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Structure-activity relationship (SAR) studies of 3-(2-amino-ethyl)-5-(4-ethoxy-benzylidene)-thiazolidine-2,4-dione: development of potential substrate-specific ERK1/2 inhibitors.

ABSTRACT: A series of analogs of 3-(2-amino-ethyl)-5-(4-ethoxy-benzylidene)-thiazolidine-2,4-dione, a putative substrate-specific ERK1/2 inhibitor, were synthesized and biologically characterized in human leukemia U937 cells to define its pharmacophore. It was discovered that shift of ethoxy substitution from the 4- to the 2-position on the phenyl ring significantly improved functional activities of inhibiting cell proliferation and inducing apoptosis. This may provide access to a new lead for developing ERK1/2 substrate-specific inhibitors.

SUBMITTER: Li Q

PROVIDER: S-EPMC6088847 | biostudies-literature | 2009 Nov

REPOSITORIES: biostudies-literature

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Structure-activity relationship (SAR) studies of 3-(2-amino-ethyl)-5-(4-ethoxy-benzylidene)-thiazolidine-2,4-dione: development of potential substrate-specific ERK1/2 inhibitors.

Li Qianbin Q Al-Ayoubi Adnan A Guo Tailiang T Zheng Hui H Sarkar Aurijit A Nguyen Tri T Eblen Scott T ST Grant Steven S Kellogg Glen E GE Zhang Shijun S

Bioorganic & medicinal chemistry letters 20090918 21

A series of analogs of 3-(2-amino-ethyl)-5-(4-ethoxy-benzylidene)-thiazolidine-2,4-dione, a putative substrate-specific ERK1/2 inhibitor, were synthesized and biologically characterized in human leukemia U937 cells to define its pharmacophore. It was discovered that shift of ethoxy substitution from the 4- to the 2-position on the phenyl ring significantly improved functional activities of inhibiting cell proliferation and inducing apoptosis. This may provide access to a new lead for developing ...[more]

PMID: 19796943

Similar Datasets

Novel Thiazolidine-2,4-dione-trimethoxybenzene-thiazole Hybrids as Human Topoisomerases Inhibitors.

Project description:Cancer is a complex and heterogeneous disease and is still one of the leading causes of morbidity and mortality worldwide, mostly as the population ages. Despite the encouraging advances made over the years in chemotherapy, the development of new compounds for cancer treatments is an urgent priority. In recent years, the design and chemical synthesis of several innovative hybrid molecules, which bring different pharmacophores on the same scaffold, have attracted the interest of many researchers. Following this strategy, we designed and synthetized a series of new hybrid compounds that contain three pharmacophores, namely trimethoxybenzene, thiazolidinedione and thiazole, and tested their anticancer properties on two breast cancer (MCF-7 and MDA-MB-231) cell lines and one melanoma (A2058) cell line. The most active compounds were particularly effective against the MCF-7 cells and did not affect the viability of the normal MCF-10A cells. Docking simulations indicated the human Topoisomerases I and II (hTopos I and II) as possible targets of these compounds, the inhibitory activity of which was demonstrated by the mean of direct enzymatic assays. Particularly, compound 7e was proved to inhibit both the hTopo I and II, whereas compounds 7c,d blocked only the hTopo II. Finally, compound 7e was responsible for MCF-7 cell death by apoptosis. The reported results are promising for the further design and synthesis of other analogues potentially active as anticancer tools.

| S-EPMC10384675 | biostudies-literature

Biological characterization of 3-(2-amino-ethyl)-5-[3-(4-butoxyl-phenyl)-propylidene]-thiazolidine-2,4-dione (K145) as a selective sphingosine kinase-2 inhibitor and anticancer agent.

Project description:In our effort to develop selective sphingosine kinase-2 (SphK2) inhibitors as pharmacological tools, a thiazolidine-2,4-dione analogue, 3-(2-amino-ethyl)-5-[3-(4-butoxyl-phenyl)-propylidene]-thiazolidine-2,4-dione (K145), was synthesized and biologically characterized. Biochemical assay results indicate that K145 is a selective SphK2 inhibitor. Molecular modeling studies also support this notion. In vitro studies using human leukemia U937 cells demonstrated that K145 accumulates in U937 cells, suppresses the S1P level, and inhibits SphK2. K145 also exhibited inhibitory effects on the growth of U937 cells as well as apoptotic effects in U937 cells, and that these effects may be through the inhibition of down-stream ERK and Akt signaling pathways. K145 also significantly inhibited the growth of U937 tumors in nude mice by both intraperitoneal and oral administration, thus demonstrating its in vivo efficacy as a potential lead anticancer agent. The antitumor activity of K145 was also confirmed in a syngeneic mouse model by implanting murine breast cancer JC cells in BALB/c mice. Collectively, these results strongly encourage further optimization of K145 as a novel lead compound for development of more potent and selective SphK2 inhibitors.

| S-EPMC3577900 | biostudies-literature

Synthesis of thiazolidine-2,4-dione derivatives: anticancer, antimicrobial and DNA cleavage studies.

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| S-EPMC5026645 | biostudies-literature

Design, synthesis, in silico studies and biological evaluation of 5-((<i>E</i>)-4-((<i>E</i>)-(substituted aryl/alkyl)methyl)benzylidene)thiazolidine-2,4-dione derivatives.

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| S-EPMC7110766 | biostudies-literature

Synthesis and in vitro antiproliferative and antibacterial activity of new thiazolidine-2,4-dione derivatives.

