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34 Xanthones were synthesized by microwave assisted technique. Their in vitro inhibition activities against five cell lines growth were evaluated. The SAR has been thoroughly discussed. 7-Bromo-1,3-dihydroxy-9 H -xanthen-9-one ( 3-1 ) was confirmed as the most active agent against MDA-MB-231 cell line growth with an IC 50 of 0.46 ± 0.03 μM. Combination of 3-1 and 5,6-dimethylxanthone-4-acetic acid ( DMXAA ) showed the best synergistic effect. Apoptosis analysis indicated different contributions of early/late apoptosis and necrosis to cell death for both monomers and the combination. Western Blot implied that t he combination regulated p53/MDM2 to a better healthy state. Furthermore, 3-1 and DMXAA arrested more cells on G2/M phase; while the combination arrested more cells on S phase. All the evidences support that the 3-1 / DMXAA combination is a better anti-cancer therapy. [ABSTRACT FROM AUTHOR]

Benzimidazo[1,2- a ]quinolines and benzo[ b ]thieno[2,3- b ]pyrido[1,2- a ]benzimidazoles with amino chains on the different positions have been evaluated by 2D and 3D assays on the human breast cancer cells. Pentacyclic derivatives were synthesized by microwave assisted amination to study the influence of the thiophene substructure on antitumor activity in comparison to tetracyclic analogues. The results obtained from 2D assay reveals that the antitumor activity is strongly dependent on the nature and position of amino chains. Tetracyclic derivatives displayed selective activity on SK-BR-3 with the 2-amino substituted derivatives as the most active ones while pentacyclic derivatives 6–16 and 21–25 showed more pronounced activity on T-47D. The evaluation of antitumor activity in the 3D assay pointed out that some of the tetracyclic and pentacyclic amino substituted derivatives showed selective activity on the MDA-MB-231 cell line. Influence of physico-chemical properties of the compounds on antiproliferative activity have been investigated by multivariate statistical methods. As a measure of lipophilicity, experimental Chrom LogD values have been determined and number of structural parameters have been calculated for investigated compounds. Main factors contributing to the antiproliferative effect for both 2D and 3D cell cultures are found to be basicity, lipophilicity, molecular weight and number of H-bond donors. [ABSTRACT FROM AUTHOR]

In this study, a series of pyrazole-based structural analogues of GGTI-DU40 ( 1 ) have been synthesized and biologically evaluated for geranylgeranyltransferase 1 (GGT1) and farnesyltransferase (FT) inhibition. The screening results revealed that 2 (IC 50 = 2.4 μM) and 5 (IC 50 = 3.1 μM) are potent GGT1 inhibitors (GGTIs), possessing higher inhibitory activity compared to the control compound 1 (IC 50 = 3.3 μM). The anti-proliferative efficacy of these compounds was further assayed against MDA-MB-231 cells which indicated a significantly higher activity of 2 (IC 50 = 7.6 μM) compared to 1 (IC 50 = 23.0 μM). To examine the capacity of the synthesized compounds to inhibit GGT1 in an intact cell, western blot analysis was performed on the MDA-MB-231 cell line, which revealed very high inhibitory cellular activity of 2 and 5 and demonstrated their capacity to inhibit prenylation of endogenous proteins. Molecular docking studies of 2 against the crystal structure of GGT1 complexed with a geranylgeranyl pyrophosphate (GGPP) Analog and a CaaX (C = cysteine, aa = aliphatic amino acids, and X = any amino acid) portion of the KKKSKTKCVIL peptide substrate revealed several hydrogen bonding interactions and π-π contacts between 2 and the binding pocket of GGT1. Together these data suggest that compound 2 could proceed to in vivo investigation to further assess its efficacy and cytotoxicity. [ABSTRACT FROM AUTHOR]

