not indispensable in the pursuit of phototoxicity. The obtained results provided new insight into ...
Source: Bioorganic and Medicinal Chemistry - June 18, 2020 Category: Chemistry Authors: Fuse S, Moriya W, Sato S, Nakamura H Tags: Bioorg Med Chem Source Type: research

Versatile near-infrared fluorescent probe for in vivo detection of A β oligomers.
Versatile near-infrared fluorescent probe for in vivo detection of Aβ oligomers. Bioorg Med Chem. 2020 Jul 01;28(13):115559 Authors: Zeng F, Yang J, Li X, Peng K, Ran C, Xu Y, Li Y Abstract Amyloid-β oligomers (AβOs) enrichment in brain is highly related to Alzheimer's pathogenesis, but tracing them in the brain by imaging technique is still a great challenge due to their heterogeneity and metastability. Herein, a new near-infrared (NIR) fluorescent probe, namely, PTO-41, was designed and synthesized to specifically target AβOs. PTO-41 possesses excellent functional properties incl...
Source: Bioorganic and Medicinal Chemistry - June 18, 2020 Category: Chemistry Authors: Zeng F, Yang J, Li X, Peng K, Ran C, Xu Y, Li Y Tags: Bioorg Med Chem Source Type: research

Discovery of novel potent GPR40 agonists containing imidazo[1,2-a]pyridine core as antidiabetic agents.
Abstract Free fatty acid receptor 1 (FFA1 or GPR40) has been studied for many years as a target for the treatment of type 2 diabetes mellitus. In order to increase potency and reduce hepatotoxicity, a series of novel compounds containing imidazo[1,2-a]pyridine scaffold as GPR40 agonist were synthesized. Compound I-14 was identified as an effective agonist as shown by the conspicuous drop in blood glucose in normal and diabetic mice. It had no risk of hepatotoxicity compared with TAK-875. Moreover, good pharmacokinetic (PK) properties of I-14 were observed (CL = 27.26 ml/h/kg, t1/2 = 5.93&n...
Source: Bioorganic and Medicinal Chemistry - June 18, 2020 Category: Chemistry Authors: Ye Z, Liu C, Zou F, Cai Y, Chen B, Zou Y, Mo J, Han T, Huang W, Qiu Q, Qian H Tags: Bioorg Med Chem Source Type: research

Design, synthesis and biological evaluation of novel pyrrolo[2,3-d]pyrimidine as tumor-targeting agents with selectivity for tumor uptake by high affinity folate receptors over the reduced folate carrier.
Abstract Tumor-targeted 6-substituted pyrrolo[2,3-d]pyrimidine benzoyl compounds based on 2 were isosterically modified at the 4-carbon bridge by replacing the vicinal (C11) carbon by heteroatoms N (4), O (5) or S (6), or with an N-substituted formyl (7), trifluoroacetyl (8) or acetyl (9). Replacement with sulfur (6) afforded the most potent KB tumor cell inhibitor, ~6-fold better than the parent 2. In addition, 6 retained tumor transport selectivity via folate receptor (FR) α and -β over the ubiquitous reduced folate carrier (RFC). FRα-mediated cell inhibition for 6 was generally equivalent to 2,...
Source: Bioorganic and Medicinal Chemistry - June 8, 2020 Category: Chemistry Authors: Golani LK, Islam F, O'Connor C, Dekhne AS, Hou Z, Matherly LH, Gangjee A Tags: Bioorg Med Chem Source Type: research

Discovery of a novel indole pharmacophore for the irreversible inhibition of myeloperoxidase (MPO).
Abstract Myeloperoxidase (MPO) activity and subsequent generation of hypochlorous acid has been associated with the killing of host-invading microorganisms (e.g. bacteria, viruses, and fungi). However, during oxidative stress, high MPO activity can damage host tissue and is linked to several chronic inflammatory conditions. Herein, we describe the development of a novel biaryl, indole-pyrazole series of irreversible mechanism-based inhibitors of MPO. Derived from an indole-containing high-throughput screen hit, optimization efforts resulted in potent and selective 6-substituted indoles with good oral bioavailabili...
Source: Bioorganic and Medicinal Chemistry - June 8, 2020 Category: Chemistry Authors: Patnaik A, Axford L, Deng L, Cohick E, Ren X, Loi S, Kecman S, Hollis-Symynkywicz M, Harrison TJ, Papillon JPN, Dales N, Hamann LG, Lee L, Regard JB, Marcinkeviciene J, Marro ML, Patterson AW Tags: Bioorg Med Chem Source Type: research

