120690-80-4Relevant academic research and scientific papers
New 13-pyridinealkyl berberine analogues intercalate to DNA and induce apoptosis in HepG2 and MCF-7 cells through ROS mediated p53 dependent pathway: Biophysical, biochemical and molecular modeling studies
Chatterjee, Sabyasachi,Mallick, Sumana,Buzzetti, Franco,Fiorillo, Gaetano,Syeda, Tanjia Monir,Lombardi, Paolo,Saha, Krishna Das,Kumar, Gopinatha Suresh
, p. 90632 - 90644 (2015)
A new series of 13-pyridinealkyl berberine analogues was synthesized and their DNA binding efficacy studied by employing spectroscopic, calorimetric and molecular modeling techniques. Analogues with more than one CH2 group showed better intercalative binding than berberine. The analogue with one CH2 group bound DNA weaker than berberine. The binding of the analogue with single CH2 group was entropy driven, while those with more than one CH2 group was favoured by both entropy and enthalpy changes. Higher salt concentration and temperature destabilized the binding. A larger contribution from non-polyelectrolytic forces to the Gibbs energy and the involvement of strong hydrophobic interactions were inferred. Molecular modeling pin pointed the specific binding site and the non-covalent interactions in the association. The best DNA binding analogue (BER5) inhibited the growth of hepatocellular and breast carcinoma most efficiently. It induced apoptosis in HepG2 and MCF-7 cells with externalization of phosphatidylserine and reactive oxygen species generation with accumulation of cells in the G0/G1 phase. Furthermore, up regulation of p53 and p21 indicated the role of p53 in BER5 mediated apoptosis. The results suggested that 13-pyridinealkyl berberine analogues intercalated to DNA much stronger than berberine, the chain length of the linker plays an important role for the binding, and they induced ROS mediated apoptosis in HepG2 and MCF-7 cells by p53 modulation.
Structure-guided, single-point modifications in the phosphinic dipeptide structure yield highly potent and selective inhibitors of neutral aminopeptidases
Vassiliou, Stamatia,W?glarz-Tomczak, Ewelina,Berlicki,Pawe?czak, Ma?gorzata,Nocek, Bogus?aw,Mulligan, Rory,Joachimiak, Andrzej,Mucha, Artur
, p. 8140 - 8151 (2014)
Seven crystal structures of alanyl aminopeptidase from Neisseria meningitides (the etiological agent of meningitis, NmAPN) complexed with organophosphorus compounds were resolved to determine the optimal inhibitor-enzyme interactions. The enantiomeric phosphonic acid analogs of Leu and hPhe, which correspond to the P1 amino acid residues of well-processed substrates, were used to assess the impact of the absolute configuration and the stereospecific hydrogen bond network formed between the aminophosphonate polar head and the active site residues on the binding affinity. For the hPhe analog, an imperfect stereochemical complementarity could be overcome by incorporating an appropriate P1 side chain. The constitution of P1′-extended structures was rationally designed and the lead, phosphinic dipeptide hPhePψ[CH2]Phe, was modified in a single position. Introducing a heteroatom/heteroatom-based fragment to either the P1 or P1′ residue required new synthetic pathways. The compounds in the refined structure were low nanomolar and subnanomolar inhibitors of N. meningitides, porcine and human APNs, and the reference leucine aminopeptidase (LAP). The unnatural phosphinic dipeptide analogs exhibited a high affinity for monozinc APNs associated with a reasonable selectivity versus dizinc LAP. Another set of crystal structures containing the NmAPN dipeptide ligand were used to verify and to confirm the predicted binding modes; furthermore, novel contacts, which were promising for inhibitor development, were identified, including a π-π stacking interaction between a pyridine ring and Tyr372.
Synthesis and BK channel-opening activity of 2-amino-1,3-thiazole derivatives
Cui, Yong-Mei,Ji, Tong-Tong,Jo, Heeji,Lin, Hai-Xia,Park, Chul-Seung,Qi, Xiao-Lei,Wang, Xue-Ying
supporting information, (2021/05/19)
A series of 2-amino-5-arylmethyl- or 5-heteroarylmethyl-1,3-thiazole derivatives were synthesized and evaluated for BK channel-opening activities in cell-based fluorescence assay and electrophysiological recording. The assay results indicated that the activities of the investigated compounds were influenced by the physicochemical properties of the substituent at benzene ring.
