Bioorganic & Medicinal Chemistry

Editorial board ()
Publication date: 1 December 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 23
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The synthesis and biological evaluation of alkyl and benzyl naphthyridinium analogs of eupolauridine as potential antimicrobial and cytotoxic agents ()
Publication date: 1 December 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 23 Author(s): Shahriyar Taghavi-Moghadam, Cecil D. Kwong, John A. Secrist, Shabana I. Khan, Alice M. Clark Eupolauridine, an indenonaphthyridine alkaloid, has been previously reported by us to exhibit antifungal activity. This study describes the synthesis of new alkyl and benzyl naphthyridinium/pyridinium analogs of eupolauridine as potential antifungal agents. A majority of the analogs exhibited antifungal activity against opportunistic pathogens such as Candida albicans and Cryptococcus neoformans. Several of them were also effective against bacteria (Staphylococcus aureus, MRS, Pseudomonas and Mycobacterium) and the malaria parasite (Plasmodium falciparum) to variable extents. A number of analogs were also cytotoxic to human cancer cell lines. Graphical abstract image
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Synthesis and antimalarial activity of N-benzylated (N-arylcarbamoyl)alkylphosphonic acid derivatives ()
Publication date: 1 December 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 23 Author(s): Christiana M. Adeyemi, Faridoon, Michelle Isaacs, Dumisani Mnkandhla, Heinrich C. Hoppe, Rui W.M. Krause, Perry T. Kaye A series of novel and readily accessible N-benzylated (N-arylcarbamoyl)alkylphosphonate esters and related compounds have been prepared as potential antimalarial agents. Bioassays reveal that some of these compounds exhibit promising activity against Plasmodium falciparum, and exhibit no significant growth inhibition of HeLa cells. Graphical abstract image
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Bis-pyridylethenyl benzene as novel backbone for amyloid-β binding compounds ()
Publication date: 1 December 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 23 Author(s): Rob J.A. Nabuurs, Varsha V. Kapoerchan, Athanasios Metaxas, Sarah Hafith, Maaike de Backer, Mick M. Welling, Wim Jiskoot, Adrianus M.C.H. van den Nieuwendijk, Albert D. Windhorst, Herman S. Overkleeft, Mark A. van Buchem, Mark Overhand, Louise van der Weerd Detection of cerebral β-amyloid (Aβ) by targeted contrast agents is of great interest for in vivo diagnosis of Alzheimer’s disease (AD). Partly because of their planar structure several bis-styrylbenzenes have been previously reported as potential Aβ imaging agents. However, these compounds are relatively hydrophobic, which likely limits their in vivo potential. Based on their structures, we hypothesized that less hydrophobic bis-pyridylethenylbenzenes may also label amyloid. We synthesized several bis-pyridylethenylbenzenes and tested whether these compounds indeed display improved solubility and lower Log P values, and studied their fluorescent properties and Aβ binding characteristics. Bis-pyridylethenylbenzenes showed a clear affinity for Aβ plaques on both human and murine AD brain sections. Competitive binding experiments suggested a different binding site than Chrysamine G, a well-known stain for amyloid. With a Log P value between 3 and 5, most bis-pyridylethenylbenzenes were able to enter the brain and label murine amyloid in vivo with the bis(4-pyridylethenyl)benzenes showing the most favorable characteristics. In conclusion, the presented results suggest that bis-pyridylethenylbenzene may serve as a novel backbone for amyloid imaging agents. Graphical abstract image
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Design, synthesis, and biological activity of novel, potent, and highly selective fused pyrimidine-2-carboxamide-4-one-based matrix metalloproteinase (MMP)-13 zinc-binding inhibitors ()
Publication date: 1 December 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 23 Author(s): Hiroshi Nara, Kenjiro Sato, Akira Kaieda, Hideyuki Oki, Haruhiko Kuno, Takashi Santou, Naoyuki Kanzaki, Jun Terauchi, Osamu Uchikawa, Masakuni Kori Matrix metalloproteinase-13 (MMP-13), a member of the collagenase family of enzymes, has been implicated to play a key role in the pathology of osteoarthritis. Recently, we have reported the discovery of a series of quinazoline-2-carboxamide based non-zinc-binding MMP-13 selective inhibitors, as exemplified by compound 1. We then continued our research of a novel class of zinc-binding inhibitors to obtain follow-up compounds with different physicochemical, pharmacokinetic, and biological activity profiles. In order to design selective MMP-13 inhibitors, we adopted a strategy of connecting a zinc-binding group with the quinazoline-2-carboxamide system, a unique S1′ binder, by an appropriate linker. Among synthesized compounds, a triazolone inhibitor 35 exhibited excellent potency (IC50 =0.071nM) and selectivity (greater than 170-fold) over other MMPs (MMP-1, 2, 3, 7, 8, 9, 10, 12, and 14) and tumor necrosis factor-α converting enzyme (TACE). In this article, the design, synthesis, and biological activity of novel zinc-binding MMP-13 inhibitors are described. Graphical abstract image
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Synthesis, activity and docking studies of phenylpyrimidine–carboxamide Sorafenib derivatives ()
Publication date: 1 December 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 23 Author(s): Wenhui Wang, Chunjiang Wu, Jianqiang Wang, Rong Luo, Caolin Wang, Xiaobo Liu, Jiqing Li, Wufu Zhu, Pengwu Zheng Two series of Sorafenib derivatives bearing phenylpyrimidine–carboxamide moiety (16a–g and 17a–p) were designed, synthesized and evaluated for the IC50 values against three cancer cell lines (A549, MCF-7 and PC-3). Two selected compounds (17f and 17n) were further evaluated for the activity against VEGFR2/KDR kinase. More than half of the synthesized compounds showed moderate to excellent activity against three cancer cell lines. Compound 17f showed equal activity to Sorafenib against MCF-7 cell line, with the IC50 values of 6.35±0.43μM. Meanwhile, compound 17n revealed more active than Sorafenib against A549 cell line, with the IC50 values of 3.39±0.37μM. Structure–activity relationships (SARs) and docking studies indicated that the second series (17a–p) showed more active than the first series (16a–g). What’s more, the introduction of fluoro atom to the phenoxy part played no significant impact on activity. In addition, the presence of electron-donating on aryl group was benefit for the activity. Graphical abstract image
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4-Carbonyl-2,6-dibenzylidenecyclohexanone derivatives as small molecule inhibitors of STAT3 signaling pathway ()
Publication date: 1 December 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 23 Author(s): Peng Ji, Congmin Yuan, Shuhua Ma, Junchao Fan, Wei Fu, Chunhua Qiao Inhibition of STAT3 signaling pathway is proposed to be a promising strategy for cancer treatment. In this study, a series of 4-carbonyl-2,6-dibenzylidenecyclohexanone derivatives were prepared and evaluated as anticancer agents. The most potent compound 13r was discovered to exhibit antiproliferative activity against a broad rang of cancer cell lines and relatively low cytotoxicity against normal human cells. Besides, 13r effectively suppressed STAT3 expression as well as phosphorylation, and surface plasmon resonance analysis confirmed the direct interaction of 13r with STAT3. Docking simulation showed that 13r could inhibit STAT3 by targeting SH2 domain. This study provided evidence for these compounds to be further developed as antitumor agents through inhibition of the STAT3 pathway. Graphical abstract image
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Synthesis of N-aryl and N-arylcarbamoylamino derivatives of 1,3-diazinane-5-carboxamide and their activity against glioblastoma LN-229 cell line ()
Publication date: 1 December 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 23 Author(s): Rebecca J. Hron, Branko S. Jursic, Donna M. Neumann Six structural motifs based on the initial (lead) structure of merbarone were designed, prepared, and tested against the glioblastoma LN-229 cell line. Three different structural moieties were modified in the search for optimal glioblastoma activity: the 1,3-diazinane moiety, the aryl moiety, and the heteroatom linker. Calculated molecular descriptors such as lipophilicity (C log P), acidic strength (calculated pK a), and polar surface area (PSA) were used to design a diverse structural library of these compounds. From six different structural motifs and 136 compounds, a handful of examples with moderate (100μg/ml), good (10μg/ml) and excellent (1μg/ml) glioblastoma activity were elucidated. Graphical abstract image
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Discovery and preliminary structure–activity relationship of 1H-indazoles with promising indoleamine-2,3-dioxygenase 1 (IDO1) inhibition properties ()