In this work we present the synthesis and characterization of six new ruthenium compounds with general formulae [Ru(L)(dppb)(bipy)]PF 6 and [Ru(L)(dppe) 2 ]PF 6 where L = salicylic acid (Sal), 4-aminosalicylic acid (AmSal) or 2,4-dihydroxybenzoic acid (DiSal), dppb = 1,4- bis (diphenylphosphino)butane, dppe = 1,2- bis (diphenylphosphino)ethane and bipy = 2,2′-bipyridine. The complexes were characterized by elemental analysis, molar conductivity, cyclic voltammetry, NMR, UV–vis and IR spectroscopies, and two by X-ray crystallography. The 31P{1H} NMR spectra of the complexes with the general formula [Ru(L)(dppe) 2 ]PF 6 showed that the phosphorus signals are solvent-dependent. Aprotic solvents, which form strong hydrogen bonds with the complexes, inhibit the free rotation of the salicylic acid-based, modifying the diphosphine cone angles, leading to distortion of the phosphorus signals in the NMR spectra. The cytotoxicity of the complexes was evaluated in MCF-7, MDA-MB-231, SKBR3 human breast tumor cells, and MCF-10 non-tumor cell lines. The complexes with the structural formula [Ru(L)(dppe) 2 ]PF 6 were the most cytotoxic, and the complex [Ru(AmSal)(dppe) 2 ]PF 6 with L = 4-aminosalicylic acid ligand was the most selective for the MDA-MB-231 cell line. This complex interacts with the transferrin and induces apoptosis through the intrinsic pathway, as demonstrated by increased levels of proteins involved in apoptotic cell death. [Display omitted] • Six Ru(II) complexes of salicylic acid and derivatives were synthesized. • Complex [Ru(AmSal)(dppe) 2 ]PF 6 – Ru(5) was the most selective against TNBC. • Ru(5) inhibited colony formation by acting as a cytotoxic and cytostatic agent. • Ru(5) induced tumor cells apoptosis, altering the mitochondrial membrane potential. • Ru (5) induced cell death through intrinsic apoptotic pathway signaling. [ABSTRACT FROM AUTHOR]

Forty eight 2-phenylnaphthalenoids were designed and successfully synthesized. Their in vitro cytotoxicities against the proliferations of MDA-MB-231, A549 and HeLa cell lines and inhibitory activities on DNA topoisomerase were evaluated. The quantitative structure–activity relationship (QSAR) studies were established on the basis of cytotoxicity data from MDA-MB-231 cell line. Among these compounds, compound 5 showed potent antiproliferative activity (IC 50 = 1 μM) against MDA-MB-231 cells and inhibitory activity on topoisomeraseIIα. Further, in vivo antitumor study with xenograft nude mice indicated that compound 5 inhibited the growth of MDA-MB-231 cells and showed lower toxicity than etoposide (VP16). This work indicates that 2-phenylnaphthalenoids represent a novel type of TopoIIα-inhibitory scaffold for developing new antitumor chemotherapeutic agents. [ABSTRACT FROM AUTHOR]

Abstract: Twenty four compounds with diversified 3-aryl acrylic amide side chains of the simplified saframycin–ecteinascidin pentacyclic skeleton were synthesized via a 14-step stereospecific route starting from l-dopa. The cytotoxicities of these compounds were tested against eight human tumor cell lines including HCT-8, BEL-7402, BGC-803, A549, A2780, MCF-7, MX-1, and MDA-MB-231. Most of these compounds exhibited potent antitumor activity, and a preliminary structure–activity relationship (SAR) was discussed. Compound 28 with 3-thiophenyl acrylic amide side chain exhibited selective cytotoxicity against MDA-MB-231 cell line with the IC50 value of 50 nM. [Copyright &y& Elsevier]

Abstract: A series of 2-hydrazinyl-4-morpholinothieno[3,2-d]pyrimidine derivatives were synthesized and evaluated for their cytotoxic activities against five cancer cell lines. Most of them exhibited moderate to significant cytotoxic activities and high-selectivity against one or more cell lines, and nearly all of them had higher potency than positive controls against MDA-MB-231 cell line. The most promising compound 15f showed strong cytotoxic activities against H460, HT-29 and MDA-MB-231 cell lines, which were 1.7- to 66.5-folds more active than 2-(1H-Indazol-4-yl)-6-((4-(methylsulfonyl)-1-piperazinyl)methyl)-4-(4-morpholinyl)thieno[3,2-d]pyrimidine(GDC-0941). To investigate the SARs of thieno[3,2-d]pyrimidine derivatives in more details, CoMFA (q 2 = 0.436, r 2 = 0.937) and CoMSIA (q 2 = 0.706, r 2 = 0.947) models on H460 cell line were established. The generated 3D-QSAR models can be used for further rational design of novel thienopyrimidines as highly potent and selective cytotoxic agents. [Copyright &y& Elsevier]

Abstract: A series of C5-substituted licofelone ([2,2-dimethyl-6-(4-chlorophenyl)-7-phenyl-2,3-dihydro-1H-pyrrolizin-5-yl]acetic acid) derivatives were developed by a parallel synthesis approach and investigated for cytotoxicity against MCF-7 and MDA-MB-231 cells as well as for anti-inflammatory potency in vitro and in vivo. Dependent on the C5-substituent, the compounds showed high selectivity for MCF-7 cells. Especially 2-oxoethyl benzoate derivatives were inactive at the MDA-MB-231 cell line and as active as 5-FU at MCF-7 cells. C5-acetyl (8a), –2-oxoethyl formiate (8e), –2-oxoethyl acetate (8f) and –2-oxoethyl propionate (8g) derivatives showed growth inhibition at both cell lines, comparable with cisplatin. Modifications significantly reduced the inhibitory potency at COX-1 and COX-2 in vitro and in the xylene-induced ear swelling assay in mice. Only compound 8a was equipotent to licofelone, ibuprofen and celecoxibe in vivo. [Copyright &y& Elsevier]