Synthesis and biological evaluation of aminothiazoles against Histoplasma capsulatum and Cryptococcus neoformans
Ishita, Keisuke,Stefanopoulos, Stavros,Khalil, Ahmed,Cheng, Xiaolin,Tjarks, Werner,Rappleye, Chad A.
supporting information, p. 2251 - 2261 (2018/03/29)
The design and synthesis of a library of forty novel 2-aminoazole analogues as well as their evaluation as antifungal compounds against Histoplasma capsulatum and Cryptococcus neoformans is described. These structures were derived from N-[5-(1-naphthaleny
Replacing triazole with diazole to optimize physicochemical properties of a click-based lead compound
Tian, Yinping,Lv, Wenhui,Meng, Qiuyue,Li, Xuewei,Zeng, Wei,Lu, Yaxin,Wang, Peng G.,Jin, Jin,Shen, Jie
, p. 2007 - 2014 (2017/08/03)
This work mainly demonstrated how the physicochemical properties of a click-based lead compound would be affected by the replacement of its triazole ring with a pyrazole or an imidazole ring. Compound A1, a click-based lead from our previous work, was a selective and moderate inhibitor against VEGFR2. Eight new derivatives of A1 were synthesized, from which a pyrazole derivative B2 was selected as a new lead. B2 maintained the in vitro activity of A1. The solubilities of B2 at pH 2.0 and pH 7.4 were enhanced to 1310 and 1.7 μg/mL, respectively. Its log D value of 3.4 would favor B2 to be modified with hydrophilic fragments to further improve intestinal solubility in our future work.
Chemo- and Regioselective Organo-Photoredox Catalyzed Hydroformylation of Styrenes via a Radical Pathway
Huang, He,Yu, Chenguang,Zhang, Yueteng,Zhang, Yongqiang,Mariano, Patrick S.,Wang, Wei
supporting information, p. 9799 - 9802 (2017/08/02)
An unprecedented, chemo- and regioselective, organo-photoredox catalyzed hydroformylation reaction of aryl olefins with diethoxyacetic acid as the formylation reagent is described. In contrast to traditional transition metal promoted ionic hydroformylation reactions, the new process follows a unique photoredox promoted, free radical pathway. In this process, a formyl radical equivalent, produced from diethoxacetic acid through a dye (4CzIPN) photocatalyzed, sequential oxidation-decarboxylation route, regio- and chemoselectively adds to a styrene substrate. Importantly, under the optimized reaction conditions the benzylic radical formed in this manner is reduced by SET from the anion radical of 4CzIPN to generate a benzylic anion. Finally, protonation produces the hydroformylation product. By using the new protocol, aldehydes can be generated regioselectively in up to 90% yield. A broad array of functional groups is tolerated in the process, which takes place under mild, metal-free conditions.
The insulin secretory action of novel polycyclic guanidines: Discovery through open innovation phenotypic screening, and exploration of structure-activity relationships
Shaghafi, Michael B.,Barrett, David G.,Willard, Francis S.,Overman, Larry E.
supporting information, p. 1031 - 1036 (2014/03/21)
We report the discovery of the glucose-dependent insulin secretogogue activity of a novel class of polycyclic guanidines through phenotypic screening as part of the Lilly Open Innovation Drug Discovery platform. Three compounds from the University of California, Irvine, 1-3, having the 3- arylhexahydropyrrolo[1,2-c]pyrimidin-1-amine scaffold acted as insulin secretagogues under high, but not low, glucose conditions. Exploration of the structure-activity relationship around the scaffold demonstrated the key role of the guanidine moiety, as well as the importance of two lipophilic regions, and led to the identification of 9h, which stimulated insulin secretion in isolated rat pancreatic islets in a glucose-dependent manner.