Publication date: 1 December 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 23 Author(s): Shan Qian, Tao He, Wei Wang, Yanying He, Man Zhang, Lingling Yang, Guobo Li, Zhouyu Wang Indoleamine 2,3-dioxygenase 1 (IDO1)-mediated kynurenine pathway of tryptophan degradation is identified as an important immune effector pathway in the tumor cells to escape a potentially effective immune response. IDO1 is an attractive target for anticancer therapy and the discovery of IDO1 inhibitors has been intensely ongoing in both academic research laboratories and pharmaceutical organizations. Our study discovered that 1H-indazole was a novel key pharmacophore with potent IDO1 inhibitory activity. A series of new 1H-indazole derivatives were synthesized and determined the enzyme inhibitory activities, and the compound 2g exhibited the highest activity with an IC50 value of 5.3μM. The structure–activity relationships (SARs) analysis of the 1H-indazole derivatives as novel IDO1 inhibitors indicated that the 1H-indazole scaffold is necessary for IDO1 inhibition, and the substituent groups at the both 4-position and 6-position largely affect inhibitory activity. The docking model exhibited that the effective interactions of 1H-indazoles with ferrous ion of heme and key residues of hydrophobic Pocket A and B ensured the IDO1 inhibitory activities. The study suggested that the 1H-indazole was a novel interesting scaffold for IDO inhibition for further development. Graphical abstract image
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Design, synthesis and biological evaluation of novel non-covalent piperidine-containing peptidyl proteasome inhibitors ()
Publication date: 1 December 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 23 Author(s): Jiankang Zhang, Lixin Gao, Jianjun Xi, Li Sheng, Yanmei Zhao, Lei Xu, Yidan Shao, Shourong Liu, Rangxiao Zhuang, Yubo Zhou, Jia Li A series of novel non-covalent piperidine-containing dipeptidyl derivatives were designed, synthesized and evaluated as proteasome inhibitors. All target compounds were tested for their proteasome chymotrypsin-like inhibitory activities, and selected derivatives were evaluated for the anti-proliferation activities against two multiple myeloma (MM) cell lines RPMI 8226 and MM-1S. Among all of these compounds, eight exhibited significant proteasome inhibitory activities with IC50 less than 20nM, and four are more potent than the positive control Carfilzomib. Compound 28 displayed the most potent proteasome inhibitory activity (IC50: 1.4±0.1nM) and cytotoxicities with IC50 values at 13.9±1.8nM and 9.5±0.5nM against RPMI 8226 and MM-1S, respectively. Additionally, the ex vivo blood cell proteasome inhibitory activities of compounds 24 and 27–29 demonstrated that the enzymatic metabolism in the whole blood could be well tolerated. All these experiments confirmed that the piperidine-containing non-covalent proteasome inhibitors are potential leads for exploring new anti-cancer drugs. Graphical abstract image
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Melanogenesis inhibitory activity of a 7-O-9′-linked neolignan from Alpinia galanga fruit ()
Publication date: 1 December 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 23 Author(s): Yoshiaki Manse, Kiyofumi Ninomiya, Ryosuke Nishi, Iyori Kamei, Yushi Katsuyama, Takahito Imagawa, Saowanee Chaipech, Osamu Muraoka, Toshio Morikawa An aqueous acetone extract from the fruit of Alpinia galanga (Zingiberaceae) demonstrated inhibitory effects on melanogenesis in theophylline-stimulated murine B16 melanoma 4A5 cells (IC50 =7.3μg/mL). Through bioassay-guided separation of the extract, a new 7-O-9′-linked neolignan, named galanganol D diacetate (1), was isolated along with 16 known compounds including 14 phenylpropanoids (2–15). The structure of 1, including its absolute stereochemistry in the C-7 position, was elucidated by means of extensive NMR analysis and total synthesis. Among the isolates, 1 (IC50 =2.5μM), 1′S-1′-acetoxychavicol acetate (2, 5.0μM), and 1′S-1′-acetoxyeugenol acetate (3, 5.6μM) exhibited a relatively potent inhibitory effect without notable cytotoxicity at effective concentrations. The following structural requirements were suggested to enhance the inhibitory activity of phenylpropanoids on melanogenesis: (i) compounds with 4-acetoxy group exhibit higher activity than those with 4-hydroxy group; (ii) 3-methoxy group dose not affect the activity; (iii) acetylation of the 1′-hydroxy moiety enhances the activity; and (iv) phenylpropanoid dimers with the 7-O-9′-linked neolignan skeleton exhibited higher activity than those with the corresponding monomer. Their respective enantiomers [1′ (IC50 =1.9μM) and 2′ (4.5μM)] and racemic mixtures [(±)-1 (2.2μM) and (±)-2 (4.4μM)] were found to exhibit melanogenesis inhibitory activities equivalent to those of the naturally occurring optical active compounds (1 and 2). Furthermore, the active compounds 1–3 inhibited tyrosinase, tyrosine-related protein (TRP)-1, and TRP-2 mRNA expressions, which could be the mechanism of melanogenesis inhibitory activity. Graphical abstract image
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Design, Synthesis and Pharmacological Evaluation of 4-Hydroxyphenylglycine and 4-Hydroxyphenylglycinol Derivatives as GPR88 Agonists ()
Publication date: Available online 1 December 2016 Source:Bioorganic & Medicinal Chemistry Author(s): Chunyang Jin, Ann M. Decker, Tiffany L. Langston The orphan receptor GPR88 is an attractive therapeutic target because of its implications in a number of basal ganglia-associated disorders. To date, pharmacological characterization of GPR88 has been limited due to the lack of potent and selective agonists and antagonists appropriate for CNS investigations. We have previously reported that GPR88 couples to Gαi proteins and modulates cAMP levels upon treatment with a small molecule agonist 2-PCCA. Recently, another chemotype of GPR88 agonist, represented by 2-AMPP [(2S)-N-((1R)-2-amino-1-(4-(2-methylpentyloxy)-phenyl)ethyl)-2-phenylpropanamide], has also been discovered. In this report, a new series of 2-AMPP structurally related 4-hydroxyphenylglycine and 4-hydroxyphenylglycinol derivatives have been designed and evaluated for agonist activity at GPR88. The structure-activity relationship (SAR) studies suggest that the amine group in 2-AMPP can be replaced by hydroxyl, ester and amide groups, resulting in analogues with good to moderate potency, whereas the phenyl group on the amide cap is essential for activity and has limited size, shape and electronic tolerance. Graphical abstract image
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Towards the development of activity-based probes for detection of Lysine-Specific Demethylase-1 activity ()
Publication date: Available online 1 December 2016 Source:Bioorganic & Medicinal Chemistry Author(s): Maria E. Ourailidou, Alessia Lenoci, Clemens Zwergel, Dante Rotili, Antonello Mai, Frank J. Dekker The implications of Lysine-Specific Demethylase-1 (LSD1) in tumorigenesis have urged scientists to develop diagnostic tools in order to explore the function of this enzyme. In this work, we present our efforts on the development of tranylcypromine (TCP)-based functionalized probes for activity-based protein profiling (ABPP) of LSD1 activity. Biotinylated forms of selected compounds enabled dose-dependent enzyme labeling of recombinant LSD1. However, treatment with LSD1 inhibitors did not clearly reduce the LSD1 labeling efficiency thus indicating that labelling using these probes in not activity dependent. This calls for alternative strategies to develop probes for ABPP of the enzyme LSD1. Graphical abstract image
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α-Pyrone derivatives, tetra/hexahydroxanthones, and cyclodepsipeptides from two freshwater fungi ()
Publication date: Available online 1 December 2016 Source:Bioorganic & Medicinal Chemistry Author(s): Tamam El-Elimat, Huzefa A. Raja, Cynthia S. Day, Hana McFeeters, Robert L. McFeeters, Nicholas H. Oberlies Eighteen (1–18) and seven (1, 4, 6–8, 17 and 18) compounds were isolated from organic extracts of axenic cultures of two freshwater fungi Clohesyomyces sp. and Clohesyomyces aquaticus (Dothideomycetes, Ascomycota), respectively. Compounds 1–12 belong to the α-pyrone class of natural products, compounds 13 and 14 were tetrahydroxanthones, compounds 15 and 16 were hexahydroxanthones, while compounds 17 and 18 were cyclodepsipeptides. The structures were elucidated using a set of spectroscopic and spectrometric techniques. The absolute configurations of compounds 2, 3, 6, and 7 were assigned via a modified Mosher’s ester method using 1H NMR data. The relative configurations of compounds 14–16 were determined through NOE data. Compounds 1, 2, 6, 8, 13, 14, and 15 were found to inhibit the essential enzyme bacterial peptidyl-tRNA hydrolase (Pth1), with (13; secalonic acid A) being the most potent. Compounds 1 and 4–18 were also evaluated for antimicrobial activity against an array of bacteria and fungi but were found to be inactive. Graphical abstract image