Immunomodulation-mediated anticancer activity of a novel compound from Brugmansia suaveolens leaves.
Abstract Immunomodulation activity-guided fractionation of ethanol extract of Brugmansia suaveolens leaves was carried out to isolate a novel compound SUPH036-022A (1) by co-culturing the test fraction/compound activated PBMC with MCF7 and A549 cancer cell lines. Assessment of immune markers in PBMC, and analysis of apoptosis markers and cell cycle was carried out for cancer cells. The structure of the isolated compound was elucidated by spectral analysis. Compound 1 enhanced the secretion of immune markers, IL-2 and IFN-γ, from PBMC. Further, compound 1 treated PBMC increased cell death in MCF7 and A549 cel...
Source: Bioorganic and Medicinal Chemistry - June 8, 2020 Category: Chemistry Authors: Kumar S, Gupta A, Saini RV, Kumar A, Dhar KL, Mahindroo N Tags: Bioorg Med Chem Source Type: research

Bisbenzylisoquinoline alkaloids and P-glycoprotein function: A structure activity relationship study.
Abstract Conflicts with the notion that specific substrate interactions were required in the control of reaction path in active transport systems, P-glycoprotein showed extraordinarily low specificity. Therefore, overexpression P-glycoprotein excluded a large number of anticancer agents from cancer cells, and multidrug resistance happened. Several kinds of bisbenzylisoqunoline alkaloids were reported to modulate P-glycoprotein function and reverse drug resistance. In order to provide more information for their structure activity relationship on P-glycoprotein function, the effects of tetrandrine, isotetrandrine, f...
Source: Bioorganic and Medicinal Chemistry - June 8, 2020 Category: Chemistry Authors: Xu W, Chen S, Wang X, Wu H, Yamada H, Hirano T Tags: Bioorg Med Chem Source Type: research

The synthesis and biological evaluation of nucleobases/tetrazole hybrid compounds: A new class of phosphodiesterase type 3 (PDE3) inhibitors.
Abstract Spired by the chemical structure of Cilostazol, a selective phosphodiesterase 3A (PDE3A) inhibitor, several novel hybrid compounds of nucleobases (uracil, 6-azauracil, 2-thiuracil, adenine, guanine, theophylline and theobromine) and tetrazole were designed and successfully synthesized and their inhibitory effects on PDE3A as well as their cytotoxicity on HeLa and MCF-7 cancerous cell lines were studied. Obtained results show the linear correlation between the inhibitory effect of synthesized compounds and their cytotoxicity. In some cases, the PDE3A inhibitory effects of synthesized compounds are higher t...
Source: Bioorganic and Medicinal Chemistry - June 8, 2020 Category: Chemistry Authors: Shekouhy M, Karimian S, Moaddeli A, Faghih Z, Delshad Y, Khalafi-Nezhad A Tags: Bioorg Med Chem Source Type: research

Synthesis of novel 3,5,6-trisubstituted 2-pyridone derivatives and evaluation for their anti-inflammatory activity.
FR, Rosa FA Abstract The inflammatory response is the reaction of living tissue to an injury of a foreign nature, such as infection and irritants, and occurs as part of the body's natural defence response. Compounds capable of inhibiting cyclooxygenase (COX) enzymes, especially COX-2, have great potential as anti-inflammatory agents. Herein we present the regioselective synthesis of 49 novel compounds based on the 2-pyridone nucleus. The topical anti-inflammatory activity of seventeen compounds was evaluated in mice by croton oil (CO) induced ear edema assay. Most of the compounds exhibited a high level of in vivo...
Source: Bioorganic and Medicinal Chemistry - June 8, 2020 Category: Chemistry Authors: Gonçalves DS, de S Melo SM, Jacomini AP, J V da Silva M, Pianoski KE, Ames FQ, Aguiar RP, Oliveira AF, Volpato H, Bidóia DL, Nakamura CV, Bersani-Amado CA, Back DF, Moura S, Paula FR, Rosa FA Tags: Bioorg Med Chem Source Type: research

Genetically encoded protein labeling and crosslinking in living Pseudomonas aeruginosa.
We report the genetic code expansion of this opportunistic pathogen by using the pyrrolysyl-tRNA synthetase-tRNA system, which enabled the genetic and site-specific incorporation of unnatural amino acids bearing bioorthogonal handles or photo-affinity groups into proteins in PA. This strategy allowed us to conduct bioorthogonal labeling and imaging of flagella, as well as site-specific photo-affinity capturing of interactions between a Type III secretion effector and its chaperone inside living bacteria. PMID: 32503693 [PubMed - as supplied by publisher] (Source: Bioorganic and Medicinal Chemistry)
Source: Bioorganic and Medicinal Chemistry - June 8, 2020 Category: Chemistry Authors: Zheng H, Lin S, Chen PR Tags: Bioorg Med Chem Source Type: research