In our continued SAR study efforts, a series of O -alkylamino-tethered salicylamide derivatives with various amino acid linkers has been designed, synthesized, and biologically evaluated as potent anticancer agents. Five selected compounds with different representative chemical structures were found to show broad anti-proliferative activities, effective against all tested ER-positive breast cancer (BC) and triple-negative breast cancer (TNBC) cell lines with low micromolar IC 50 values. Among these compounds, compound 9a (JMX0293) maintained good potency against MDA-MB-231 cell line (IC 50 = 3.38 ± 0.37 μM) while exhibiting very low toxicity against human non-tumorigenic breast epithelial cell line MCF-10A (IC 50 > 60 μM). Further mechanistic studies showed that compound 9a could inhibit STAT3 phosphorylation and contribute to apoptosis in TNBC MDA-MB-231 cells. More importantly, compound 9a significantly suppressed MDA-MB-231 xenograft tumor growth in vivo without significant toxicity, indicating its great potential as a promising anticancer drug candidate for further clinical development. [Display omitted] • A series of novel salicylamide derivatives has been synthesized as potent anticancer agents. • Compound 9a showed micromolar potency against various breast cancer cell lines. • Compound 9a exhibited very low toxicity against MCF-10A cell lines (IC 50 > 60 μM). • Compound 9a could inhibit STAT3 phosphorylation and promote apoptosis. • Compound 9a significantly suppressed TNBC MDA-MB-231 xenograft tumor growth in vivo. [ABSTRACT FROM AUTHOR]

The dysfunction of histone deacetylase (HDACs) is closely related to tumorigenesis and development, which has been emerged as an attractive drug design target for cancer therapy. In the present study, we designed and synthesized a series of novel HDAC inhibitors using a substituted quinazoline as the capping group and attaching 3, 5-dimethylbenyl as a potential metabolic site protector. 23g and 23h were demonstrated potent HDAC inhibitory activities and anti-proliferative effects against MDA-MB-231 cells. In addition, 23g and 23h both could significantly increase the acetylation level of intracellular proteins, especially in α-Tubulin and HSP90. 23g and 23h displayed a slight different anti-tumor mechanism, 23g mainly induced apoptosis while 23h induced obviously ER-Stress. Furthermore, 23g and 23h both induced autophagy and migration inhibition. In pharmacokinetics assay, 23g showed a significant improvement of pharmacokinetic profile for oral administration. Additionally, 23g presented more potent anti-proliferation and anti-migration activity than SAHA in zebrafish MDA-MB-231 cell line-derived xenograft model. Together, these results demonstrate that 23g is a novel oral HDAC inhibitor with a potential capacity of treating breast cancer. Image 1 • A series of novel histone deacetylase inhibitors were designed and synthesized based on pharmacokinetic profile. • 23g and 23h both promoted apoptosis, autophagy and suppressed migration. • 23g showed significant improved pharmacokinetic profiles for breast cancer therapy. [ABSTRACT FROM AUTHOR]

A series of hybrids of MEK inhibitor and nitric oxide donor have been designed and synthesized. Compound 18h 4-(3-((3-(2-fluoro-3-((N-methylsulfamoyl)amino)benzyl)-4-methyl-2-oxo-2H-chromen-7-yl)oxy) propoxy)-3-(phenylsulfonyl)-1,2,5-oxadiazole 2-oxide] was proven to be more potent than the clinical compound RO5126766 in MDA-MB-231 cells. Compound 18h can significantly reduce the levels of pMEK and pERK, induce cell apoptosis in MDA-MB-231 cells, and release NO in cells efficiently, suggesting that these hybrids, while displaying the properties of both MEK inhibitors and NO donors have a mechanism of action different from that of MEK inhibitors and NO donors. Thus, we are able to report a series of multitarget hybrids with better antitumor potency than a known MEK inhibitor and NO donor. Image 1 • A series of hybrids of MEK inhibitor and NO donor were designed and synthesized. • Compound 18h shows better cell proliferation inhibition effects than RO5126766 in MDA-MB-231 cells. • Compound 18h significantly reduces levels of pMEK and pERK in MDA-MB-231 cells. • Compound 18h can induce apoptosis in the MDA-MB-231 cell line. • Compound 18h can release NO in cells. [ABSTRACT FROM AUTHOR]