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Small molecule mimics of DFTamP1, a database designed anti-Staphylococcal peptide ()
Publication date: Available online 30 November 2016 Source:Bioorganic & Medicinal Chemistry Author(s): Yuxiang Dong, Tamara Lushnikova, Radha M. Golla, Xiaofang Wang, Guangshun Wang Antimicrobial peptides (AMPs) are important templates for developing new antimicrobial agents. Previously, we developed a database filtering technology that enabled us to design a potent anti-Staphylococcal peptide DFTamP1. Using this same design approach, we now report the discovery of a new class of bis-indole diimidazolines as AMP small molecule mimics. The best compound killed multiple S. aureus clinical strains in both planktonic and biofilm forms. The compound appeared to target bacterial membranes with antimicrobial activity and membrane permeation ability similar to daptomycin. Graphical abstract image
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Synthesis and characterization of novel, conjugated, fluorescent DNJ derivatives for α-glucosidase recognition ()
Publication date: Available online 30 November 2016 Source:Bioorganic & Medicinal Chemistry Author(s): Akihiko Hatano, Yuichi Kanno, Yuya Kondo, Yuta Sunaga, Hatsumi Umezawa, Munehiro Okada, Hideshi Yamada, Ren Iwaki, Atsushi Kato, Koji Fukui A series of five new fluorescent deoxynojirimycin (DNJ) conjugates were synthesized and evaluated for their inhibitory effect (IC50) on several α- and β-glucosidases. Three of the conjugates showed enhanced activity. The two synthetic conjugates, DNJ-CF3 1 and DNJ-Me 2, exhibited improved α-glucosidase inhibitory effects compared to DNJ and miglitol. Interestingly, conjugates 1 and 2 showed strong inhibition of almond-derived β-glucosidase, in contrast to the inhibition tendencies of other inhibitors. Conjugate 5 strongly inhibited rat intestinal maltase, even at 0.10 μM. A docking study indicated that all five conjugates bind to the active site of α-glucosidase (PDB: 3L4V, derived from homo sapiens). The DNJ portion of the conjugate fits into the cavity of the enzyme, and the fluorescent part locates randomly on the outside surface. Thus, it is likely that these conjugates can specifically recognize intestinal cells, specifically the α-glucosidase on cell membranes. Graphical abstract image
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Synthesis and biological evaluation of phosphate isosters of fosmidomycin and analogs as inhibitors of Escherichia coli and Mycobacterium smegmatis 1-deoxyxylulose 5-phosphate reductoisomerases ()
Publication date: Available online 30 November 2016 Source:Bioorganic & Medicinal Chemistry Author(s): Mathilde Munier, Denis Tritsch, Fanny Krebs, Jérémy Esque, Andréa Hemmerlin, Michel Rohmer, Roland H. Stote, Catherine Grosdemange-Billiard Hydroxamate analogs of fosfoxacin, the phosphate homolog of fosmidomycin, have been synthesized and their activitytested on Escherichia coli and Mycobacterium smegmatis DXRs. Except for compound 4b, the IC50 values of phosphate derivatives are approximately 10 fold higher than those of the corresponding phosphonates. Although their inhibitory activity on Escherichia coli DXR is less efficient than their phosphonate analogs, we report the ability of phosphate compounds to inhibit the growth of Escherichia coli. This work points out that the uptake of fosfoxacin and its analogues is taking place via the GlpT and UhpT transporters. As expected, these compounds are inefficient to inhibit the growth of M. smegmatis growth inhibition probably due to a lack of uptake. Graphical abstract image
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Synthesis and immunological evaluation of a low molecular weight saccharide with TLR-4 agonist activity ()
Publication date: Available online 30 November 2016 Source:Bioorganic & Medicinal Chemistry Author(s): Vikram Basava, Heather Romlein, Constantine Bitsaktsis, Cecilia H. Marzabadi The paucity of FDA approved adjuvants renders the synthesis, characterization, and use of new compounds as vaccine adjuvants, a necessity. For this purpose, a novel saccharide analog has been synthesized from glucosamine, pyruvylated galactose and 1,4-cyclohexanediol and its biological efficacy was determined in innate immune cells. More specifically, we assessed the production of pro-inflammatory cytokines from the murine monocyte cell line, Raw 264.7 and from C57 BL/6 mouse peritoneal macrophages following exposure to the saccharide analog. Our data conclude that the novel saccharide has immunostimulatory activity on mouse macrophages as indicated by the elevated levels of IL-6 and TNF-α in culture supernatants. This effect was TLR-4-dependent but TLR-2-independent. Our data, suggest TLR-4 agonism; a key feature of vaccine adjuvants. Graphical abstract image
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Synthesis of novel C4-benzazole naphthalimide derivatives with potent anti-tumor properties against murine melanoma ()
Publication date: Available online 30 November 2016 Source:Bioorganic & Medicinal Chemistry Author(s): Yen-Ta Lu, Tien-Ling Chen, Kuo-Song Chang, Chia-Ming Chang, Tsai-Yin Wei, Jen-Wei Liu, Chih-Ang Hsiao, Tzenge-Lien Shih Novel C4-benzazole naphthalimide derivatives were synthesized and tested in vitro and in vivo as anti-cancer drugs. Among these synthetic molecules, compounds 9 and 10 exhibited cytotoxicity against murine B16F10 melanoma cells. In addition, the above-mentioned compounds significantly suppressed lung tumor metastasis with no visible sign of toxicity. Graphical abstract image
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Synthesis and optimization of novel α-phenylglycinamides as selective TRPM8 antagonists ()
Publication date: Available online 30 November 2016 Source:Bioorganic & Medicinal Chemistry Author(s): Jun-ichi Kobayashi, Hideaki Hirasawa, Tetsuji Ozawa, Tomonaga Ozawa, Hiroo Takeda, Yoshikazu Fujimori, Osamu Nakanishi, Noboru Kamada, Tetsuya Ikeda Transient receptor potential melastatin 8 (TRPM8) is activated by innocuous cold and chemical substances, and antagonists of this channel have been considered to be effective for pain and urinary diseases. N-(3-aminopropyl)-2-{[(3-methylphenyl)methyl]oxy}-N-(2-thienylmethyl)benzamide hydrochloride (AMTB), a TRPM8 antagonist, was proposed to be effective for overactive bladder and painful bladder syndrome; however, there is a potential risk of low blood pressure. We report herein the synthesis and structure–activity relationships of novel phenylglycine derivatives that led to the identification of KPR-2579 (20l), a TRPM8 selective antagonist. KPR-2579 reduced the number of icilin-induced wet-dog shakes and rhythmic bladder contraction in rats, with no negative cardiovascular effects at the effective dose. Graphical abstract image
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Effects of new fluorinated analogues of GABA, pregabalin bioisosters, on the ambient level and exocytotic release of [3H]GABA from rat brain nerve terminals ()
Publication date: Available online 30 November 2016 Source:Bioorganic & Medicinal Chemistry Author(s): T. Borisova, N. Pozdnyakova, E. Shaitanova, I. Gerus, M. Dudarenko, G. Haufe, V. Kukhar Recently, we have shown that new fluorinated analogues of γ-aminobutyric acid (GABA), bioisosters of pregabalin (β-i-Bu-GABA), i.e. β-polyfluoroalkyl-GABAs (FGABAs), with substituents: β-CF3-β-OH (1), β-CF3 (2); β-CF2CF2H (3), are able to increase the initial rate of [3H]GABA uptake by isolated rat brain nerve terminals (synaptosomes), and this effect is higher than that of pregabalin. So, synthesized FGABAs are structural but not functional analogues of GABA. Herein, we assessed the effects of synthesized FGABAs (100 μM) on the ambient level and exocytotic release of [3H]GABA in nerve terminals and compared with those of pregabalin (100 μM). It was shown that FGABAs 1-3 did not influence the ambient level of [3H]GABA in the synaptosomal preparations, and this parameter was also not altered by pregabalin. During blockage of GABA transporters GAT1 by specific inhibitor NO-711, FGABAs and pregabalin also did not change ambient [3H]GABA in synaptosomal preparations. Exocytotic release of [3H]GABA from synaptosomes decreased in the presence of FGABAs 1-3 and pregabalin, and the effects of FGABAs 1 & 3 were more significant than those of FGABAs 2 and pregabalin. FGABAs 1-3/pregabalin-induced decrease in exocytotic release of [3H]GABA from synaptosomes was not a result of changes in the potential of the plasma membrane. Therefore, new synthesized FGABAs 1 & 3 were able to decrease exocytotic release of [3H]GABA from nerve terminals more effectively in comparison to pregabalin. Absence of unspecific side effects of FGABAs 1 & 3 on the membrane potential makes these compounds perspective for medical application. Graphical abstract image
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Structure-activity relationship of the inhibitory effects of flavonoids on nitric oxide production in RAW264.7 cells ()