Rational design, synthesis and biological evaluation of novel multitargeting anti-AD iron chelators with potent MAO-B inhibitory and antioxidant activity.
Abstract A series of (3-hydroxypyridin-4-one)-coumarin hybrids were developed and investigated as potential multitargeting candidates for the treatment of Alzheimer's disease (AD) through the incorporation of iron-chelating and monoamine oxidase B (MAO-B) inhibition. This combination endowed the hybrids with good capacity to inhibit MAO-B as well as excellent iron-chelating effects. The pFe3+ values of the compounds were ranging from 16.91 to 20.16, comparable to more potent than the reference drug deferiprone (DFP). Among them, compound 18d exhibited the most promising activity against MAO-B, with an IC50 value o...
Source: Bioorganic and Medicinal Chemistry - June 8, 2020 Category: Chemistry Authors: Jiang X, Guo J, Lv Y, Yao C, Zhang C, Mi Z, Shi Y, Gu J, Zhou T, Bai R, Xie Y Tags: Bioorg Med Chem Source Type: research

Design, synthesis, and evaluation of a novel macrocyclic anti-EV71 agent.
We describe here the design, synthesis, and evaluation of a macrocyclic peptidomimetic as a potent agent targeting enterovirus A71 (EV71). The compound has a 15-membered macrocyclic ring in a defined conformation. Yamaguchi esterification reaction was used to close the 15-membered macrocycle instead of the typical Ru-catalyzed ring-closing olefin metathesis reaction. The crystallographic characterization of the complex between this compound and its target, 3C protease from EV71, validated the design and paved the way for the generation of a new series of anti-EV71 agents. PMID: 32503695 [PubMed - as supplied by publis...
Source: Bioorganic and Medicinal Chemistry - June 8, 2020 Category: Chemistry Authors: Li P, Wu S, Xiao T, Li Y, Su Z, Wei W, Hao F, Hu G, Lin F, Chen X, Gu Z, Lin T, He H, Li J, Chen S Tags: Bioorg Med Chem Source Type: research

Cytosolic delivery of peptidic STAT3 SH2 domain inhibitors.
Abstract The signal transducer and activator of transcription 3 (STAT3) protein is constitutively activated in several cancers. STAT3 activity can be blocked by inhibiting its Src Homology 2 (SH2) domain, but phosphotyrosine and its isosteres have poor bioavailability. In this work, we develop peptide-based inhibitors of STAT3-SH2 by combining chemical strategies that have proven effective for targeting other SH2 domains. These strategies include a STAT3-specific selectivity sequence, non-hydrolyzable phosphotyrosine isosteres, and a high-efficiency cell-penetrating peptide. Peptides that combined these three stra...
Source: Bioorganic and Medicinal Chemistry - June 8, 2020 Category: Chemistry Authors: Cerulli RA, Shehaj L, Tosic I, Jiang K, Wang J, Frank DA, Kritzer JA Tags: Bioorg Med Chem Source Type: research

Discovery of N-substituted-3-phenyl-1,6-naphthyridinone derivatives bearing quinoline moiety as selective type II c-Met kinase inhibitors against VEGFR-2.
Abstract New N-substituted-3-phenyl-1,6-naphthyridinone derivatives are designed and synthesized, based on structural modification of our previously reported compound 3. Extensive enzyme-based SAR studies and PK evaluation led to the discovery of compound 4r, with comparable c-Met potency to that of Cabozantinib and high VEGFR-2 selectivity, while Cabozantinib displayed no VEGFR-2 selectivity. More importantly, at oral doses of 45 mg/kg (Q.D.), compound 4r exhibits significant tumor growth inhibition (93%) in a U-87MG human gliobastoma xenograft model. The promising selectivity against VEGFR-2 and excellent t...
Source: Bioorganic and Medicinal Chemistry - June 8, 2020 Category: Chemistry Authors: Xu H, Wang M, Wu F, Zhuo L, Huang W, She N Tags: Bioorg Med Chem Source Type: research

Computational-aided design of a library of lactams through a diversity-oriented synthesis strategy.
Trabocchi A Abstract Small molecule libraries for virtual screening are becoming a well-established tool for the identification of new hit compounds. As for experimental assays, the library quality, defined in terms of structural complexity and diversity, is crucial to increase the chance of a successful outcome in the screening campaign. In this context, Diversity-Oriented Synthesis has proven to be very effective, as the compounds generated are structurally complex and differ not only for the appendages, but also for the molecular scaffold. In this work, we automated the design of a library of lactams by applyin...
Source: Bioorganic and Medicinal Chemistry - June 8, 2020 Category: Chemistry Authors: Saldívar-González FI, Lenci E, Calugi L, Medina-Franco JL, Trabocchi A Tags: Bioorg Med Chem Source Type: research

