A375P Human Melanoma Cell Line Research Articles

Design and synthesis of new imidazo[1,2-a]pyridine and imidazo[1,2-a]pyrazine derivatives with antiproliferative activity against melanoma cells

Melanoma is an aggressive form of skin cancer and it is generally associated with poor prognosis in patients with late-stage disease. Due to the increasing occurrence of melanoma, there is a need for the development of novel therapies. A new series of diarylamide and diarylurea derivatives containing imidazo[1,2-a]pyridine or imidazo[1,2-a]pyrazine scaffold was designed and synthesized to investigate their in vitro efficacy against the A375P human melanoma cell line. We found several compounds expressing submicromolar IC50 values against the A375P cells, from which 15d, 17e, 18c, 18h, 18i demonstrated the highest potencies with IC50 below 0.06 μM.

Synthesis of quinolinylaminopyrimidines and quinazolinylmethylaminopyrimidines with antiproliferative activity against melanoma cell line

Synthesis of a new series of quinolinylaminopyrimidines 1a–k and quinazolinylmethylaminopyrimidines 2a–i containing aminoquinoline and aminoquinazoline as hinge regions is described. Their in vitro antiproliferative activities against A375P human melanoma cell line were tested. Among them, compounds 1h and 1k exhibited the highest antiproliferative activities against A375P cell line with IC50 values in sub-micromolar scale. Compounds 1i, 2b and 2g showed similar potency against A375P to Sorafenib as a reference compound. The representative compound 1h showed high, dose-dependent inhibition of MEK and ERK kinases.

Design, synthesis and biological evaluation of benzyl 2-(1H-imidazole-1-yl) pyrimidine analogues as selective and potent Raf inhibitors

The synthesis of a novel series of (4-aminobenzyl/benzoyl)-1H-imidazol-1-yl pyrimidin-2-yl derivatives 9, 10, 18, 19 and their in vitro antiproliferative activities against the A375P human melanoma cell line and the U937 human leukemic monocyte lymphoma cell line are described. Potent antiproliferative effects were found from 9l, 9s and 10c; 10c was found to be a highly potent and selective BRAF V600E and CRAF inhibitor (IC50=38.3nM and 8.79nM).

ChemInform Abstract: Synthesis of New Pyrimidinylaminobenzene Derivatives and Their Antiproliferative Activities Against Melanoma Cell Line.

AbstractDiaryl amide (I) and diaryl urea (II) derivatives possessing a pyrimidinylaminobenzene scaffold are synthesized and some of them are screened for their in vitro antiproliferative activities against A375P human melanoma cell line.

Synthesis of New Pyrimidinylaminobenzene Derivatives and Their Antiproliferative Activities against Melanoma Cell Line

Center for Biomaterials, Korea Institute of Science and Technology, P.O. Box 131, Cheongryang, Seoul 130-650, KoreaReceived April 15, 2013, Accepted May 7, 2013A series of new diarylamide and diarylurea derivatives possessing pyrimidinylaminobenzene scaffold wassynthesized. Their in vitro antiproliferative activities were tested against A375P human melanoma cell line.Among them, compounds 1a-c, k and 2b-d, f, g, j, l showed superior potencies against A375P humanmelanoma cell line to Sorafenib. In particular, compound 2f possessing 3-fluoro-5-trifluoromethyl moietyexhibited the highest potency with IC

Synthesis and Antiproliferative Activity of New Aminoisoquinolinylurea Derivatives against Melanoma Cell Line

A series of new diarylureas possessing aminoisoquinoline scaffold was synthesized, and their in vitro antiproliferative activity against A375P human melanoma cell line was tested. Compounds 1d, 1l, 1n, 1p, 1q, and 1t showed superior potency against A375P to Sorafenib. The highest potency was shown by compound 1p possessing 3,5-bis(trifluoromethyl)phenyl terminal ring with <TEX>$IC_{50}$</TEX> value of <TEX>$0.41{\mu}M$</TEX>.