Publication date: Available online 29 November 2016 Source:Bioorganic & Medicinal Chemistry Author(s): Wen-Jun Jiang, Akihiro Daikonya, Mitsuyoshi Ohkawara, Takashi Nemoto, Ryusuke Noritake, Tomoko Takamiya, Susumu Kitanaka, Hiroshi Iijima We isolated flavonoids from herbal specimens from the Tibetan region (Sophora yunnanensis and Rhodiola sacra) that suppress nitric oxide (NO) production in macrophages stimulated by lipopolysaccharide and interferon-γ. The isolated flavonoids carry symmetric substitutions in the B ring (R3’ = R5’). We analyzed the quantitative structure-activity relationship of the inhibitory activity by comparative molecular field analysis (CoMFA) using this series of flavonoids. Use of flavonoids with symmetrical substitutions in the B ring made it simpler to align molecules because it was not necessary to consider a huge number of combinations due to the B-ring conformation. The CoMFA model, whose cross-validated q 2 value was 0.705, suggested the existence of a hydroxy group at the 5-position, the choice of the A/C-ring scaffold (chromane or chromene) and electrostatic field around the B ring are important for NO inhibitory activity. Flavonoids synthesized based on the CoMFA model exhibited significant inhibitory potential against NO production, validating the predictive capability of the CoMFA model. Graphical abstract image
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3-Amino-thieno[2,3-b]pyridines as microtubule-destabilising agents: Molecular modelling and biological evaluation in the sea urchin embryo and human cancer cells ()
Publication date: Available online 29 November 2016 Source:Bioorganic & Medicinal Chemistry Author(s): Chatchakorn Eurtivong, Victor Semenov, Marina Semenova, Leonid Konyushkin, Olga Atamanenko, Jóhannes Reynisson, Alex Kiselyov A series of 3-amino-thieno[2,3-b]pyridines was prepared and tested in a phenotypic sea urchin embryo assay to identify potent and specific molecules that affect tubulin dynamics. The most active compounds featured a tricyclic core ring system with a fused cycloheptyl or cyclohexyl substituent and unsubstituted or alkyl-substituted phenyl moiety tethered via a carboxamide. Low nano-molar potency was observed in the sea urchin embryos for the most active compounds (1–5) suggestive of a microtubule-destabilising effect. The molecular modelling studies indicated that the tubulin colchicine site is inhibited, which often leads to microtubule-destabilisation in line with the sea urchin embryo results. Finally, the identified hits displayed a robust growth inhibition (GI50 of 50–250 nM) of multidrug-resistant melanoma MDA-MB-435 and breast MDA-MB-468 human cancer cell lines. This work demonstrates that for the thieno[2,3-b]pyridines the most effective mechanism of action is microtubule-destabilisation initiated by binding to the colchicine pocket. Graphical abstract image
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Design and Synthesis of Phosphoryl-substituted Diphenylpyrimidines (Pho-DPPYs) as Potent Bruton’s Tyrosine Kinase (BTK) Inhibitors: Targeted Treatment of B Lymphoblastic Leukemia Cell Lines ()
Publication date: Available online 29 November 2016 Source:Bioorganic & Medicinal Chemistry Author(s): Yang Ge, Haijun Yang, Changyuan Wang, Qiang Meng, Lei Li, Huijun Sun, Yuhong Zhen, Kexin Liu, Yanxia Li, Xiaodong Ma A family of phosphoryl-substituted diphenylpyrimidine derivatives (Pho-DPPYs) were synthesized and biologically evaluated as potent BTK inhibitors in this study. Compound 7b was found to markedly inhibit BTK activity at concentrations of 0.82 nmol/L, as well as to suppress the proliferations of B-cell leukemia cell lines (Ramos and Raji) expressing high levels of BTK at concentrations of 3.17 μM and 6.69 μM. Moreover, flow cytometry analysis results further indicated that 7b promoted cell apoptosis to a substantial degree. In a word, compound 7b is a promising BTK inhibitor for the treatment of B-cell lymphoblastic leukemia. Graphical abstract image
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Coumarins and other fused bicyclic heterocycles with selective tumor-associated carbonic anhydrase isoforms inhibitory activity ()
Publication date: Available online 29 November 2016 Source:Bioorganic & Medicinal Chemistry Author(s): Murat Bozdag, Ahmed Mahmoud Alafeefy, Abdul Malik Altamimi, Daniela Vullo, Fabrizio Carta, Claudiu T. Supuran Herein we report for the first time a series of 2-benzamido-N-(2-oxo-4-(methyl/trifluoromethyl)-2H-chromen-7-yl) benzamide 3a-f and substituted quinazolin-4(3H)-ones and 2H-benzo[e][1,2,4]thiadiazin-3(4H)-one 1,1-dioxides (5, 6, 8 and 10a-c) as selective inhibitors of the tumor associated hCA IX and XII isoforms. Among the compounds reported the trifluoromethyl derivative 3d resulted the most potent against these CA isoforms with KIs of 10.9 and 6.7 nM. Graphical abstract image
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Discovery of biphenyl imidazole derivatives as potent antifungal agents: Design, synthesis, and structure-activity relationship studies ()
Publication date: Available online 28 November 2016 Source:Bioorganic & Medicinal Chemistry Author(s): Dongmei Zhao, Shizhen Zhao, Liyu Zhao, Xiangqian Zhang, Peng Wei, Chunchi Liu, Chenzhou Hao, Bin Sun, Xin Su, Maosheng Cheng Fungal infections have became a serious medical problem due to their high incidence and mortality. We describe the discovery and structure-activity relationships studies (SARs) of a series of novel biphenyl imidazole derivatives with excellent antifungal activities against Candida albicans and Cryptococcus neoformans. The most promising compounds 12f-g and 19a-b exhibited excellent activity with minimum inhibitory concentration (MIC) values in the range of 0.03125 to 2 μg/mL. Preliminary mechanism studies showed that the potent antifungal activity of compound 12g stemed from inhibition of CYP51 in Candida albicans. Furthermore, compounds 12g and 19b exhibited low inhibition profiles for various human cytochrome P450 isoforms. The SARs and binding mode established in this study will be useful for further lead optimization. Graphical abstract image
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Multitarget drug design strategy against Alzheimer’s disease: Homoisoflavonoid Mannich base derivatives serve as acetylcholinesterase and monoamine oxidase B dual inhibitors with multifunctional properties ()
Publication date: Available online 28 November 2016 Source:Bioorganic & Medicinal Chemistry Author(s): Yan Li, Xiaoming Qiang, Li Luo, Xia Yang, Ganyuan Xiao, Yunxiaozhu Zheng, Zhongcheng Cao, Zhipei Sang, Fu Su, Yong Deng A series of homoisoflavonoid Mannich base derivatives were designed, synthesized and evaluated as multifunctional agents against Alzheimer’s disease. It demonstrated that most of the derivatives were selective AChE and MAO-B dual inhibitors with good multifunctional properties. Among them, compound 10d displayed the comprehensive advantages, with excellent AChE and MAO-B inhibitory activities (IC50 = 2.49 ± 0.08 nM and 1.74 ± 0.0581 μM, respectively), good self- and Cu2+-induced Aβ 1-42 aggregation inhibitory potency, antioxidant activity, biometal chelating ability and high BBB permeability. These multifunctional properties make 10d as an excellent candidate for the development of efficient drugs against AD. Graphical abstract image
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Coating lanthanide nanoparticles with carbohydrate ligands elicits affinity for HeLa and RAW264.7 cells, enhancing their photodamaging effect ()
Publication date: Available online 28 November 2016 Source:Bioorganic & Medicinal Chemistry Author(s): Takashi Kanamori, Takashi Sawamura, Tatsumi Tanaka, Izumi Sotokawa, Ryota Mori, Kotaro Inada, Akihiro Ohkubo, Shun-Ichiro Ogura, Yasutoshi Murayama, Eigo Otsuji, Hideya Yuasa Lanthanide nanoparticles (LNPs) conjugated with monosaccharides were synthesized as a photon energy-upconverting nanodevice with affinity to cancer cells. The conjugates were designed to selectively damage the cancer cells containing protoporphyrin IX, a photosensitizer endogenously synthesized from priorly administrated 5-aminolevlunic acid (ALA), by a highly tissue-penetrative near-infrared (NIR) irradiation. First of all, the affinities of monosaccharides toward cells (HeLa, RAW264.7, and MKN45) were assessed by a novel cell aggregation assay with trivalent monosaccharide-citric acid conjugates. As a result, HeLa exhibited high affinity for glucose, while RAW264.7 for glucose, galactose, mannose, and fucose. A similar cell-monosaccharide affinity was microscopically observed when the cells were mixed with monosaccharide-LNP conjugates and rinsed, in which the high affinity LNP probes luminesced on the cells. The high affinity monosaccharide-LNPs showed greater photodamaging effects than the unmodified LNP toward the corresponding cells, when the cells were pretreated with ALA and irradiated by NIR. This study demonstrates that carbohydrates can be used as selective ligands for cancer cells in a photodynamic therapy with LNP. Graphical abstract image
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An in-tether sulfoxide chiral center influences the biophysical properties of the N-capped peptides ()