Project description:In our present research, we synthesised new thiazolidine-2,4-diones (12-28). All the newly synthesised compounds were evaluated for antiproliferative and antibacterial activity. Antiproliferative evaluation was carried out using normal human skin fibroblasts and tumour cell lines: A549, HepG2, and MCF-7. The IC50 values were determined for tested compounds revealing antiproliferative activity. Moreover, safety index (SI) was calculated. Among all tested derivatives, the compound 18 revealed the highest antiproliferative activity against human lung, breast, and liver cancer cells. More importantly, the derivative 18 showed meaningfully lower IC50 values when compared to the reference substance, irinotecan, and relatively high SI values. Moreover, newly synthesised compounds were screened for the bacteria growth inhibition in vitro. According to our screening results, most active compound was the derivative 18 against Gram-positive bacteria. Therefore, it may be implied that the novel compound 18 appears to be a very promising agent for anticancer treatment.

| S-EPMC6010082 | biostudies-literature

3-{1-[(2,4-Dinitrophenyl)hydrazino]-ethyl-idene}-5-(1-methylpropyl)pyrrolidine-2,4-dione.

Project description:In the title compound, C(16)H(19)N(5)O(6), two intramolecular N-H⋯O hydrogen bonds help to establish the conformation. In the crystal, intermolecular N-H⋯O links result in chains propagating in [010].

| S-EPMC2977683 | biostudies-literature

3-Amino-5,5-di-phenyl-imidazolidine-2,4-dione.

Project description:The title compound, C15H13N3O2, crystallizes with two independent mol-ecules in the asymmetric unit, which differ considerably in the dihedral angles made between the phenyl groups and the five-membered rings [47.19 (8) and 61.16 (9)° in one mol-ecule and 55.04 (10) and 55.00 (8)° in the other]. In the crystal, N-H⋯O hydrogen bonds generate columnar units having approximate fourfold rotational symmetry about axes parallel to b.

| S-EPMC3998397 | biostudies-literature

Synthesis, α-glucosidase inhibition and molecular docking studies of novel thiazolidine-2,4-dione or rhodanine derivatives.

Project description:A series of novel thiazolidine-2,4-dione or rhodanine derivatives (5a-5k, 6a-6k) were synthesized and evaluated for their α-glucosidase inhibitory activity. The majority of compounds exhibited potent inhibitory activity in the range of 5.44 ± 0.13 to 50.45 ± 0.39 μM, when compared to the standard drug acarbose (IC50 = 817.38 ± 6.27 μM). Among the compounds in the series, compounds 5k, 6a, 6b, 6e, 6h and 6k showed potent inhibitory potential with IC50 values of 20.95 ± 0.21, 16.11 ± 0.19, 7.72 ± 0.16, 7.91 ± 0.17, 6.59 ± 0.15 and 5.44 ± 0.13 μM, respectively. Compound 6k (IC50 = 5.44 ± 0.13 μM), containing chloro and rhodanine groups at the 2- and 4-positions of the phenyl ring respectively, was found to be the most active compound that inhibits α-glucosidase activity. Furthermore, molecular docking studies were performed to understand the binding interactions between the molecule and enzyme.

| S-EPMC6072357 | biostudies-literature

3-[1-(2-Hy-droxy-anilino)ethyl-idene]-3H-chromen-2,4-dione.

Project description:The title compound is a new amino-coumarin derivative, C17H13NO4, and was synthesized by the condensation of 2-amino-phenol and 3-acetyl-4-hy-droxy-coumarin. An intra-molecular N-H⋯O hydrogen bond generates an S(6) ring motif. In the crystal, the molecules are linked into chains extending in the [010] direction by O-H⋯O hydrogen bonds. There is also a π-π stacking inter-action between the bicyclic coumarin fragment and the phenol ring [centroid-centroid distance = 3.7510 (14) Å], and these ring systems form between them a dihedral angle of 53.3 (2)°. Intermolecular hydrogen bond C-H⋯O hydrogen bonding is also observed in the interconnection of the crystal packing.

| S-EPMC3793787 | biostudies-literature

(Z)-5-(2,4-Dihydroxybenzylidene)thiazolidine-2,4-dione Prevents UVB-Induced Melanogenesis and Wrinkle Formation through Suppressing Oxidative Stress in HRM-2 Hairless Mice.

Project description:Background. Uncontrolled melanogenesis and wrinkle formation are an indication of photoaging. Our previous studies demonstrated that (Z)-5-(2,4-dihydroxybenzylidene)thiazolidine-2,4-dione (MHY498) inhibited tyrosinase activity and melanogenesis in vitro. Objective. To examine in vivo effects of MHY498 as an antiaging compound on UVB-induced melanogenesis and wrinkle formation, we topically applied MHY498 on dorsal skin of HRM-2 hairless mice. Methods. Using histological analysis, we evaluated effects of MHY498 on melanogenesis and wrinkle formation after UVB exposure. In addition, related molecular signaling pathways were examined using western blotting, fluorometric assay, and enzyme-linked immunosorbent assay. Results. MHY498 suppressed UVB-induced melanogenesis by inhibiting phosphorylation of CREB and translocation of MITF protein into the nucleus, which are key factors for tyrosinase expression. Consistently, tyrosinase protein levels were notably reduced in the dorsal skin of the hairless mice by MHY498 treatment. Furthermore, MHY498 inhibited UVB-induced wrinkle formation and collagen fiber destruction by increasing type 1 procollagen concentration and decreasing protein expression levels of MMPs, which play an essential role in collagen fiber degradation. As a mechanism, MHY498 notably ameliorated UVB-induced oxidative stress and NF-κB activation in the dermal skin of the hairless mice. Conclusion. Our study suggests that MHY498 can be used as a therapeutic or cosmetic agent for preventing uncontrolled melanogenesis and wrinkle formation.

| S-EPMC4875997 | biostudies-literature

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