Design, Synthesis, and Preliminary Cytotoxicity Evaluation of New Diarylureas and Diarylamides Possessing 1,3,4-Triarylpyrazole Scaffold

A series of new diarylureas and diarylamides possessing 1,3,4-triarylpyrazole scaffold was synthesized and their in vitro antiproliferative activities against A375P human melanoma cell line and NCI-60 cell line panel were tested. Compounds 9, 11, 12, 14, and 17-21 showed superior potency against A375P to Sorafenib. Over the NCI-60 cancer cell line panel, compound 14 possessing a methoxy group, amide linker, and 4-chloro-3-(trifluoromethyl)phenyl terminal ring showed the highest potency and broad-spectrum anticancer activity. Compound 13 showed high selectivity towards leukemia subpanel over other cancer types.

Design, synthesis, and antiproliferative activity of new 1H-pyrrolo[3,2-c]pyridine derivatives against melanoma cell lines. Part 2

A new series of diarylureas and diarylamides possessing 1H-pyrrolo[3,2-c]pyridine scaffold was designed and synthesized. Their in vitro antiproliferative activities against A375P human melanoma cell line and NCI-9 human melanoma cell line panel were tested. All the target compounds, except three amino derivatives 8g, h and 9h, demonstrated superior potencies against A375P to Sorafenib. In addition, compounds 8a and 9b–f demonstrated higher potencies than Vemurafenib against A375P. Compounds 8c and 9b were 7.50 and 454.90 times, respectively, more selective towards A375P melanoma cells over NIH3T3 fibroblasts. Furthermore, compounds 8d, e and 9a–d, f demonstrated very high potencies against the nine tested melanoma cell lines at the NCI. The bisamide derivatives 9a–c, f showed 2-digit nanomolar IC50 values over different cell lines of the NCI-9 melanoma cell lines.

ChemInform Abstract: New Imidazo[2,1‐b]thiazole Derivatives: Synthesis, in vitro Anticancer Evaluation, and in silico Studies.

AbstractCompounds (IIIb), (IIIf), (IVb), and (IVd)—(IVg) exhibit higher activity against A375P human melanoma cell line than the reference compound sorafenib.

New diarylureas and diarylamides possessing acet(benz)amidophenyl scaffold: Design, synthesis, and antiproliferative activity against melanoma cell line

A series of new diarylurea and diarylamide derivatives possessing acet(benz)amidophenyl scaffold was synthesized. Their in vitro antiproliferative activity was tested against A375P human melanoma cell line. Compounds 1c,d and 2c,d showed the highest potencies with IC50 values in sub-micromolar scale. In addition, compounds 1b,e,l and 2e,l were more potent than Sorafenib but with IC50 values in micromolar range. Moreover, compound 2c was equipotent to Vemurafenib, and 2d showed higher potency than Vemurafenib against A375P. Molar refractometry calculation and ADME profiling of the highest potent four derivatives 1c,d and 2c,d are also reported.

ChemInform Abstract: New Diarylureas and Diarylamides Containing 1,3,4‐Triarylpyrazole Scaffold: Synthesis, Antiproliferative Evaluation Against Melanoma Cell Lines, ERK Kinase Inhibition, and Molecular Docking Studies.

AbstractDerivatives (Ib)—(Id), and (IIIa)—(IIIc) show the highest potency against A375P human melanoma cell line.

Design, Synthesis, and Antiproliferative Activity of 3,4‐Diarylpyrazole‐1‐carboxamide Derivatives Against Melanoma Cell Line

Synthesis of a new series of 3,4-diarylpyrazole-1-carboxamide derivatives is described. Their antiproliferative activity against A375P human melanoma cell line was tested and the effect of substituents on the diarylpyrazole scaffold was investigated. The biological results indicated that five synthesized compounds (Ig, Ii, IIc, IIg, and IIh) exhibited similar activity to Sorafenib. In addition, three compounds (IIa, IIb, and IIi) were more potent than Sorafenib. Among all of these derivatives, compound IIa which has dimethylamino and phenolic moieties showed the most potent antiproliferative activity against A375P human melanoma cell line. Virtual screening was carried out through docking of the most potent compound IIa into the domain of V600E-b-Raf and the binding mode was studied.

