Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Design, synthesis, and antiproliferative and CDK2-cyclin a inhibitory activity of novel flavopiridol analogues.

ABSTRACT: The design and synthesis of a small library of 8-amidoflavone, 8-sulfonamidoflavone, 8-amido-7-hydroxyflavone, and heterocyclic analogues of flavopiridol is reported. The potential activity of these compounds as kinase inhibitors was evaluated by cytotoxicity studies in MCF-7 and ID-8 cancer cell lines and inhibition of CDK2-Cyclin A enzyme activity in vitro. The antiproliferative and CDK2-Cyclin A inhibitory activity of these analogues was significantly lower than the activity of flavopiridol. Molecular docking simulations were carried out and these studies suggested a different binding orientation inside the CDK2 binding pocket for these analogues compared to flavopiridol.

SUBMITTER: Ahn YM

PROVIDER: S-EPMC1876666 | biostudies-literature | 2007 Jan

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Design, synthesis, and antiproliferative and CDK2-cyclin a inhibitory activity of novel flavopiridol analogues.

Ahn Yu Mi YM Vogeti Lakshminarayana L Liu Chun-Jing CJ Santhapuram Hari K R HK White Jonathan M JM Vasandani Veena V Mitscher Lester A LA Lushington Gerald H GH Hanson Paul R PR Powell Douglas R DR Himes Richard H RH Roby Katherine F KF Ye Qizhuang Q Georg Gunda I GI

Bioorganic & medicinal chemistry 20061101 2

The design and synthesis of a small library of 8-amidoflavone, 8-sulfonamidoflavone, 8-amido-7-hydroxyflavone, and heterocyclic analogues of flavopiridol is reported. The potential activity of these compounds as kinase inhibitors was evaluated by cytotoxicity studies in MCF-7 and ID-8 cancer cell lines and inhibition of CDK2-Cyclin A enzyme activity in vitro. The antiproliferative and CDK2-Cyclin A inhibitory activity of these analogues was significantly lower than the activity of flavopiridol. ...[more]

PMID: 17123821

Similar Datasets

Populene D analogues: design, concise synthesis and antiproliferative activity.

Project description:An efficient and concise synthesis of nine populene D analogues was performed using an iodine-catalyzed Prins cyclization as the key transformation. The antiproliferative activity of these new pyrans against several cancer cell lines was then investigated. Among them, an isochromene with moderate activity (mean logGI(50) = 0.91) was found. Additionally, compounds with selectivity toward the tumor cell lines NCI-ADR/RES, OVCAR-3, and HT29 were discovered.

| S-EPMC6269118 | biostudies-literature

Monoamine Oxidase Inhibitory Activity of Novel Pyrazoline Analogues: Curcumin Based Design and Synthesis.

Project description:A series of new 2-methoxy-4-(5-phenyl-4,5-dihydro-1H-pyrazol-3-yl)phenolderivatives, 4-13, were synthesized and tested for their human MAO inhibitory activity. All the compounds were found to be selective and reversible toward hMAO-A except 4, a selective inhibitor of hMAO-B and 12, a nonselective inhibitor. Compound 7 was found to be a potent inhibitor of hMAO-A with Ki = 0.06 ± 0.003 ?M and was having selectivity index of (SI = 1.02 × 10(-5)). It was found to be better than standard drug, Moclobemide (hMAO-A with Ki = 0.11 ± 0.01 ?M) with selectivity index of SI = 0.049. Molecular docking simulation was carried out to understand the crucial interactions responsible for selectivity and potency.

| S-EPMC4716609 | biostudies-literature

Design and Synthesis of Novel Dehydroepiandrosterone Analogues as Potent Antiproliferative Agents.

Project description:The aim of the present study was to determine the cytotoxic effects of a series of novel dehydroepiandrosterone derivatives containing triazole at the C16 position on human cancer cells. The cancer cells used in the present study were A549, Hela, HepG-2, BEL7402, MCF-7, and HCT116. Several of the synthesised compounds exhibited potent antiproliferative effects. The most promising compound was (E)-3-hydroxy-16-((1-(4-iodophenyl)-1H-1,2,3-triazole-4-yl)methylene)-10,13-dimet-hyl-1,3,4,7,8,9,10,11,12,13,15,16-dodecahydro-2H-cyclopenta[a]phenanthren-17(14)-one (compound 2n), which showed considerably high antiproliferative activity in the HepG-2 cell line, with an IC50 value of 9.10 µM, and considerably high activity against the MCF-7 cell line, with an IC50 value of 9.18 µM. Flow cytometry assays demonstrated that compound 2n exerted antiproliferative effects by arresting cells in the G2 phase of the cell cycle and inducing apoptosis.

| S-EPMC6225165 | biostudies-literature

Novel piperine-carboximidamide hybrids: design, synthesis, and antiproliferative activity via a multi-targeted inhibitory pathway.