Corrigendum to "A truncated RHAMM protein for discovering novel therapeutic peptides" [Bioorg. Med. Chem. 26 (2018) 5194-5203].
Corrigendum to "A truncated RHAMM protein for discovering novel therapeutic peptides" [Bioorg. Med. Chem. 26 (2018) 5194-5203]. Bioorg Med Chem. 2020 May 16;:115543 Authors: Hauser-Kawaguchi A, Tolg C, Peart T, Milne M, Turley EA, Luyt LG PMID: 32423782 [PubMed - as supplied by publisher] (Source: Bioorganic and Medicinal Chemistry)
Source: Bioorganic and Medicinal Chemistry - May 16, 2020 Category: Chemistry Authors: Hauser-Kawaguchi A, Tolg C, Peart T, Milne M, Turley EA, Luyt LG Tags: Bioorg Med Chem Source Type: research

Design, synthesis and SAR study of bridged tricyclic pyrimidinone carboxamides as HIV-1 integrase inhibitors.
Abstract The design, synthesis and structure-activity relationships associated with a series of bridged tricyclic pyrimidinone carboxamides as potent inhibitors of HIV-1 integrase strand transfer are described. Structural modifications to these molecules were made in order to examine the effect on potency towards wild-type and clinically-relevant resistant viruses. The [3.2.2]-bridged tricyclic system was identified as an advantageous chemotype, with representatives exhibiting excellent antiviral activity against both wild-type viruses and the G140S/Q148H resistant virus that arises in response to therapy with ral...
Source: Bioorganic and Medicinal Chemistry - May 4, 2020 Category: Chemistry Authors: Patel M, Naidu BN, Dicker I, Higley H, Lin Z, Terry B, Protack T, Krystal M, Jenkins S, Parker D, Panja C, Rampulla R, Mathur A, Meanwell NA, Walker MA Tags: Bioorg Med Chem Source Type: research

Discovery and structure-activity relationships study of positive allosteric modulators of the M3 muscarinic acetylcholine receptor.
We report here the discovery and a comprehensive structure--activity relationships (SARs) study of novel positive allosteric modulators (PAMs) of the M3 mAChR through a high throughput screening (HTS) campaign. Compound 9 exhibited potent in vitro PAM activity towards the M3 mAChR and significant enhancement of muscle contraction in a concentration-dependent manner when applied to isolated smooth muscle strips of rat bladder. Compound 9 also showed excellent subtype selectivity over other subtypes of mAChRs including M1, M2, and M4 mAChRs, and moderate selectivity over the M5 mAChR, indicating that compound 9 is an M3-pref...
Source: Bioorganic and Medicinal Chemistry - April 30, 2020 Category: Chemistry Authors: Tanaka H, Negoro K, Koike T, Tsukamoto I, Yokoyama K, Maeda J, Inagaki Y, Shimoshige Y, Ino K, Ishizu K, Takahashi T Tags: Bioorg Med Chem Source Type: research

Synthesis and biological evaluation of triazolyl-substituted benzyloxyacetohydroxamic acids as LpxC inhibitors.
Holl R Abstract The bacterial deacetylase LpxC is a promising target for the development of antibiotics selectively combating Gram-negative bacteria. To improve the biological activity of the reported benzyloxyacetohydroxamic acid 9 ((S)-N-hydroxy-2-{2-hydroxy-1-[4-(phenylethynyl)phenyl]ethoxy}acetamide), its hydroxy group was replaced by a triazole ring. Therefore, in divergent syntheses, triazole derivatives exhibiting rigid and flexible lipophilic side chains, different configurations at their stereocenter, and various substitution patterns at the triazole ring were synthesized, tested for antibacterial and Lp...
Source: Bioorganic and Medicinal Chemistry - April 25, 2020 Category: Chemistry Authors: Hoff K, Mielniczuk S, Agoglitta O, Iorio MT, Caldara M, Bülbül EF, Melesina J, Sippl W, Holl R Tags: Bioorg Med Chem Source Type: research

