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Bioorganic & Medicinal Chemistry

Alex George, Idris Raji, Bekir Cinar, Omer Kucuk, Adegboyega K Oyelere
Androgen receptor (AR) signaling is vital to the viability of all forms of prostate cancer (PCa). With the goal of investigating the effect of simultaneous inhibition and depletion of AR on viability of PCa cells, we designed, synthesized and characterized the bioactivities of bifunctional agents which incorporate the independent cancer killing properties of an antiandrogen and genistein, and the AR downregulation effect of genistein within a single molecular template. We observed that a representative conjugate, 9b, is much more cytotoxic to both LNCaP and DU145 cells relative to the antiandrogen and genistein building blocks as single agents or their combination...
February 15, 2018: Bioorganic & Medicinal Chemistry
N George Bendzunas, Sabrina Dörfler, Karolin Autenrieth, Daniela Bertinetti, Erik M F Machal, Eileen J Kennedy, Friedrich W Herberg
Generation of the second messenger molecule cAMP mediates a variety of cellular responses which are essential for critical cellular processes. In response to elevated cAMP levels, cAMP dependent protein kinase (PKA) phosphorylates serine and threonine residues on a wide variety of target substrates. In order to enhance the precision and directionality of these signaling events, PKA is localized to discrete locations within the cell by A-kinase anchoring proteins (AKAPs). The interaction between PKA and AKAPs is mediated via an amphipathic α-helix derived from AKAPs which binds to a stable hydrophobic groove formed in the dimerization/docking (D/D) domain of PKA-R in an isoform-specific fashion...
February 12, 2018: Bioorganic & Medicinal Chemistry
Shinya Yokosaka, Akiko Izawa, Chizuka Sakai, Eri Sakurada, Yasuhiro Morita, Yukihiro Nishio
Dolastatin 10 (1) is a highly potent cytotoxic microtubule inhibitor (cytotoxicity IC50 < 5.0 nM) and several of its analogs have recently been used as payloads in antibody drug conjugates. Herein, we describe the design and synthesis of a series of novel dolastatin 10 analogs useful as payloads for conjugated drugs. We explored analogs containing functional groups at the thiazole moiety at the C-terminal of dolastatin 10. The functional groups included amines, alcohols, and thiols, which are representative structures used in known conjugated drugs...
February 11, 2018: Bioorganic & Medicinal Chemistry
Hesham Haffez, David R Chisholm, Natalie J Tatum, Roy Valentine, Christopher Redfern, Ehmke Pohl, Andrew Whiting, Stefan Przyborski
Retinoids, such as all-trans-retinoic acid (ATRA), regulate cellular differentiation and signalling pathways in chordates by binding to nuclear retinoic acid receptors (RARα/β/γ). Polar interactions between receptor and ligand are important for binding and facilitating the non-polar interactions and conformational changes necessary for RAR-mediated transcriptional regulation. The constraints on activity and RAR-type specificity with respect to the structural link between the polar and non-polar functions of synthetic retinoids are poorly understood...
February 10, 2018: Bioorganic & Medicinal Chemistry
Hidefumi Yoshinaga, Tomoaki Nishida, Izumi Sasaki, Taro Kato, Hitomi Oki, Kazuki Yabuuchi, Tomohiro Toyoda
We have previously shown that SMP-304, a serotonin uptake inhibitor with weak 5-HT1A partial agonistic activity, may act under high serotonin levels as a 5-HT1A antagonist that improves the onset of paroxetine in the rat swimming test. However, SMP-304 is mostly metabolized by CYP2D6, indicating limited efficacy among individuals and increased side effects. To reduce CYP2D6 metabolic contribution and enhance SERT/5-HT1A binding affinity, we carried out a series of substitutions at the bromine atom in the left part of the benzene ring of SMP-304 and replaced the right part of SMP-304 with a chroman-4-one...