Project description:A new series of piperine-carboximidamide hybrids VIa-k was developed as a new cytotoxic agent targeting EGFR, BRAF, and CDK2. The antiproliferative effect against four cancer cells was investigated against erlotinib. Hybrids VIc, VIf, VIg, VIi, and VIk have the highest antiproliferative activity. Compounds VIc, VIf, VIg, VIi, and VIk inhibited EGFR with IC50 values ranging from 96 to 127 nM. Compounds VIf and VIk had the most potent inhibitory activity as BRAFV600E (IC50 = 49 and 40 nM, respectively) and were discovered to be potent inhibitors of cancer cell proliferation (GI50 = 44 and 35 nM against four cancer cell lines, respectively). Compound VIk, the most effective derivative as an antiproliferative agent, demonstrated potent anti-CDK2 action with an IC50 value of 12 nM, which is 1.5-fold more potent than the reference dinaciclib. Finally, VIc, VIf, and VIk have a high capacity to inhibit LOX-IMVI cell line survival.

| S-EPMC9721426 | biostudies-literature

Potent Quinoline-Containing Combretastatin A-4 Analogues: Design, Synthesis, Antiproliferative, and Anti-Tubulin Activity.

Project description:A novel series of quinoline derivatives of combretastatin A-4 incorporating rigid hydrazone and a cyclic oxadiazole linkers were synthesized and have demonstrated potent tubulin polymerization inhibitory properties. Many of these novel derivatives have shown significant antiproliferative activities in the submicromolar range. The most potent compound, 19h, demonstrated superior IC50 values ranging from 0.02 to 0.04 µM against four cancer cell lines while maintaining low cytotoxicity in MCF-10A non-cancer cells, thereby suggesting 19h's selectivity towards proliferating cancer cells. In addition to tubulin polymerization inhibition, 19h caused cell cycle arrest in MCF-7 cells at the G2/M phase and induced apoptosis. Collectively, these findings indicate that 19h holds potential for further investigation as a potent chemotherapeutic agent targeting tubulin.

| S-EPMC7698209 | biostudies-literature

Design, Synthesis, Docking Study, and Antiproliferative Evaluation of Novel Schiff Base-Benzimidazole Hybrids with VEGFR-2 Inhibitory Activity.

Project description:A new series of Schiff-benzimidazole hybrids 3a-o has been designed and synthesized. The structure of the target compounds was proved by different spectroscopic and elemental analysis tools. The target compounds were evaluated for their in vitro cytotoxic activity against 60 cancer cell lines according to NCI single- and five-dose protocols. Consequently, four compounds were further examined against the most sensitive lung cancer A549 and NCI-H460 cell lines. Compounds 3e and 3g were the most active, achieving 3.58 ± 0.53, 1.71 ± 0.17 and 1.88 ± 0.35, 0.85 ± 0.24 against A549 and NCI-H460 cell lines, respectively. Moreover, they showed remarkable inhibitory activity on the VEGFR-2 TK with 86.23 and 89.89%, respectively, as compared with Sorafenib (88.17%). Moreover, cell cycle analysis of NCI-H460 cells treated with 3e and 3g showed cellular cycle arrest at both G1 and S phases (supported by caspases-9 study) with significant pro-apoptotic activity, as indicated by annexin V-FITC staining. The binding interactions of these compounds were confirmed through molecular docking studies; the most active compounds displayed complete overlay with, and a similar binding mode and pose to, Sorafenib, a reference VEGFR-2 inhibitor.

| S-EPMC9862622 | biostudies-literature

Design, Synthesis, and Antiproliferative Activity of Novel Neocryptolepine-Rhodanine Hybrids.

Project description:A series of novel neocryptolepine-rhodanine hybrids (9a,b, 11a-d, 14, and 16a,b) have been synthesized by combining neocryptolepine core 5 modified at the C-11 position with rhodanine condensed with the appropriate aryl/hetero aryl aldehydes. Based on these findings, the structures of the hybrids were confirmed by spectral analyses. By employing the MTT assay, all hybrids were tested for their in vitro antiproliferative activity against two cancer cell lines, including MDA-MB-231 (human breast) and HepG-2 (hepatocellular carcinoma). Interestingly, the IC50 values of all hybrids except 9b and 11c showed activity comparable to the standard anticancer drug, 5-fluorouracil, against HepG-2 cancer cells. Furthermore, the cytotoxicity of all the synthesized hybrids was investigated on a normal skin human cell line (BJ-1), and the results showed that these compounds had no significant cytotoxicity toward these healthy cells at the highest concentration used in this study. This study also indicated that the active hybrids exert their cytotoxic activity via the induction of apoptosis. A molecular docking study was used to shed light on the molecular mechanism of their anticancer activity. The docking results revealed that the hybrids exert their mode of action through DNA intercalation. Furthermore, in silico assessment for pharmacokinetic properties was performed on the most potent compounds, which revealed candidates with good bioavailability, high tolerability with cell membranes, and positive drug-likeness values.

| S-EPMC9656124 | biostudies-literature

Novel Acrylate-Based Derivatives: Design, Synthesis, Antiproliferative Screening, and Docking Study as Potential Combretastatin Analogues.