New imidazo[2,1- b]thiazole derivatives: Synthesis, in vitro anticancer evaluation, and in silico studies

A series of 18 new imidazo[2,1- b]thiazole derivatives was synthesized. Their in vitro antiproliferative activities against A375P human melanoma cell line and NCI-60 cell line panel were tested. Compounds 15, 16, 18, 22, 26– 28, and 31 showed superior potency against A375P to sorafenib. In addition, compounds 26 and 27 showed selectivity toward melanoma cell lines than for other cancer types. Both compounds exerted sub-micromolar IC 50 values over 7 (including A375P) and 6 melanoma cell lines, respectively. In silico studies are also reported. ADME profiling, in silico toxicity, drug-likeness, and drug-score data of compounds 26 and 27 are promising.

Design, synthesis, and antiproliferative activity of new 1 H-pyrrolo[3,2- c]pyridine derivatives against melanoma cell lines

Synthesis of a new series of diarylureas and diarylamides having 1 H-pyrrolo[3,2- c]pyridine scaffold is described. Their in vitro antiproliferative activity against A375P human melanoma cell line was tested and the effect of substituents on pyrrolo[3,2- c]pyridine nucleus was investigated. The newly synthesized compounds, except three N-tolyl derivatives ( 8f, 9f, and 9h), generally showed superior activity against A375P to Sorafenib. Among all of these derivatives, compounds 8b, 8g, and 9a–e showed the highest potency against A375P with IC 50 in nanomolar range. In addition, compounds 8d, 8e, 8h, 9g, 9i, and 9j were more potent than Sorafenib but with IC 50 in micromolar range. Compounds 8b, 8g, 9b–d, and 9i demonstrated higher selectivity towards A375P compared with NIH3T3 fibroblasts. The most potent diarylurea 8g and diarylamide 9d were further tested and showed high potency over nine melanoma cell lines at the NCI.

Discovery and initial SAR of pyrimidin-4-yl-1 H-imidazole derivatives with antiproliferative activity against melanoma cell lines

The synthesis of a novel series of pyrimidin-4-yl-1 H-imidazol-2-yl derivatives 7, 8, 9 and their antiproliferative activities against A375P human melanoma cell line and WM3629 cell line were described. Most compounds showed superior antiproliferative activities compared to Sorafenib, the well-known RAF inhibitor. Among them, 7a exhibited potent activities on both cell lines (IC 50 = 0.62 and 4.49 μM, respectively) and turned out to be a selective and potent CRAF inhibitor.

IL-1alpha gene-transfected human melanoma cells increase tumor-cell adhesion to endothelial cells and their retention in the lung of nude mice.

The interleukin-1alpha(IL-1) gene was introduced by retroviral gene transfer into the A375P human melanoma cell line. Two hygromycin-resistant colonies, colony 3 and colony 6, which respectively do not and do express and release IL-1, were selected on the basis of Northern blot and ELISA. Both colonies adhered to resting human endothelial cells (EC) to the same extent. Pre-treatment of EC for 6 hr with conditioned medium (CM) from colony 6, but not from colony 3, increased the adhesion of A375P melanoma and HT-29 colon-carcinoma cells to EC. This increase was blocked by adding interleukin-l-receptor antagonist (IL-1ra) to the EC monolayer. Treatment of EC with colony-6-CM increased the expression of intercellular-adhesion molecule I (ICAM-1), vascular-cell-adhesion molecule I (VCAM-1) and E-selectin. Co-cultivation of colony-6 but not colony-3 melanoma cells with EC caused time-dependent increased expression of these adhesion proteins, reflecting their kinetics of expression on EC. Treating the EC with monoclonal antibodies to VCAM-1 and E-selectin abolished the colony-6-CM-induced increase in adhesion respectively to A375P melanoma and HT-29 colon-carcinoma cells. In vivo, i.v. injection of colony-6 cells in nude mice increased the expression of VCAM-1 on lung microvascular EC. The retention of radiolabeled A375P melanoma cells in the lung was increased in nude mice primed with colony-6 cells, but not with colony-3 cells, injected 6 hr earlier. These results demonstrate that IL-1 produced constitutively by transformed A375P melanoma cells is functionally active, inducing adhesion molecules on EC that enhance their adhesiveness for tumor cells and increase tumor-cell retention in the lung of nude mice.