February 8, 2018: Bioorganic & Medicinal Chemistry
Jianbin Sun, Junli Shao, Changli Sun, Yongxiang Song, Qinglian Li, Laichun Lu, Yunfeng Hu, Chun Gui, Hua Zhang, Jianhua Ju
Borrelidin A (1) is produced by several species of Streptomyces and within its bioactive scaffold, the vinylic nitrile moiety is essential for activity. We report herein newly discovered members of the borrelidin family, borrelidin F (2), borrelidin G (3), borrelidin H (4) and borrelidin I (5); all were isolated from Streptomyces rochei SCSIO ZJ89 originating from a mangrove-derived sediment sample. These structurally diverse metabolites enabled a number of new structure-activity relationships (SARs) to be identified, especially with respect to the different configurations at the C11-OH and C12-C15 double bonds for which the absolute configurations were determined using spectroscopic methods...
February 7, 2018: Bioorganic & Medicinal Chemistry
Nam Hoang, Xuan Zhang, Chunxiao Zhang, Van Vo, Feng Leng, Lovely Saxena, Feng Yin, Fei Lu, Guangrong Zheng, Pradip Bhowmik, Hui Zhang
LSD1/KDM1 is a histone demethylase that preferentially removes methyl groups from the mono- and di-methylated lysine 4 in histone H3 (H3K4), key marks for active chromatin for transcriptional activation. LSD1 is essential for pluripotent embryonic stem cells and embryonic teratocarcinoma/carcinoma cells and its expression is often elevated in various cancers. We developed a new LSD1 inhibitor, CBB3001, which potently inhibited LSD1 activity both in vitro and in vivo. CBB3001 also selectively inhibited the growth of human ovarian teratocarcinoma PA-1 and mouse embryonic carcinoma F9 cells, caused the downregulation of pluripotent stem cell proteins SOX2 and OCT4...
February 7, 2018: Bioorganic & Medicinal Chemistry
Hongwu Liu, Jianwei Wu, Ying Ge, Aibo Li, Jia Li, Zhengshi Liu, Yungen Xu, Qingxiang Xu, Yuyan Li
A novel series of non-peptide proteasome inhibitors (PIs) that act on chymotrypsin-like (ChT-L) of the proteasome were developed. These PIs bearing 4-aromatic sulfonyl naphthalene-based scaffold and Leu-boronic moiety as covalent bonding group displayed far better activity than PI-8182 for inhibiting ChT-L in preliminary biological activity test. The results showed that 2a (IC50 = 6.942 μM, MCF-7) and 2c (IC50 = 6.905 μM, MCF-7) displayed higher anti-proliferative activities than Bortezomib (IC50 = 18...
February 6, 2018: Bioorganic & Medicinal Chemistry
Chieyeon Chough, Misuk Joung, Sunmin Lee, Jaemin Lee, Jong Hoon Kim, B Moon Kim
A series of 3(R)-aminopyrrolidine derivatives were designed and synthesized for JAK1-selective inhibitors through the modification of tofacitinib's core structure, (3R,4R)-3-amino-4-methylpiperidine. From the new core structures, we selected (R)-N-methyl-N-(pyrrolidin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine as a scaffold for further SAR studies. From biochemical enzyme assays and liver microsomal stability tests, (R)-3-(3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)pyrrolidin-1-yl)-3-oxopropanenitrile (6) was chosen for further in vivo test through oral administration...
February 3, 2018: Bioorganic & Medicinal Chemistry
Susana Maza, Noel Gandia-Aguado, José L de Paz, Pedro M Nieto
Here, we present the preparation of a sulfated, fully protected tetrasaccharide derivative following the glycosaminoglycan (GAG)-related sequence GlcNAc-β(1 → 4)-Glc-β(1 → 3). The tetramer was efficiently assembled via an iterative glycosylation strategy using monosaccharide building blocks. A fluorous tag was attached at position 6 of the reducing end unit enabling the purification of reaction intermediates by simple fluorous solid phase extraction. Fluorescence polarization competition experiments revealed that the synthesized tetrasaccharide strongly interacts with two heparin-binding growth factors, midkine and FGF-2 (IC50 of 270 nM and 2...