Project description:A variety of 3-(4-chlorophenyl) acrylic acids 4a,b and 3-(4-chlorophenyl)acrylate esters 5a-i were synthesized and structurally proven by spectroscopic studies such as IR, 1H NMR, and 13C NMR as well as mass spectrometry. All substances were investigated for their antiproliferative efficacy against the MDA-MB-231 cell line. Among these, acrylic acid compound 4b demonstrated the most potent cytotoxic effect with an IC50 value of 3.24 ± 0.13 μM, as compared to CA-4 (IC50 = 1.27 ± 09 μM). Additionally, acrylic acid molecule 4b displayed an inhibitory effect against β-tubulin polymerization with a percentage inhibition of 80.07%. Furthermore, compound 4b was found to produce considerable cell cycle arrest at the G2/M stage and cellular death, as demonstrated by FACS analysis. In addition, the in vivo antitumor screening of the sodium salt of acrylic acid 4b was carried out, and the results have shown that the tested molecule showed a significant decrease in viable EAC count and EAC volume, accompanied by a considerable increase in the life span prolongation, if compared to the positive control group. Furthermore, molecular modeling studies were performed to understand how the highly efficient chemicals 4b and 5e interact with the colchicine-binding region on tubulin. This work aims to shed light on the reasons behind their exceptional cytotoxicity and their better capacity to inhibit tubulin in comparison to CA-4.

| S-EPMC10586439 | biostudies-literature

Novel benzylidene benzofuranone analogues as potential anticancer agents: design, synthesis and in vitro evaluation based on CDK2 inhibition assays.

Project description:The classical anticancer agents do not have their efficacy on inhibiting the G2 phase of the cell cycle. There are a very few reports available on drugs that work at G2 phase. Flavopiridol is one such drug candidate. In the current study, we sought to make analogues of flavopiridol. Still, the conditions used during their synthesis were unfavourable for the formation of flavopiridol and led to the generation of benzofuranones. In the present work, a new series of benzylidene benzofuranones were designed, synthesized and evaluated for their antioxidant, anti-colorectal cancer activity. Molecular docking, MMGBSA and molecular dynamics studies were conducted to assess their binding affinity at the active site of CDK2. Based on the cytotoxicity exhibited by test compounds, the compound NISOA4 (from isopropyl series) was further selected for mechanistic anticancer studies on HCT 116 cell lines. The compound selected was evaluated by comet assay, DNA fragmentation assay, cell cycle analysis, apoptosis detection by annexin FITC, semi-quantitative RTPCR based gene expression studies and FRET assay on the target CDK2/Cyclin A. Compound NISOA4 exhibited marked olive moments in comet assay studies. The apoptotic DNA fragmentation for compound NISOA4 demonstrated a marked change in the DNA fragmentation. The compound exhibited cell cycle arrest at G2/M phase at both the test concentrations. Apoptosis induction was observed at both the test concentrations and the compound was found to be a potent proapoptotic agent. It exhibited marked inhibition for the CDK2 gene expression and did not show any effect on CyclinA gene expression. However, the compound NISOA4 along with other analogues showed appreciable inhibition for the CDK2/Cyclin A target enzyme.Supplementary informationThe online version contains supplementary material available at 10.1007/s13205-022-03312-1.

| S-EPMC9440176 | biostudies-literature

Design, Synthesis, and Monoamine Oxidase B Selective Inhibitory Activity of <i>N</i>-Arylated Heliamine Analogues.

Project description:Monoamine oxidase B (MAO-B) metabolizes monoamines such as dopamine regarding neural transmission and controls its level in the mammalian's brain. When MAO-B metabolizes dopamine abnormally, normal neurotransmission does not occur, and central nervous system disorders such as Parkinson's disease may develop. Although several MAO inhibitors have been developed, most of them have no selectivity between monoamine oxidase A (MAO-A) and MAO-B, or they work irreversibly against the enzyme. This report describes the first case of screening of N-arylated heliamine derivatives to develop novel MAO-B selective inhibitors that can be synthesized concisely by microwave-assisted Pd nanoparticle-catalyzed Buchwald-Hartwig amination. We discovered that the derivatives 4h, 4i, and 4j display inhibitory activity against MAO-B with IC50 values of 1.55, 13.5, and 5.08 μM, respectively.

| S-EPMC9575162 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data