Publication date: Available online 25 November 2016 Source:Bioorganic & Medicinal Chemistry Author(s): Jingxu Li, Yuan Tian, Dongyuan Wang, Yujie Wu, Xiyang Ye, Zigang Li Thanks to their large binding interfaces, peptides are attractive ligands targeting protein-protein interactions compared with small molecules. Various strategies to improve peptides’ pharmaceutical properties have been developed to constrain peptides into their functional three-dimensional structures. In our previous work, we reported that an in-tether chiral center could modulate peptides’ biophysical properties. Herein, we applied this concept to construct a chiral sulfoxide center into the N-terminal end-cap system. We proved that this in-tether sulfoxide chiral center influences the structure of this N-capped template. In addition, longer peptides targeting estrogen receptor were also synthesized and we revealed that this chiral center could also modulate binding affinity to estrogen receptor alpha with enhanced protease resistance. Graphical abstract image
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5-Substituted-benzylsulfanyl-thiophene-2-sulfonamides with effective carbonic anhydrase inhibitory activity: Solution and crystallographic investigations ()
Publication date: Available online 25 November 2016 Source:Bioorganic & Medicinal Chemistry Author(s): Jekaterīna Ivanova, Agnese Balode, Raivis Žalubovskis, Janis Leitans, Andris Kazaks, Daniela Vullo, Kaspars Tars, Claudiu T. Supuran A series of 5-substituted-benzylsulfanyl-thiophene-2-sulfonamides was prepared by reacting 5-bromo-thiophene-2-sulfonamide with 5-substituted-benzyl mercaptans. The new compounds were investigated as carbonic anhydrase (CA, EC 4.2.1.1) inhibitors. The cytosolic human (h) isoforms hCA I was poorly inhibited by the new sulfonamides (KIs in the range of 683-4250 nM), whereas hCA II, and the transmembrane, tumor associated isoforms hCA IX and XII were effectively inhibited in the subnanomolar – nanomolar range. A high resolution X-ray crystal structure of the adduct of hCA II with one of the new sulfonamides allowed us to rationalize the excellent inhibitory activity of these heterocyclic sulfonamides. Graphical abstract image
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Cellular uptake of glucoheptoamidated poly(amidoamine) PAMAM G3 dendrimer with amide-conjugated biotin, a potential carrier of anticancer drugs ()
Publication date: Available online 25 November 2016 Source:Bioorganic & Medicinal Chemistry Author(s): Łukasz Uram, Magdalena Szuster, Aleksandra Filipowicz, Magdalena Zaręba, Elżbieta Wałajtys-Rode, Stanisław Wołowiec In search for soluble derivatives of PAMAM dendrimers as potential carriers for hydrophobic drugs, the conjugates of PAMAM G3 with biotin, further converted into glycodendrimer with d-glucoheptono-1,4-lactone, were prepared. Polyamidoamine dendrimer (PAMAM) of third generation, G3 was functionalized with four biotin equivalents covalently attached to terminal amine nitrogens via amide bond G34B. The remaining 28 amine groups were blocked by glucoheptoamide substituents (gh) to give G34B28gh or with one fluorescein equivalent (attached by reaction of G34B with fluorescein isothiocyanate, FITC) via thiourea bond as FITC followed by exhaustive glucoheptoamidation to get G34B27gh1F. As a control the G3 substituted totally with 32 glucoheptoamide residues, G3gh and its fluorescein labeled analogue G331gh1F were synthesized. The glucoheptoamidation of PAMAM G0 dendrimer with glucoheptono-1,4-lactone was performed in order to fully characterize the 1H NMR spectra of glucoheptoamidated PAMAM dendrimers and to control the derivatization of G3 with glucoheptono-1,4-lactone. Another two derivatives of G3, namely G34B28gh1F′ and G332ghF′, with ester bonded fluorescein were also obtained. Biological properties of obtained dendrimer conjugates were estimated in vitro with human cell lines: normal fibroblast (BJ) and two cancer glioblastoma (U-118 MG) and squamous carcinoma (SCC-15), including cytotoxicity by reduction of XTT and neutral red (NR) assays. Cellular uptake of dendrimer conjugates was evaluated with confocal microscopy. Obtained results confirmed, that biotinylated bioconjugates have always lower cytotoxicity and 3–4 times higher cellular uptake than non-biotinylated dendrimer conjugates in all cell lines. Comparison of various cell lines revealed different dose-dependent cell responses and the lower cytotoxicity of examined dendrimer conjugates for normal fibroblasts and squamous carcinoma, as compared with much higher cytotoxic effects seen in glioblastoma cell line. Synthetized multi-functional conjugate (G34B27gh1F) is a promising candidate as biocompatible vehicle for hydrophobic molecules used in anticancer therapy. Graphical abstract image
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Synthesis and evaluation of a 68Ga-labeled bradykinin B1 receptor agonist for imaging with positron emission tomography ()
Publication date: Available online 23 November 2016 Source:Bioorganic & Medicinal Chemistry Author(s): Guillaume Amouroux, Zhengxing Zhang, Jinhe Pan, Silvia Jenni, Chengcheng Zhang, Navjit Hundal-Jabal, Nadine Colpo, Jutta Zeisler, Kuo-Shyan Lin, François Bénard A novel 68Ga-labeled bradykinin B1 receptor (B1R) agonist, 68Ga-Z01115, was synthesized and evaluated for imaging with positron emission tomography (PET). Z01115 exhibited good binding affinity (Ki =25.4±5.1nM) to hB1R. 68Ga-Z01115 was prepared in 74±5 decay-corrected radiochemical yield with >99% radiochemical purity and 155±89GBq/µmol (4.2±2.4Ci/μmol) specific activity. 68Ga-Z01115 was stable in vitro in mouse plasma (93% remaining intact after 60min incubation), and relatively stable in vivo (51±5% remaining intact at 5min post-injection). PET imaging and biodistribution studies in mice showed that 68Ga-Z01115 cleared rapidly from nontarget tissues/organs, and generated high target-to-nontarget contrast images. The uptake of 68Ga-Z01115 in B1R-positive (B1R+) tumor was 5.65±0.59%ID/g at 1h post-injection. Average contrast ratios of B1R+ tumor-to-B1R− tumor, -to-blood and -to-muscle were 24.3, 24.4 and 82.9, respectively. Uptake of 68Ga-Z01115 in B1R+ tumors was reduced by ∼90% with co-injection of cold standard, confirming it was mediated by B1R. Our data suggest that 68Ga-Z01115 is a promising tracer for imaging the expression of B1R that is overexpressed in a variety of cancers. Graphical abstract image
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Design, synthesis and analgesic/anti-inflammatory evaluation of novel diarylthiazole and diarylimidazole derivatives towards selective COX-1 inhibitors with better gastric profile ()
Publication date: Available online 23 November 2016 Source:Bioorganic & Medicinal Chemistry Author(s): Ahmed H. Abdelazeem, Mohammed T. El-Saadi, Asmaa G. Safi El-Din, Hany A. Omar, Samir M. El-Moghazy The inhibition of gastric cyclooxygenase 1 (COX-1) enzyme was believed to be the major cause of non-steroidal anti-inflammatory drugs (NSAIDs)-induced gastric ulcer. Recent studies disproved this belief and showed that the gastric tissues vulnerability is not solely connected to COX-1 inhibition. This work aimed at exploring and rationalizing the differential analgesic and anti-inflammatory activities of novel selective COX-1 inhibitors with improved gastric profile. Two novel series of 4,5-diarylthiazole and diarylimidazole were designed, synthesized in analogy to selective COX-1 inhibitors (mofezolac and FR122047) which lack gastric damaging effects. The new compounds were evaluated in vitro for their COXs inhibitory activity and in vivo for their anti-inflammatory and analgesic potentials. Four compounds; diphenylthiazole glycine derivatives (15a, 15b) and diphenylimidazolo acetic acid derivatives (19a, 19b), which possess carboxylic acid group exhibited significant activity and selectivity against COX-1 over COX-2. Of these compounds, (4,5-bis(4-methoxyphenyl)thiazol-2-yl)glycine 15b was the most potent compound against COX-1 with an inhibitory half maximal concentration (IC50) of 0.32μM and a selectivity index (COX-2 IC50/COX-1 IC50) of 28.84. Furthermore, an ulcerogenicity study was performed where the tested compounds demonstrated a significant gastric tolerance. Interestingly, the most selective COX-1 inhibitor showed higher analgesic activity in vivo as expected compared to their moderate anti-inflammatory activity. This study underscores the need for further design and development of novel analgesic agents with low tendency to cause gastric damage based on improving their COX-1 affinity and selectivity profile. Graphical abstract image
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Influence of Chain Length on the Activity of Tripeptidomimetic Antagonists for CXC Chemokine Receptor 4 (CXCR4) ()