February 3, 2018: Bioorganic & Medicinal Chemistry
Archana S Gurjar, Mrunali N Darekar, Keng Yoon Yeong, Luyi Ooi
Alzheimer's disease (AD) is a progressive neurodegenerative disorder with multiple factors associated with its pathogenesis. Our strategy against AD involves design of multi-targeted 2-substituted-4,5-diphenyl-1H-imidazole analogues which can interact and inhibit AChE, thereby, increasing the synaptic availability of ACh, inhibit BuChE, relieve induced oxidative stress and confer a neuroprotective role. Molecular docking was employed to study interactions within the AChE active site. In silico ADME study was performed to estimate pharmacokinetic parameters...
February 2, 2018: Bioorganic & Medicinal Chemistry
Mizuho Hanaki, Kazuma Murakami, Sumie Katayama, Ken-Ichi Akagi, Kazuhiro Irie
(R)-Apomorphine (1) has the potential to reduce the accumulation of amyloid β-protein (Aβ42), a causative agent of Alzheimer's disease (AD). Although the inhibition of Aβ42 aggregation by 1 is ascribable to the antioxidative effect of its phenol moiety, its inhibitory mechanism at the molecular level remains to be fully elucidated. LC-MS and UV analyses revealed that 1 is autoxidized during incubation to produce an unstable o-quinone form (2), which formed a Michael adduct with Lys 16 and 28 of Aβ42. A further autoxidized form of 1 (3) with o-quinone and phenanthrene moieties suppressed Aβ42 aggregation comparable to 1, whereas treating 1 with a reductant, tris(2-carboxyethyl)phosphine diminished its inhibitory activity...
February 2, 2018: Bioorganic & Medicinal Chemistry
Zhongcheng Cao, Jie Yang, Rui Xu, Qin Song, Xiaoyu Zhang, Hongyan Liu, Xiaoming Qiang, Yan Li, Zhenghuai Tan, Yong Deng
A series of 4'-OH-flurbiprofen-chalcone hybrids were designed, synthesized and evaluated as potential multifunctional agents for the treatment of Alzheimer's disease. The biological screening results indicated that most of these hybrids exhibited good multifunctional activities. Among them, compounds 7k and 7m demonstrated the best inhibitory effects on self-induced Aβ1-42 aggregation (60.0% and 78.2%, respectively) and Cu2+-induced Aβ1-42 aggregation (52.4% and 95.0%, respectively). Moreover, these two representative compounds also exhibited good antioxidant activities, MAO inhibitions, biometal chelating abilities and anti-neuroinflammatory activities in vitro...
February 2, 2018: Bioorganic & Medicinal Chemistry
Kenya Matsushita, Tomomi Nakata, Naoko Takeda-Okuda, Satomi Nadanaka, Hiroshi Kitagawa, Jun-Ichi Tamura
We synthesized the biotinylated chondroitin sulfate tetrasaccharides CS-CC [-3)βGalNAc6S(1-4)βGlcA(1-]2 and CS-DD [-3)βGalNAc6S(1-4)βGlcA2S(1-]2 which possess sulfate groups at O-6 of GalNAc and an additional sulfate group at O-2 of GlcA, respectively. We also analyzed interactions among CS-CC and CS-DD and the antibodies 2H6 and LY111, both of which are known to bind with CS-A, while CS-DD was shown for the first time to bind with both antibodies.
February 2, 2018: Bioorganic & Medicinal Chemistry
Jesús A Romero, María E Acosta, Neira D Gamboa, Michael R Mijares, Juan B De Sanctis, Jaime E Charris
Chemically modified versions of bioactive substances, are particularly useful in overcoming barriers associated with drug formulation, drug delivery and poor pharmacokinetic properties. In this study, a series of fourteen (E)-methyl 2-(7-chloroquinolin-4-ylthio)-3-(4-hydroxyphenyl) acrylate (2-15) were prepared by using a one step synthesis from 1 previously described by us as potential antimalarial and antitumor agent. Molecules were evaluated as inhibitors of β-hematin formation, where most of them showed a significant inhibition value (% > 70)...