Chroman-4-one- and chromone-based sirtuin 2 inhibitors with antiproliferative properties in cancer cells
Seifert, Tina,Malo, Marcus,Kokkola, Tarja,Engen, Karin,Fridén-Saxin, Maria,Wallén, Erik A. A.,Lahtela-Kakkonen, Maija,Jarho, Elina M.,Luthman, Kristina
, p. 9870 - 9888 (2015/02/05)
Sirtuins (SIRTs) catalyze the NAD+-dependent deacetylation of Nε-acetyl lysines on various protein substrates. SIRTs are interesting drug targets as they are considered to be related to important pathologies such as inflammation and aging-associated diseases. We have previously shown that chroman-4-ones act as potent and selective inhibitors of SIRT2. Herein we report novel chroman-4-one and chromone-based SIRT2 inhibitors containing various heterofunctionalities to improve pharmacokinetic properties. The compounds retained both high SIRT2 selectivity and potent inhibitory activity. Two compounds were tested for their antiproliferative effects in breast cancer (MCF-7) and lung carcinoma (A549) cell lines. Both compounds showed antiproliferative effects correlating with their SIRT2 inhibition potency. They also increased the acetylation level of α-tubulin, indicating that SIRT2 is likely to be the target in cancer cells. A binding mode of the inhibitors that is consistent with the SAR data was proposed based on a homology model of SIRT2.
New tetraphosphorus ligands for highly linear selective hydroformylation of allyl and vinyl derivatives
Cai, Chaoxian,Yu, Shichao,Cao, Bonan,Zhang, Xumu
experimental part, p. 9992 - 9998 (2012/09/07)
New tetraphosphorus ligands have been developed and applied in the rhodium-catalyzed regioselective hydroformylation of a variety of functionalized allyl and vinyl derivatives. Remarkably high linear selectivity was obtained by these tetraphosphorus ligands. The ligand that bears strong electron-withdrawing 2,4-difluorophenyl groups is the most effective one in affording linear aldehydes. The Rh/tetraphosphorus ligand catalyst is highly effective to produce linear aldehydes from functionalized allyl derivatives with heteroatoms or aromatic groups directly adjacent to the allyl group. For vinyl derivatives, the ligand is highly linear selective for acrylic derivatives, styrene, vinyl pyridine, and vinyl phthalimide. Linear to branch ratios of 26:1 and 10:1 were obtained for the hydroformylation of styrene and allyl cyanide, respectively. New tetraphosphorus ligands have been developed and applied in the rhodium-catalyzed regioselective hydroformylation of a variety of allyl and vinyl olefins (see scheme). Remarkably high linear selectivities were obtained by these ligands. Linear-to-branch ratios of 26:1 and 10:1 were obtained for the hydroformylation of styrene and allyl cyanide, respectively. Copyright
N-substituted piperidinyl alkyl imidazoles: Discovery of methimepip as a potent and selective histamine H3 receptor agonist
Kitbunnadaj, Ruengwit,Hashimoto, Takeshi,Poli, Enzo,Zuiderveld, Obbe P.,Menozzi, Alessandro,Hidaka, Ryoko,De Esch, Iwan J. P.,Bakker, Remko A.,Menge, Wiro M. P. B.,Yamatodani, Atsushi,Coruzzi, Gabriella,Timmerman, Henk,Leurs, Rob
, p. 2100 - 2107 (2007/10/03)
In this study, we continue our efforts toward the development of potent and highly selective histamine H3 receptor agonists. We introduced various alkyl or aryl alkyl groups on the piperidine nitrogen of the known H3/H4 agonist immepip and its analogues (1-3a). We observed that N-methyl-substituted immepip (methimepip) exhibits high affinity and agonist activity at the human histamine H3 receptor (pK i = 9.0 and pEC50 = 9.5) with a 2000-fold selectivity at the human H3 receptor over the human H4 receptor and more than a 10000-fold selectivity over the human histamine H1 and H 2 receptors. Methimepip was also very effective as an H3 receptor agonist at the guinea pig ileum (pD2 = 8.26). Moreover, in vivo microdialysis (in rat brain) showed that methimepip reduces the basal level of brain histamine to about 25% after a 5 mg/kg intraperitoneal administration.