Publication date: Available online 21 November 2016 Source:Bioorganic & Medicinal Chemistry Author(s): Markus Baumann, Mohammad Musarraf Hussain, Nina Henne, Daniel Moya Garrote, Stefanie Karlshøj, Torgils Fossen, Mette M. Rosenkilde, Jon Våbenø, Bengt Erik Haug Here we report a series of close analogues of our recently published scaffold-based tripeptidomimetic CXCR4 antagonists, containing positively charged guanidino groups in R1 and R2, and an aromatic group in R3. While contraction/elongation of the guanidine carrying side chains (R1 and R2) resulted in loss of activity, introduction of bromine in position 1 on the naphth-2-ylmethyl moiety (R3) resulted in an EC50 of 61 μM (mixture of diastereoisomers) against wild-type CXCR4; thus, the antagonistic activity of these tripeptidomimetics seems to be amenable to optimization of the aromatic moiety. Moreover, for analogues carrying a naphth-2-ylmethyl substituent, we observed that a Pictet-Spengler like cyclization side reaction depended on the nature of the R1 substituent. Graphical abstract image
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Discovery of 4-sulfamoyl-phenyl-β-lactams as a new class of potent carbonic anhydrase isoforms I, II, IV and VII inhibitors: the first example of subnanomolar CA IV inhibitors ()
Publication date: Available online 19 November 2016 Source:Bioorganic & Medicinal Chemistry Author(s): Srinivas Angapelly, P.V. Sri Ramya, Andrea Angeli, Simona Maria Monti, Martina Buonanno, Mallika Alvala, Cladiu T. Supuran, Mohammed Arifuddin A series of benzenesulfonamides incorporating 1,3,4-trisubstituted-β-lactam moieties was prepared from sulfanilamide Schiff bases and in situ obtained ketenes, by using the Staudinger cycloaddition reaction. The new compounds were assayed as inhibitors of four human isoforms of the metalloenzyme carbonic anhydrase (hCA, EC 4.2.1.1) involved in various physiological/pathological conditions, hCA I, II, IV and VII. Excellent inhibitory activity was observed against all these isoforms, as follows: hCA I, involved in some eye diseases was inhibited with KIs in the range of 7.3 – 917 nM; hCA II, an antiglaucoma drug target, with KIs in the range of 0.76 – 163 nM. hCA IV, an isoform involved in several pathological conditions such as glaucoma, retinitis pigmentosa and edema was potently inhibited by the lactam-sulfonamides, with KIs in the range of 0.53 – 51.0 nM, whereas hCA VII, a recently validated anti-neuropathic pain target was the most inhibited isoform by these derivatives, with KIs in the range of 0.68 – 9.1 nM. The structure-activity relationship for inhibiting these CAs with the new lactam-sulfonamides is discussed in detail Graphical abstract image
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Cyclic citrullinated MBP87–99 peptide stimulates T cell responses: Implications in triggering disease ()
Publication date: Available online 19 November 2016 Source:Bioorganic & Medicinal Chemistry Author(s): Vasso Apostolopoulos, George Deraos, Minos-Timotheos Matsoukas, Stephanie Day, Lily Stojanovska, Theodore Tselios, Maria-Eleni Androutsou, John Matsoukas Amino acid mutations to agonist peptide epitopes of myelin proteins have been used to modulate immune responses and experimental autoimmune encephalomyelitis (EAE, animal model of multiple sclerosis). Such amino acid alteration are termed, altered peptide ligands (APL). We have shown that the agonist myelin basic protein (MBP) 87–99 epitope (MBP87–99) with crucial T cell receptor (TCR) substitutions at positions 91 and 96 (K91,P96 (TCR contact residues) to R91,A96; [R91,A96]MBP87–99) results in altered T cell responses and inhibits EAE symptoms. In this study, the role of citrullination of arginines in [R91,A96]MBP87–99 peptide analog was determined using in vivo experiments in combination with computational studies. The immunogenicity of linear [Cit91,A96,Cit97]MBP87–99 and its cyclic analog – cyclo(87–99)[Cit91,A96,Cit97]MBP87–99 when conjugated to the carrier mannan (polysaccharide) were studied in SJL/J mice. It was found that mannosylated cyclo(87–99)[Cit91,A96,Cit97]MBP87–99 peptide induced strong T cell proliferative responses and IFN-gamma cytokine secretion compared with the linear one. Moreover, the interaction of linear and cyclic peptide analogs with the major histocompatibility complex (MHC II, H2-IAs) and TCR was analyzed using molecular dynamics simulations at the receptor level, in order to gain a better understanding of the molecular recognition mechanisms that underly the different immunological profiles of citrullinated peptides compared to its agonist native counterpart MBP87–99 epitope. The results demonstrate that the citrullination of arginine in combination with the backbone conformation of mutated linear and cyclic analogs are significant elements for the immune response triggering the induction of pro-inflammatory cytokines. Graphical abstract image
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Enhanced potency of bivalent small molecule gp41 inhibitors ()
Publication date: Available online 19 November 2016 Source:Bioorganic & Medicinal Chemistry Author(s): Vladimir Sofiyev, Hardeep Kaur, Beth A. Snyder, Priscilla A. Hogan, Roger G. Ptak, Peter Hwang, Miriam Gochin Low molecular weight peptidomimetic inhibitors with hydrophobic pocket binding properties and moderate fusion inhibitory activity against HIV-1 gp41-mediated cell fusion were elaborated by increasing the available surface area for interacting with the heptad repeat-1 (HR1) coiled coil on gp41. Two types of modifications were tested: 1) increasing the overall hydrophobicity of the molecules with an extension that could interact in the HR1 groove, and 2) forming symmetrical dimers with two peptidomimetic motifs that could potentially interact simultaneously in two hydrophobic pockets on the HR1 trimer. The latter approach was more successful, yielding 40–60times improved potency against HIV fusion over the monomers. Biophysical characterization, including equilibrium binding studies by fluorescence and kinetic analysis by Surface Plasmon Resonance, revealed that inhibitor potency was better correlated to off-rates than to binding affinity. Binding and kinetic data could be fit to a model of bidentate interaction of dimers with the HR1 trimer as an explanation for the slow off-rate, albeit with minimal cooperativity due to the highly flexible ligand structures. The strong cooperativity observed in fusion inhibitory activity of the dimers implied accentuated potency due to the transient nature of the targeted intermediate. Optimization of monomer, dimer or higher order structures has the potential to lead to highly potent non-peptide fusion inhibitors by targeting multiple hydrophobic pockets. Graphical abstract image
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Synthesis, antioxidant and antichagasic properties of a selected series of hydroxy-3-arylcoumarins ()
Publication date: Available online 19 November 2016 Source:Bioorganic & Medicinal Chemistry Author(s): Natalia Robledo-O’Ryan, Maria João Matos, Saleta Vazquez-Rodriguez, Lourdes Santana, Eugenio Uriarte, Mauricio Moncada-Basualto, Francisco Mura, Michel Lapier, Juan Diego Maya, Claudio Olea-Azar Oxidative stress is involved in several parasitic diseases such as Chagas. Agents able to selectively modulate biochemical processes involved in the disease represent promising multifunctional agents for the delay or abolishment of the progression of this pathology. In the current work, differently substituted hydroxy-3-arylcoumarins are described, exerting both antioxidant and trypanocidal activity. Among the compounds synthesized, compound 8 showed the most interesting profile, presenting a moderate scavenging ability for peroxyl radicals (ORAC-FL=2.23) and a high degree of selectivity towards epimastigotes stage of the parasite T. cruzi (IC50 =1.31μM), higher than Nifurtimox (drug currently used for treatment of Chagas disease). Interestingly, the current study revealed that small structural changes in the hydroxy-3-arylcoumarin core allow modulating both activities, suggesting that this scaffold has desirable properties for the development of promising classes of antichagasic compounds. Graphical abstract image
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N-Propargylpiperidines with naphthalene-2-carboxamide or naphthalene-2-sulfonamide moieties: Potential multifunctional anti-Alzheimer’s agents ()
Publication date: Available online 19 November 2016 Source:Bioorganic & Medicinal Chemistry Author(s): Urban Košak, Damijan Knez, Nicolas Coquelle, Boris Brus, Anja Pišlar, Florian Nachon, Xavier Brazzolotto, Janko Kos, Jacques-Philippe Colletier, Stanislav Gobec In the brains of patients with Alzheimer’s disease, the enzymatic activities of butyrylcholinesterase (BChE) and monoamine oxidase B (MAO-B) are increased. While BChE is a viable therapeutic target for alleviation of symptoms caused by cholinergic hypofunction, MAO-B is a potential therapeutic target for prevention of neurodegeneration in Alzheimer’s disease. Starting with piperidine-based selective human (h)BChE inhibitors and propargylamine-based MAO inhibitors, we have designed, synthesized and biochemically evaluated a series of N-propargylpiperidines. All of these compounds inhibited hBChE with good selectivity over the related enzyme, acetylcholinesterase, and crossed the blood-brain barrier in a parallel artificial membrane permeation assay. The crystal structure of one of the inhibitors (compound 3) in complex with hBChE revealed its binding mode. Three compounds (4, 5, 6) showed concomitant inhibition of MAO-B. Additionally, the most potent hBChE inhibitor 7 and dual BChE and MAO-B inhibitor 6 were non-cytotoxic and protected neuronal SH-SY5Y cells from toxic amyloid β-peptide species. Graphical abstract image