February 2, 2018: Bioorganic & Medicinal Chemistry
Yusuke Kawamoto, Toshikazu Bando, Hiroshi Sugiyama
Pyrrole-imidazole polyamides (Py-Im polyamides) are cell-permeable compounds that bind to the minor groove of double-stranded DNA in a sequence-specific manner without causing denaturation of the DNA. These compounds can be used to control gene expression and to stain specific sequences in cells. Here, we review the history, structural variations, and functional investigations of Py-Im polyamides.
February 1, 2018: Bioorganic & Medicinal Chemistry
Kang Jin, Kathy Hiu Laam Po, Wang Yeuk Kong, Chung Hei Lo, Chun Wah Lo, Ho Yin Lam, Amaya Sirinimal, Jonathan Avraham Reuven, Sheng Chen, Xuechen Li
Teixobactin is a structurally and mechanistically novel antimicrobial peptide with potent activities against Gram-positive pathogens. It contains l-allo-enduracididine (End) residue which is not readily accessible. In this report, we have used convergent Ser Ligation as the key step to prepare a series of teixobactin analogues with End being substituted with its non-isostere moieties. Among these analogues, compounds T16, T27 and T29 exhibited the best antimicrobial activities against different Gram-positive bacteria with MICs ranging from 0...
February 1, 2018: Bioorganic & Medicinal Chemistry
Sungjin Ahn, Moonyoung Lee, Seungchan An, Sooyeol Hyun, Jiho Hwang, Jongkook Lee, Minsoo Noh
Adiponectin is a major adipocytokine secreted from mammalian adipocytes. Relatively low expression of adiponectin is associated with various human metabolic diseases and some cancers. Adiponectin-secreting compounds have therapeutic potential for these diseases. Adipogenesis of human bone marrow-mesenchymal stem cells (hBM-MSCs) has been used as a phenotypic assay to find adiponectin secreting compounds. In a phytochemical library screen, 2-formyl-komarovicine, 1-(quinolin-8-yl)-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indole-2-carbaldehyde, isolated from Nitraria komarovii was identified as a potential adiponectin-secreting compound...
February 1, 2018: Bioorganic & Medicinal Chemistry
Tran Thi Thu Trang, Lise Dieltjens, Geert Hooyberghs, Kai Waldrant, Denis S Ermolat'ev, Erik V Van der Eycken, Hans P L Steenackers
The increased tolerance of biofilms against disinfectants and antibiotics has stimulated research into new methods of biofilm prevention and eradication. In our previous work, we have identified the 5-aryl-2-aminoimidazole core as a scaffold that demonstrates preventive activity against biofilm formation of a broad range of bacterial and fungal species. Inspired by the dimeric nature of natural 2-aminoimidazoles of the oroidin family, we investigated the potential of dimers of our decorated 5-aryl-2-aminoimidazoles as biofilm inhibitors...
January 31, 2018: Bioorganic & Medicinal Chemistry
Mario D Martínez, Alberto A Ghini, M Virginia Dansey, Adriana S Veleiro, Adali Pecci, Lautaro D Alvarez, Gerardo Burton
The Liver X receptors (LXRs) are members of the nuclear receptor family, that play fundamental roles in cholesterol transport, lipid metabolism and modulation of inflammatory responses. In recent years, the synthetic steroid N,N-dimethyl-3β-hydroxycholenamide (DMHCA) arised as a promising LXR ligand. This compound was able to dissociate certain beneficial LXRs effects from those undesirable ones involved in triglyceride metabolism. Here, we synthetized a series of DMHCA analogues with different modifications in the steroidal nucleus involving the A/B ring fusion, that generate changes in the overall conformation of the steroid...
January 31, 2018: Bioorganic & Medicinal Chemistry
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