Sulfonamide-based 4-anilinoquinoline derivatives as novel dual Aurora kinase (AURKA/B) inhibitors: Synthesis, biological evaluation and in silico insights.
Abstract Aurora kinases (AURKs) were identified as promising druggable targets for targeted cancer therapy. Aiming at the development of novel chemotype of dual AURKA/B inhibitors, herein we report the design and synthesis of three series of 4-anilinoquinoline derivatives bearing a sulfonamide moiety (5a-d, 9a-d and 11a-d). The % inhibition of AURKA/B was determined for all target quinolines, then compounds showed more than 50% inhibition on either of the enzymes, were evaluated further for their IC50 on the corresponding enzyme. In particular, compound 9d displayed potent AURKA/B inhibitory activities with IC50 o...
Source: Bioorganic and Medicinal Chemistry - April 25, 2020 Category: Chemistry Authors: Al-Sanea MM, Elkamhawy A, Paik S, Lee K, El Kerdawy AM, Syed Nasir Abbas B, Joo Roh E, Eldehna WM, Elshemy HAH, Bakr RB, Ali Farahat I, Alzarea AI, Alzarea SI, Alharbi KS, Abdelgawad MA Tags: Bioorg Med Chem Source Type: research

Exploring tryptamine conjugates as pronucleotides of phosphate-modified 7-methylguanine nucleotides targeting cap-dependent translation.
We report the synthesis of six new tryptamine conjugates containing N7-methylguanosine mono- and diphosphate and their analogs modified with thiophosphate moiety. These new potential pronucleotides and the expected products of their activation were characterized by biophysical and biochemical methods to determine their affinity towards eIF4E, their ability to inhibit translation in vitro, their susceptibility to enzymatic degradation and their turnover in cell extract. The results suggest that compounds containing the thiophosphate moiety may act as pronucleotides that release low but sustainable concentrations of 7-methyl...
Source: Bioorganic and Medicinal Chemistry - April 25, 2020 Category: Chemistry Authors: Golojuch S, Kopcial M, Strzelecka D, Kasprzyk R, Baran N, Sikorski PJ, Kowalska J, Jemielity J Tags: Bioorg Med Chem Source Type: research

Structure-activity relationship analyses of fusidic acid derivatives highlight crucial role of the C-21 carboxylic acid moiety to its anti-mycobacterial activity.
Abstract Fusidic acid (FA) is a potent congener of the fusidane triterpenoid class of antibiotics. Structure-activity relationship (SAR) studies suggest the chemical structure of FA is optimal for its antibacterial activity. SAR studies from our group within the context of a drug repositioning approach in tuberculosis (TB) suggest that, as with its antibacterial activity, the C-21 carboxylic acid group is indispensable for its anti-mycobacterial activity. Further studies have led to the identification of 16-deacetoxy-16β-ethoxyfusidic acid (58), an analog which exhibited comparable activity to FA with an in v...
Source: Bioorganic and Medicinal Chemistry - April 25, 2020 Category: Chemistry Authors: Singh K, Kaur G, Shanika PS, Dziwornu GA, Okombo J, Chibale K Tags: Bioorg Med Chem Source Type: research

Conformational analysis by NMR and molecular dynamics of adamantane-doxorubicin prodrugs and their assemblies with β-cyclodextrin: A focus on the design of platforms for controlled drug delivery.
This study proves that Ad-h-Dox prodrug can be an optimum prodrug and act as a building block for a more complex drug transport system. PMID: 32359883 [PubMed - as supplied by publisher] (Source: Bioorganic and Medicinal Chemistry)
Source: Bioorganic and Medicinal Chemistry - April 22, 2020 Category: Chemistry Authors: González-Méndez I, Aguayo-Ortiz R, Sorroza-Martínez K, Solano JD, Porcu P, Rivera E, Dominguez L Tags: Bioorg Med Chem Source Type: research

Design and synthesis of 1,3-benzothiazinone derivatives as potential anti-inflammatory agents.
Abstract A series of 1,3-benzothiazinone derivatives were designed and synthesized for pharmacological assessments. Among the synthesized 19 compounds, some compounds showed high activities on inhibiting LPS-induced nitrite oxide and TNF-α production, down-regulating COX-2 and increasing IL-10 production in RAW264.7 cells. All the compounds had no obvious cytotoxicity in in vitro assay. LD50 value of compound 25 was greater than 2000 mg/kg, which was safer than meloxicam. Compound 25 significantly inhibited phosphorylation of NF-κB and STAT3 in LPS-induced RAW264.7 cells. Inhibition of synthesized...
Source: Bioorganic and Medicinal Chemistry - April 22, 2020 Category: Chemistry Authors: Li J, Fan X, Deng J, Liang Y, Ma S, Lu Y, Zhang J, Shi T, Tan W, Wang Z Tags: Bioorg Med Chem Source Type: research