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A novel curcumin derivative which inhibits P-glycoprotein, arrests cell cycle and induces apoptosis in multidrug resistance cells ()
Publication date: Available online 19 November 2016 Source:Bioorganic & Medicinal Chemistry Author(s): Vanessa Lopes-Rodrigues, Ana Oliveira, Marta Correia-da-Silva, Madalena Pinto, Raquel T. Lima, Emília Sousa, M. Helena Vasconcelos Cancer multidrug resistance (MDR) is a major limitation to the success of cancer treatment and is highly associated with the overexpression of drug efflux pumps such as P-glycoprotein (P-gp). In order to achieve more effective chemotherapeutic treatments, it is important to develop P-gp inhibitors to block/decrease its activity. Curcumin (1) is a secondary metabolite isolated from the turmeric of Curcuma longa L.. Diverse biological activities have been identified for this compound, particularly, MDR modulation in various cancer cell models. However, curcumin (1) has low chemical stability, which severely limits its application. In order to improve stability and P-gp inhibitory effect, two potential more stable curcumin derivatives were synthesized as building blocks, followed by several curcumin derivatives. These compounds were then analyzed in terms of antitumor and anti-P-gp activity, in two MDR and sensitive tumor lines (from chronic myeloid leukemia and non-small cell lung cancer). We identified from a series of curcumin derivatives a novel curcumin derivative (1,7-bis(3-methoxy-4-(prop-2-yn-1-yloxy)phenyl)hepta-1,6-diene-3,5-dione, 10) with more potent antitumor and anti-P-gp activity than curcumin (1). This compound (10) was shown to promote cell cycle arrest (at the G2/M phase) and induce apoptosis in the MDR chronic myeloid leukemia cell line. Therefore it is a really interesting P-gp inhibitor due to its ability to inhibit both P-gp function and expression. Graphical abstract image
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Design, synthesis and biological evaluation of alkylamino biphenylamides as Hsp90 C-terminal inhibitors ()
Publication date: Available online 19 November 2016 Source:Bioorganic & Medicinal Chemistry Author(s): Gaurav Garg, Huiping Zhao, Brian S.J. Blagg Hsp90 is a promising therapeutic target for the development of anti-cancer agents due to its integral role in the stability and function of proteins associated with all ten hallmarks of cancer. Novobiocin, a coumarin antibiotic, was the first natural product identified that targeted the Hsp90 C-terminal domain and manifested anti-proliferative activity (SKBr3 IC50 ∼700μM). Subsequent structural investigations on novobiocin led to analogues with significantly improved anti-proliferative activity against multiple cancer cell lines. In an effort to develop more efficacious and diverse analogues, it was recently found that the coumarin ring of novobiocin could be replaced with the biphenyl core without compromising activity. Based on these prior studies, a series of alkylamino biphenylamides was designed, synthesized and evaluated for anti-proliferative activity against two breast cancer cell lines. SAR studies demonstrated that the incorporation of an alkylamino side chain onto the biphenyl core improved anti-proliferative activity and resulted in compounds that exhibit sub-micromolar to mid-nanomolar activity through Hsp90 inhibition. Importantly, these studies indicate the presence of a hydrophilic region about the central core that can be exploited for the design of new inhibitors. Graphical abstract image
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Synthesis and binding monitoring of a new nanomolar PAMAM-based matrix metalloproteinases inhibitor (MMPIs) ()
Publication date: Available online 19 November 2016 Source:Bioorganic & Medicinal Chemistry Author(s): Linda Cerofolini, Veronica Baldoneschi, Elisa Dragoni, Andrea Storai, Marianna Mamusa, Debora Berti, Marco Fragai, Barbara Richichi, Cristina Nativi Dendrimers are efficient drug delivery systems particularly useful in ocular diseases. In particular, low generation PAMAM dendrimers are non-toxic and non-immunogenic and they provide an enhancement of the residence time of drugs in the eyes. In this context, the synthesis of the PAMAM-based matrix metalloproteinases inhibitor 5, is reported. In particular, we demonstrated that 5 strongly binds (18.0nM±2.5nM) MMP-9, the most relevant MMP responsible of ocular surface damages in induced dry eyes syndrome (DES). Graphical abstract image
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Computer design, synthesis, and bioactivity analyses of drugs like fingolimod used in the treatment of multiple sclerosis ()
Publication date: Available online 18 November 2016 Source:Bioorganic & Medicinal Chemistry Author(s): Gurbet Çelik Turgut, Doğukan Doyduk, Yılmaz Yıldırır, Serkan Yavuz, Atilla Akdemir, Ali Dişli, Alaattin Şen Multiple sclerosis (MS) is a very common disease of vital importance. In the MS treatment, some drugs such as fingolimod which help to protect nerves from damage are used. The main goal of the drug therapy in MS is to take control of the inflammation which leads to the destruction of myelin and axons in nerve cell and thus prevent and stop the progression of the disease. Fingolimod (FTY720) is an orally active immunomodulatory drug that has been used for the treatment of relapsing-remitting multiple sclerosis. It is a sphingosine-1-phosphate receptor modulator which prevents lymphocytes from contributing to an autoimmune reaction by inhibiting egress of lymphocytes them from lymph nodes. In this study, we have computer designed, synthesized and characterized two novel derivatives of FTY720, F1-12h and F2-9, and have determined their underlying mechanism of their beneficial effect in SH-SY5Y, SK-N-SH, and U-118 MG cell lines. For this purpose, we first determined the regulation of the cAMP response element (CRE) activity and cAMP concentration by F1-12h and F2-9 together with FTY720 using pGL4.29 luciferase reporter assay and cAMP immunoassay, respectively. Then, we have determined their effect on MS- and GPCR-related gene expression profiles using custom arrays along with FTY720 treatment at non-toxic doses (EC10). It was found that both derivatives significantly activate CRE and increase cAMP concentration in all three cell lines, indicating that they activate cAMP pathway through cell surface receptors as FTY720 does. Furthermore, F1-12h and F2-9 modulate the expression of the pathway related genes that are important in inflammatory signaling, cAMP signaling pathway, cell migration as well as diverse receptor and transcription factors. Expression of the genes involved in myelination was also increased by the treatment with F1-12h and F2-9. In summary, our data demonstrate that the two novel FTY720 derivatives act as anti-inflammatory ultimately by influencing the gene expression via the cAMP and downstream transcription factor CRE pathway. In conclusion, F1-12h and F2-9 might contribute future therapies for autoimmune diseases such as multiple sclerosis. Graphical abstract image
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Synthesis, evaluation and molecular modelling studies of 2-(carbazol-3-yl)-2-oxoacetamide analogues as a new class of potential pancreatic lipase inhibitors ()
Publication date: Available online 18 November 2016 Source:Bioorganic & Medicinal Chemistry Author(s): S.N.C. Sridhar, George Ginson, P.O. Venkataramana Reddy, Mukund P. Tantak, Dalip Kumar, Atish T. Paul A series of twenty four 2-(carbazol-3-yl)-2-oxoacetamide analogues were synthesized, characterized and evaluated for their pancreatic lipase (PL) inhibitory activity. Porcine PL was used against 4-nitrophenyl butyrate (method A) and tributyrin (methods B and C) as substrates during the PL inhibition assay. Compounds 7e, 7f and 7p exhibited potential PL inhibitory activity (IC50 values of 6.31, 8.72 and 9.58μM, respectively in method A; and Xi50 of 21.85, 21.94 and 26.2, respectively in method B). Further, inhibition kinetics of 7e, 7f and 7p against PL, using method A, revealed their competitive nature of inhibition. A comparison of the inhibition profiles of the top three compounds in methods B and C, provided a preliminary idea of covalent bonding of the compounds with Ser 152 of PL. Molecular docking studies of the compounds 7a–x into the active site of human PL (PDB ID: 1LPB) was in agreement with the in vitro results, and highlighted probable covalent bond formation with Ser 152 apart from hydrophobic interactions with the lid domain. Molecular dynamics simulation of 7e complexed with PL, further confirmed the role of aromatic groups in stabilising the ligand (RMSD ⩽4Å). The present study led to the identification of 2-(carbazol-3-yl)-2-oxoacetamide analogues 7a–x as a new class of potential PL inhibitors. Graphical abstract image
