排序方式: 共有257条查询结果,搜索用时 145 毫秒
31.
《Bioorganic & medicinal chemistry》2020,28(2):115231
Sirtuins (SIRT1–SIRT7) are an evolutionary conserved family of NAD+-dependent protein deacylases regulating the acylation state of ε-N-lysine residues of proteins thereby controlling key biological processes. Numerous studies have found association of the aberrant enzymatic activity of SIRTs with various diseases like diabetes, cancer and neurodegenerative disorders. Previously, we have shown that substituted 2-alkyl-chroman-4-one/chromone derivatives can serve as selective inhibitors of SIRT2 possessing an antiproliferative effect in two human cancer cell lines. In this study, we have explored the bioisosteric replacement of the chroman-4-one/chromone core structure with different less lipophilic bicyclic scaffolds to overcome problems associated to poor physiochemical properties due to a highly lipophilic substitution pattern required for achieve a good inhibitory effect. Various new derivatives based on the quinolin-4(1H)-one scaffold, bicyclic secondary sulfonamides or saccharins were synthesized and evaluated for their SIRT inhibitory effect. Among the evaluated scaffolds, the benzothiadiazine-1,1-dioxide-based compounds showed the highest SIRT2 inhibitory activity. Molecular modeling studies gave insight into the binding mode of the new scaffold-replacement analogues. 相似文献
32.
《Bioorganic & medicinal chemistry letters》2014,24(16):3673-3682
Owing to their inherent three-dimensionality and structural novelty, spiro scaffolds have been increasingly utilized in drug discovery. In this brief review, we highlight selected examples from the primary medicinal chemistry literature during the last three years to demonstrate the versatility of spiro scaffolds. With recent progress in synthetic methods providing access to spiro building blocks, spiro scaffolds are likely to be used more frequently in drug discovery. 相似文献
33.
Biao Lu Song Huang Jingsong Cao Qiyue Hu Ru Shen Hong Wan Dan Wang Jijun Yuan Lei Zhang Jiayin Zhang Minsheng Zhang Weikang Tao Lianshan Zhang 《Bioorganic & medicinal chemistry》2018,26(3):581-589
A novel series of benzodihydrofuran derivatives was developed as potent MEK inhibitors through scaffold hopping based on known clinical compounds. Further SAR exploration and optimization led to another benzofuran series with good oral bioavailability in rats. One of the compounds EBI-1051 (28d) demonstrated excellent in vivo efficacy in colo-205 tumor xenograft models in mouse and is suitable for pre-clinical development studies for the treatment of melanoma and MEK associated cancers. Compared to AZD6244, EBI-1051 showed superior potency in some cancer cell lines such as colon-205, A549 and MDA-MB-231. 相似文献
34.
《Bioorganic & medicinal chemistry》2016,24(21):5249-5257
In order to address the current downturn in the drug discovery pipeline, initiatives are being undertaken to synthesise screening libraries of sp3-rich, low molecular weight compounds. As part of the European Lead Factory initiative, the synthesis and derivatisation of a simple hexahydrooxazolo[5,4-c]pyridin-2(1H)-one bicyclic carbamate has been achieved. The synthetic route employed involved a telescoped hetero-Diels–Alder/[2,3]-sigmatropic rearrangement/cyclisation sequence to deliver the desired core scaffold containing two points for further diversification. When applied, this synthesis was found to be robust and scalable which allowed the production of a 155 compound library. 相似文献
35.
Takehiko Iwaki Yuji Nakamura Taisaku Tanaka Yasuyuki Ogawa Osamu Iwamoto Yoshihiko Okamura Yumi Kawase Mayumi Furuya Yoshiaki Oyama Takahiro Nagayama 《Bioorganic & medicinal chemistry letters》2017,27(21):4904-4907
Novel thienopyrimidine compounds 2 and 3 were discovered from high-throughput screening as Natriuretic Peptide Receptor A (NPR-A) agonists. Scaffold hopping of a thienopyrimidine ring to a quinazoline ring, introduction of the basic functional group and optimization of the substituent on the 6-position of the benzene ring of quinazoline led to improved agonistic activity. We discovered compound 48, which showed potent agonistic activity for NPR-A with an EC50 value of 0.073 μM, indicating 350-fold potency compared to the hit compound 3. 相似文献
36.
Yamashita T Deguchi K Sehara Y Lukic-Panin V Zhang H Kamiya T Abe K 《Neurochemical research》2009,34(4):707-710
Possible strategies for treating ischemic stroke include: (1) Neuroprotection: preventing damaged neurons from undergoing
apoptosis in the acute phase of cerebral ischemia; (2) Stem cell therapy: the repair of broken neuronal networks with newly
born neurons in the chronic phase of cerebral ischemia. Firstly, we studied the neuroprotective effect of a calcium channel
blocker, azelnidipine, or a by-product of heme degradation, biliverdin, in the ischemic brain. These results revealed both
azelnidipine and biliverdin had a neuroprotective effect in the ischemic brain through their anti-oxidative property. Secondly,
we investigated the role of granulocyte colony-stimulating factor (G-CSF) by administering G-CSF to rats after cerebral ischemia
and found G-CSF plays a critical role in neuroprotection. Lastly, we developed a restorative stroke therapy with a bio-affinitive
scaffold, which is able to provide an appropriate environment for newly born neurons. In the future, we will combine these
strategies to develop more effective therapies for treatment of strokes.
Special issue article in honor of Dr. Akitane Mori. 相似文献
37.
38.
Xiaodong Xiao Bang K. Vu Dimiter S. Dimitrov 《Biochemical and biophysical research communications》2009,387(2):387-202
Isolated immunoglobulin CH2 domains were proposed as scaffolds for selection of binders with potential effector functions. We tested the feasibility of this approach by constructing a large (size 5 × 1010) library where all amino acids in two loops (BC and FG) were mutated to four residues (Y, A, D, or S). Three binders were selected from this library by panning against a gp120-CD4 complex. The strongest binder, m1a1, recognized specifically a highly conserved CD4i epitope and inhibited to various extents seven out of nine HIV-1 isolates from different clades. The loop BC and the conformational state of the scaffold are critical for its binding. These results provide a proof of concept for the potential of CH2 as a scaffold for construction of libraries containing potentially useful binders. The newly identified HIV-1 inhibitors could be further improved to candidate therapeutics and/or used as research reagents for exploration of conserved gp120 structures. 相似文献
39.
40.
The capability of human pluripotent stem cells(h PSCs) to differentiate into a variety of cells in the human body holds great promise for regenerative medicine. Many substrates exist on which h PSCs can be self-renewed, maintained and expanded to further the goal of clinical application of stem cells. In this review, we highlight numerous extracellular matrix proteins, peptide and polymer based substrates, scaffolds and hydrogels that have been pioneered. We discuss their benefits and shortcomings and offer future directions as well as emphasize commercially available synthetic peptidesas a type of substrate that can bring the benefits of regenerative medicine to clinical settings. 相似文献