Secondary metabolites from Isodon ternifolius (D. Don) Kudo and their anticancer activity as DNA topoisomerase IB and Tyrosyl-DNA phosphodiesterase 1 inhibitors.
Abstract Based on DNA topoisomerase IB (TOP1) and tyrosyl-DNA phosphodiesterase 1 (TDP1) inhibition of the ethanol extract of the roots of Isodon ternifolius (D. Don) Kudo (Labiatae), its secondary metabolites has been studied. Two new compounds, an ent-abietane diterpenoid isodopene A (1) and a 2,3-seco-triterpene isodopene B (13), along with 25 known compounds were isolated. Their structures were elucidated by spectroscopic analysis and theoretical calculations. The enzyme-based assays indicated that 1 and 13 showed strong (+++) and moderate (++) TOP1 inhibition, respectively. Two chalcone derivatives 11 and 12 ...
Source: Bioorganic and Medicinal Chemistry - April 22, 2020 Category: Chemistry Authors: Zhang HL, Zhang Y, Yan XL, Xiao LG, Hu DX, Yu Q, An LK Tags: Bioorg Med Chem Source Type: research

Discovery of novel, potent, and orally bioavailable pyrido[2,3-d][1]benzazepin-6-one antagonists for parathyroid hormone receptor 1.
Abstract Structural modification of a 1,4-benzodiazepin-2-one-based PTHR1 antagonist 5, a novel type of PTHR1 antagonist previously synthesized in our laboratories, yielded compound 10, which had better chemical stability than compound 5. Successive optimization of the lead 10 improved aqueous solubility, metabolic stability, and animal pharmacokinetics, culminating in the identification of DS37571084 (12). Our study paves the way for the discovery of novel and orally bioavailable PTHR1 antagonists. PMID: 32345459 [PubMed - as supplied by publisher] (Source: Bioorganic and Medicinal Chemistry)
Source: Bioorganic and Medicinal Chemistry - April 22, 2020 Category: Chemistry Authors: Arai Y, Kiyotsuka Y, Kagechika K, Nishi T, Inui M, Nagamochi M, Oyama K, Izumi M Tags: Bioorg Med Chem Source Type: research

Cytotoxicity of 4-substituted quinoline derivatives: Anticancer and antileishmanial potential.
Abstract Chemical modifications of quinoline moiety have been recognized as a useful strategy to development of new drugs. Here, the cytotoxicity of a set of twenty-four 4-substituted quinolines (named HTI) was screened for their antitumor and antileishmanial potential in vitro, and the underlying mechanisms investigated. HTI 21 and HTI 22 exhibited the highest cytotoxicity, being selected to the subsequent studies. Both derivatives induced caspase-dependent apoptosis associated to the dissipation of the mitochondrial transmembrane potential (ΔΨ) and ROS generation. HTI-induced cell death was calcium dep...
Source: Bioorganic and Medicinal Chemistry - April 20, 2020 Category: Chemistry Authors: Costa CA, Lopes RM, Ferraz LS, Esteves GNN, Di Iorio JF, Souza AA, de Oliveira IM, Manarin F, Judice WAS, Stefani HA, Rodrigues T Tags: Bioorg Med Chem Source Type: research

Synthetic bioactive olivetol-related amides: The influence of the phenolic group in cannabinoid receptor activity.
Abstract Focusing on the importance of the free phenolic hydroxyl moiety, a family of 23 alkylresorcinol-based compounds were developed and evaluated for their cannabinoid receptor binding properties. The non-symmetrical hexylresorcinol derivative 29 turned out to be a CB2-selective competitive antagonist/inverse agonist endowed with good potency. Both the olivetol- and 5-(2-methyloctan-2-yl)resorcinol-based derivatives 23 and 24 exhibited a significant antinociceptive activity. Interestingly, compound 24 proved to be able to activate both cannabinoid and TRPV1 receptors. Even if cannabinoid receptor subtype selec...
Source: Bioorganic and Medicinal Chemistry - April 20, 2020 Category: Chemistry Authors: Brizzi A, Aiello F, Boccella S, Cascio MG, De Petrocellis L, Frosini M, Gado F, Ligresti A, Luongo L, Marini P, Mugnaini C, Pessina F, Corelli F, Maione S, Manera C, Pertwee RG, Di Marzo V Tags: Bioorg Med Chem Source Type: research

An aza-nucleoside, fragment-like inhibitor of the DNA repair enzyme alkyladenine glycosylase (AAG).
Abstract The DNA repair enzyme AAG has been shown in mice to promote tissue necrosis in response to ischaemic reperfusion or treatment with alkylating agents. A chemical probe inhibitor is required for investigations of the biological mechanism causing this phenomenon and as a lead for drugs that are potentially protective against tissue damage from organ failure and transplantation, and alkylative chemotherapy. Herein, we describe the rationale behind the choice of arylmethylpyrrolidines as appropriate aza-nucleoside mimics for an inhibitor followed by their synthesis and the first use of a microplate-based assay...
Source: Bioorganic and Medicinal Chemistry - April 15, 2020 Category: Chemistry Authors: Mas Claret E, Al Yahyaei B, Chu S, Elliott RM, Imperato M, Lopez A, Meira LB, Howlin BJ, Whelligan DK Tags: Bioorg Med Chem Source Type: research