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Editorial board ()
Publication date: 15 November 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 22
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Cyclen-based Gd3+ complexes as MRI contrast agents: Relaxivity enhancement and ligand design ()
Publication date: 15 November 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 22 Author(s): Haroon Ur Rashid, Marco Antonio Utrera Martines, Juliana Jorge, Paula Martin de Moraes, Muhammad Naveed Umar, Kamin Khan, Hanif Ur Rehman Magnetic Resonance Imaging (MRI) is a noninvasive radiology technique used to examine the internal organs of human body. It is useful for the diagnosis of structural abnormalities in the body. Contrast agents are used to increase the sensitivity of this technique. 1,4,7,10-Tetraazacyclododecane (cyclen) is a macrocyclic tetraamine. Its derivatives act as useful ligands to produce stable complexes with Gd3+ ion. Such chelates are investigated as MRI contrast agents. Free Gd3+ ion is extremely toxic for in vivo use. Upon complexation with a cyclen-based ligand, it is trapped in the preformed central cavity of the ligand resulting in the formation of a highly stable Gd3+-chelate. Better kinetic and thermodynamic stability of cyclen-based MRI contrast agents decrease their potential toxicity for in vivo use. Consequently, such agents have proved to be safest for clinical applications. Relaxivity is the most important parameter used to measure the effectiveness of a contrast agent. A number of factors influence this parameter. This article elucidates detailed strategies to increase relaxivity of cyclen-based MRI contrast agents. 1,4,7,10-Tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) and 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid (DO3A) are two key ligands derived from cyclen. They also act as building blocks for the synthesis of novel ligands. A few important methodologies for the synthesis of DOTA and DO3A derivatives are described. Moreover, the coordination geometry of chelates formed by these ligands and their derivatives is discussed as well. Novel ligands can be developed by the appropriate derivatization of DOTA and DO3A. Gd3+-chelates of such ligands prove to be useful MRI contrast agents of enhanced relaxivity, greater stability, better clearance, lesser toxicity and higher water solubility. Graphical abstract image
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ArgTX-636, a polyamine isolated from spider venom: A novel class of melanogenesis inhibitors ()
Publication date: 15 November 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 22 Author(s): Marion Verdoni, Hermine Roudaut, Harold De Pomyers, Didier Gigmes, Denis Bertin, José Luis, Abd Haq Bengeloune, Kamel Mabrouk To discover new molecules with an inhibitory activity of melanogenesis a hundred of scorpions, snakes, spiders and amphibians venoms were screened for their capacity to inhibit mushroom tyrosinase using 3,4-l-dihydroxyphenylalanine (l-DOPA) as substrate. The Argiope lobata spider venom proved to be the most active. HPLC fraction containing Argiotoxine-636 (ArgTX-636), a polyamine known for its numerous biological activities, was found to also show a good regulation activity of melanogenesis by inhibiting DOPA and 5,6-dihydroxyindole-2-carboxylic acid (DHICA) oxidases activities, wore by tyrosinase (TYR) and tyrosinase-related protein 1 (TRP-1), respectively. Our results demonstrate that ArgTX-636 reduced the mushroom tyrosinase activity in a dose-dependent way with a maximal half inhibitory concentration (IC50) value of 8.34μM, when l-DOPA is used as substrate. The Lineweaver–Burk study showed that ArgTX-636 is a mixed type inhibitor of the diphenolase activity. Moreover, ArgTX-636 inhibits DHICA oxydase activity of mushroom tyrosinase activity with IC50 at 41.3μM. ArgTX-636 has no cytotoxicity in B16F10 melanoma cells at concentrations up to 42.1μM. The effect of ArgTX-636 on melanogenesis showed that melanin production in B16F10 melanoma cell decreased by approximatively 70% compared to untreated cells. ArgTX-636 displayed no significant effect on the TYR expression while the protein level of TRP-1 decreased in B16F10 cells. Thus, ArgTX-636 could have particular interest for cosmetic and/or pharmaceutical use in order to reduce important dermatoses in black and mixed skins. Graphical abstract image
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Conjugation of N-acylhydrazone and 1,2,4-oxadiazole leads to the identification of active antimalarial agents ()
Publication date: 15 November 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 22 Author(s): José Maurício dos Santos Filho, Diogo Manoel Alves de Queiroz e Silva, Taís Soares Macedo, Helena Mariana Pitangueira Teixeira, Diogo Rodrigo Magalhaes Moreira, Soura Challal, Jean-Luc Wolfender, Emerson Ferreira Queiroz, Milena Botelho Pereira Soares Malaria, caused by several Plasmodium species, is the major life-threatening parasitic infection worldwide. Due to the parasite resistance to quinoline based drugs, the search for antimalarial agents is necessary. Here, we report the structural design, synthesis and antiparasitic evaluation of two novel series of 1,2,4-oxadiazoles in conjugation to N-acylhydrazones, both groups recognized as privileged structures, as well as the studies on the antimalarial activity of 16 previous described analogues. By varying substituents attached to the phenyl ring, it was possible to retain, enhance or increase the antiparasitic activity in comparison to the nonsubstituted derivatives. Replacement of substituted aryl rings by ferrocenyl and cinnamyl moieties attached in the N-acylhydrazone ablated the antiparasitic response, evidencing the structural features associated with the activity. Active compounds exhibited in vitro potency similar to mefloquine, but not all inhibited β-hematin formation. Additionally, the active compounds displayed low cytotoxicity in HepG2 cells and did not cause hemolysis in uninfected erythrocytes. In Plasmodium berghei-infected mice, the compounds reduced parasitemia but exhibited limited efficacy in increasing mice survival when compared to chloroquine, suggesting that pharmacological improvement is still necessary. Graphical abstract image
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In vivo effective dibenzo[b,d]furan-1-yl-thiazoles as novel PDE-4 inhibitors ()
Publication date: 15 November 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 22 Author(s): Gopalan Balasubramanian, Sukunath Narayanan, Lavanya Andiappan, Thirunavukkarasu Sappanimuthu, Saravanan Thirunavukkarasu, Shamundeeswari Sundaram, Saravanakumar Natarajan, Naresh Sivaraman, Sridharan Rajagopal, Fakrudeen Ali Ahamed Nazumudeen, Sanjeev Saxena, Santosh L. Vishwakarma, Shridhar Narayanan, Ganapavarapu V.R. Sharma, Chidambaram V. Srinivasan, Narasimhan Kilambi Herein we report the synthesis, PDE-4B and TNF-α inhibitory activities of a few dibenzo[b,d]furan-1-yl-thiazole derivatives. The hydroxycyclohexanol amide derivatives 14, 18, 24, 29, 31 and 33 exhibited promising in vitro PDE-4B and TNF-α inhibitory activities. Compound 24 showed good systemic availability in preclinical animal models and was also found to be non-toxic (exploratory mutagenicity test). Further it exhibited promising results in in vivo asthma/COPD and Uveitis models. Graphical abstract image
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Pyrazolo[1,5a]pyrimidines as a new class of FUSE binding protein 1 (FUBP1) inhibitors ()
Publication date: 15 November 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 22 Author(s): Stefanie Hauck, Kerstin Hiesinger, Sabrina Khageh Hosseini, Janosch Achenbach, Ricardo M. Biondi, Ewgenij Proschak, Martin Zörnig, Dalibor Odadzic The transcriptional regulator FUSE binding protein 1 (FUBP1) is aberrantly upregulated in various malignancies, fulfilling its oncogenic role by the deregulation of critical genes involved in cell cycle control and apoptosis regulation. Thus, the pharmaceutical inhibition of this protein would represent an encouraging novel targeted chemotherapy. Here, we demonstrate the identification and initial optimization of a pyrazolo[1,5a]pyrimidine-based FUBP1 inhibitor derived from medium throughput screening, which interferes with the binding of FUBP1 to its single stranded target DNA FUSE. We were able to generate a new class of FUBP1 interfering molecules with in vitro and biological activity. In biophysical assays, we could show that our best inhibitor, compound 6, potently inhibits the binding of FUBP1 to the FUSE sequence with an IC50 value of 11.0μM. Furthermore, hepatocellular carcinoma cells exhibited sensitivity towards the treatment with compound 6, resulting in reduced cell expansion and induction of cell death. Finally, we provide insights into the corresponding SAR landscape, leading to a prospective enhancement in potency and cellular efficacy. Graphical abstract image
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