Benzoxepinones: A new isoform-selective class of tumor associated carbonic anhydrase inhibitors.
Abstract Benzoxepinones ("homocoumarins") are identified as a new class of selective inhibitors for tumor associated human carbonic anhydrases (hCA, EC 4.2.1.1) isoforms IX and XII. Similar to coumarins, they do not inhibit or poorly inhibit cytosolic human (h) isoforms hCA I and II, but act as nanomolar inhibitors of the trans-membrane, tumor associated isoforms hCA IX and XII. PMID: 32327349 [PubMed - as supplied by publisher] (Source: Bioorganic and Medicinal Chemistry)
Source: Bioorganic and Medicinal Chemistry - April 14, 2020 Category: Chemistry Authors: Grandane A, Nocentini A, Werner T, Zalubovskis R, Supuran CT Tags: Bioorg Med Chem Source Type: research

Synthesis and cytotoxic effects of 2-thio-3,4-dihydroquinazoline derivatives as novel T-type calcium channel blockers.
Abstract In our previous work, a series of 2-amino-3,4-dihydroquinazoline derivativesusing an electron acceptor group was reported to be potent T-type calcium channel blockers and exhibit strong cytotoxic effects against various cancerous cell lines. To investigate the role of the guanidine moiety in the 2-amino-3,4-dihydroquinazoline scaffold as a pharmacophore for dual biological activity, a new series of 2-thio-3,4-dihydroquniazoline derivatives using an electron donor group at the C2-position was synthesized and evaluated for T-type calcium channel blocking activity and cytotoxic effects against two human canc...
Source: Bioorganic and Medicinal Chemistry - April 14, 2020 Category: Chemistry Authors: Nam Y, Ryu KD, Jang C, Moon YH, Kim M, Ko D, Chung KS, Gandini MA, Lee KT, Zamponi GW, Lee JY Tags: Bioorg Med Chem Source Type: research

Discovery of a new potent inhibitor of mushroom tyrosinase (Agaricus bisporus) containing 4-(4-hydroxyphenyl)piperazin-1-yl moiety.
tto R Abstract Tyrosinase (TYR, EC 1.14.18.1) plays a pivotal role in mammalian melanogenesis and enzymatic browning of plant-derived food. Therefore, tyrosinase inhibitors (TYRIs) can be of interest in cosmetics and pharmaceutical industries as depigmentation compounds as well as anti-browning agents. Starting from 4-benzylpiperidine derivatives that showed good inhibitory properties toward tyrosinase from Agaricus bisporus (TyM), we synthesized a new series of TYRIs named 3-(4-benzyl-1-piperidyl)-1-(4-phenylpiperazin-1-yl)propan-1-one and 2-(4-benzyl-1-piperidyl)-1-(4-phenylpiperazin-1-yl)ethanone derivatives. A...
Source: Bioorganic and Medicinal Chemistry - April 12, 2020 Category: Chemistry Authors: De Luca L, Germanò MP, Fais A, Pintus F, Buemi MR, Vittorio S, Mirabile S, Rapisarda A, Gitto R Tags: Bioorg Med Chem Source Type: research

Synthesis, state-of-the-art NMR-binding and molecular modeling study of new benzimidazole core derivatives as Pin1 inhibitors: Targeting breast cancer.
Abstract New series of benzimidazole ring core conjugated with either dithiocarbamate or thiopropyl linkers, hybridized with different secondary amines were synthesized; 5-15 and 22-31; respectively. The new compounds were characterized by different spectroscopic techniques (1H, 13C 1D & 2D NMR, ESI-MS and IR). They were screened for in vitro anticancer activity against breast cancer using MCF7 cell line. The results obtained revealed that compounds 5, 12, 15 and 25 were the most active among the synthesized series exhibiting IC50 
Source: Bioorganic and Medicinal Chemistry - April 11, 2020 Category: Chemistry Authors: Nashaat S, Henen MA, El-Messery SM, Eisa H Tags: Bioorg Med Chem Source Type: research

Exploratory studies on CA-15L, an anti-HIV active HIV-1 capsid fragment.
Abstract Utilizing overlapping fragment peptide libraries covering the whole sequence of an HIV-1 capsid (CA) protein with the addition of an octa-arginyl moiety, we had previously found several peptides with anti-HIV-1 activity. Herein, among these potent CA fragment peptides, CA-15L was examined because this peptide sequence overlaps with Helix 7, a helix region of the CA protein, which may be important for oligomerization of the CA proteins. A CA-15L surrogate with hydrophilic residues, and its derivatives, in which amino acid sequences are shifted toward the C-terminus by one or more residues, were synthesized...
Source: Bioorganic and Medicinal Chemistry - April 8, 2020 Category: Chemistry Authors: Tsuji K, Owusu KB, Kobayakawa T, Wang R, Fujino M, Kaneko M, Yamamoto N, Murakami T, Tamamura H Tags: Bioorg Med Chem Source Type: research

Induction of enantio-selective apoptosis in human leukemia HL-60 cells by (S)-erypoegin K, an isoflavone isolated from Erythrina poeppigiana.
Abstract Erypoegin K, an isoflavone isolated from the stem bark of Erythrina poeppigiana, has potent apoptosis-inducing effect on human leukemia HL-60 cells. Erypoegin K has a chiral carbon at the C-2'' position of its furan ring and naturally occurs as a racemic mixture of (S)- and (R)-isomers. In the present study, we semi-synthesized (RS)-erypoegin K from genistein and separated the optical isomers by HPLC using a chiral column to characterize its apoptosis-inducing activity. Apoptotic cell death was assessed by analyzing caspase-3 and caspase-9 activation, nuclear fragmentation, and genomic DNA ladder formatio...
Source: Bioorganic and Medicinal Chemistry - April 8, 2020 Category: Chemistry Authors: Hikita K, Saigusa S, Takeuchi Y, Matsuyama H, Nagai R, Kato K, Murata T, Tanaka H, Wagh YS, Asao N, Kaneda N Tags: Bioorg Med Chem Source Type: research

Deuteration of the farnesyl terminal methyl groups of δ-tocotrienol and its effects on the metabolic stability and ability of inducing G-CSF production.
Deuteration of the farnesyl terminal methyl groups of δ-tocotrienol and its effects on the metabolic stability and ability of inducing G-CSF production. Bioorg Med Chem. 2020 Apr 08;:115498 Authors: Liu X, Gao Z, Fu Q, Song L, Zhang P, Zhang X, Hendrickson H, Crooks PA, Zhou D, Zheng G Abstract δ-tocotrienol (DT3), a member of vitamin E family, has been shown to have a potent radio-protective effect. However, its application as a radioprotectant is limited, at least in part, by its short plasma elimination half-life and low bioavailability. In an effort to increase the metabolic stability ...
Source: Bioorganic and Medicinal Chemistry - April 8, 2020 Category: Chemistry Authors: Liu X, Gao Z, Fu Q, Song L, Zhang P, Zhang X, Hendrickson H, Crooks PA, Zhou D, Zheng G Tags: Bioorg Med Chem Source Type: research

A novel Golgi mannosidase inhibitor: Molecular design, synthesis, enzyme inhibition, and inhibition of spheroid formation.
Abstract Effective chemotherapy for solid cancers is challenging due to a limitation in permeation that prevents anticancer drugs from reaching the center of the tumor, therefore unable to limit cancer cell growth. To circumvent this issue, we planned to apply the drugs directly at the center by first collapsing the outer structure. For this, we focused on cell-cell communication (CCC) between N-glycans and proteins at the tumor cell surface. Mature N-glycans establish CCC; however, CCC is hindered when numerous immature N-glycans are present at the cell surface. Inhibition of Golgi mannosidases (GMs) results in t...
Source: Bioorganic and Medicinal Chemistry - April 8, 2020 Category: Chemistry Authors: Koyama R, Kano Y, Kikushima K, Mizutani A, Soeda Y, Miura K, Hirano T, Nishio T, Hakamata W Tags: Bioorg Med Chem Source Type: research

Progress towards drug discovery for Friedreich's Ataxia: Identifying synthetic oligonucleotides that more potently activate expression of human frataxin protein.
Abstract Friedreich's Ataxia (FRDA) is an incurable genetic disease caused by an expanded trinucleotide AAG repeat within intronic RNA of the frataxin (FXN) gene. We have previously demonstrated that synthetic antisense oligonucleotides or duplex RNAs that are complementary to the expanded repeat can activate expression of FXN and return levels of FXN protein to near normal. The potency of these compounds, however, was too low to encourage vigorous pre-clinical development. We now report testing of "gapmer" oligonucleotides consisting of a central DNA portion flanked by chemically modified RNA that incre...
Source: Bioorganic and Medicinal Chemistry - April 5, 2020 Category: Chemistry Authors: Shen X, Wong J, Prakash TP, Rigo F, Li Y, Napierala M, Corey DR Tags: Bioorg Med Chem Source Type: research