Growing evidence suggests that aberrant epigenetic regulation of gene function is strongly related to the genesis of cancer. Unlike genetic mutations, the ability to reprogram the epigenetic ...landscape in the cancer epigenome is one of the most promising target therapies in both treatment and reversibility of drug resistance. Epigenetic alterations in cancer development and progression may be the basis for the individual variation in drug response. Thus, this review focuses on the emerging area of pharmaco(epi)genomics, specifically highlighting epigenetic reprogramming during tumorigenesis and how epigenetic markers are targeted as a therapy (epidrugs) and the clinical implications of this for cancer treatment.
Urokinase plasminogen activator (uPA) is a biomarker and therapeutic target for several cancer types whose inhibition has been shown to slow tumor growth and metastasis. In this work, ...crystallographic data of uPA complexed with distinct ligands (PDB id: 1SQA, 1SQO, and 1FV9) were used to perform quantum biochemistry calculations based on the framework of density functional theory (DFT) and within the molecular fractionation with conjugated caps (MFCC) scheme. Our calculations revealed a total energy interaction of -107.30, -99.5, and -35.30 kcal mol-1 for two naphthamidine-based compounds (Ul1 and UI2) and 2-amino-5-hydroxybenzimidazole (172), respectively, which are in good agreement with known inhibitory experiments. Residues Asp189, Ser190, Cys191-Cys220, Gln192, Trp 215, Gly216, and Gly219 were identified as the main interacting amino acid residues with interaction energy contributions lower than -4.0 kcal mol-1 for uPA/UI1 and UPA/UI2 complexes. In the case of compound 172, our calculations have shown that the most important interactions occur with residues Asp189, Cys191-Cys220, and Ser190. Our results highlight the relevance of the protonation state of ligands and residues and that the naphthamidine scaffold of UI1 and UI2 is the main determinant of their potency, followed by their aminopyrimidine substitution. Altogether, the results of this work contribute to the understanding of the uPA binding mechanisms of the inhibitory compounds Ul1 and 172, stimulating the use of quantum biochemistry theoretical approaches for the development of new uPA inhibitors as new medicines for cancer treatment.
A series of forty-seven quinoxaline derivatives, 2-(XYZC6H2CHN–NH)-quinoxalines, 1, have been synthesized and evaluated for their activity against four cancer cell lines: potent cytotoxicities were ...found (IC50 ranging from 0.316 to 15.749μM). The structure–activity relationship (SAR) analysis indicated that the number, the positions and the type of substituents attached to the aromatic ring are critical for biological activity. The activities do not depend on the electronic effects of the substituents nor on the lypophilicities of the molecules. A common feature of active compounds is an ortho-hydroxy group in the phenyl ring. A potential role of these ortho-hydroxy derivatives is as N,N,O-tridentate ligands complexing with a vital metal, such as iron, and thereby preventing proliferation of cells. The most active compound was (1: X,Y=2,3-(OH)2, Z=H), which displayed a potent cytotoxicity comparable to that of the reference drug doxorubicin.
Pisosterol, a triterpene derived from Pisolithus tinctorius, exhibits potential antitumor activity in various malignancies. However, the molecular mechanisms that mediate the pisosterol-specific ...effects on glioma cells remain unknown.
This study aimed to evaluate the antitumoral effects of pisosterol on glioma cell lines.
The 3-4,5-dimethylthiazol-2-yl-2,5-diphenyl tetrazolium bromide (MTT) and trypan blue exclusion assays were used to evaluate the effect of pisosterol on cell proliferation and viability in glioma cells. The effect of pisosterol on the distribution of the cells in the cell cycle was performed by flow cytometry. The expression and methylation pattern of the promoter region of MYC, ATM, BCL2, BMI1, CASP3, CDK1, CDKN1A, CDKN2A, CDKN2B, CHEK1, MDM2, p14ARF and TP53 was analyzed by RT-qPCR, western blotting and bisulfite sequencing PCR (BSP-PCR).
Here, it has been reported that pisosterol markedly induced G2/M arrest and apoptosis and decreased the cell viability and proliferation potential of glioma cells in a dose-dependent manner by increasing the expression of ATM, CASP3, CDK1, CDKN1A, CDKN2A, CDKN2B, CHEK1, p14ARF and TP53 and decreasing the expression of MYC, BCL2, BMI1 and MDM2. Pisosterol also triggered both caspase-independent and caspase-dependent apoptotic pathways by regulating the expression of Bcl-2 and activating caspase-3 and p53.
It has been, for the first time, confirmed that the ATM/ATR signaling pathway is a critical mechanism for G2/M arrest in pisosterol-induced glioma cell cycle arrest and suggests that this compound might be a promising anticancer candidate for further investigation.
A total of forty-three compounds were synthesized, including thirty-two new ones. Among those compounds, seventeen were selected and tested on human tumor cell lines: PC-3 (prostate adenocarcinoma), ...HCT-116 (colorectal tumor), NCIH-460 (lung carcinoma), SKMEL-103 (melanoma) and AGP-01 (gastric tumor). Alkynylated 1,2,4-oxadiazoles 2m, 3g and 3k exhibited antiproliferative activities against NCIH-460 in culture. Alkynylated N-cyclohexyl-1,2,4-oxadiazoles 3a-m and bis-heterocycle glucoglycero-1,2,3-triazole-N-cyclohexyl-1,2,4-oxadiazole derivatives 5a-k and 6–11 were evaluated for their in vitro efficacy towards Mycobacterium tuberculosis (Mtb) H37Ra and H37Rv strains. In general, glycerosugars conjugated to 1,2,4-oxadiazole via a 1,2,3-triazole linkage (5a, 5e, 5j, 5k, and 7) showed in vitro inhibitory activity against Mtb (H37Rv). The largest molecules bis-triazoles 10 and 11, proved inactive against TB. Probably, the absence of the N-cyclohexyl group in compound 8 and 1,2,4-oxadiazole nucleus in compound 9 were responsible for its low activity. Glucoglycero-triazole-oxadiazole derivatives 5e (10 μM) and 7 (23.9 μM) were the most promising antitubercular compounds, showing a better selective index than when tested against RAW 264.7 and HepG2 cells. Vero cell were used to investigate cytotoxicity of compounds 5a, 5h, 5j, 5k, and these compounds showed good cell viability. Further, in silico studies were performed for most active compounds (5e and 7) with potential drug targets, DprE1 and InhA of Mtb to understand possible interactions aided with molecular dynamic simulation (100ns).
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•Forty-one compounds were synthesized and tested for human tumor cell lines and/or tuberculosis (H37Ra and H37Rv strains).•Alkynylated 1,2,4-oxadiazoles were effective as antiproliferative agents (lung carcinoma, NCIH-460) with IC50 = 3–17 μM.•Glucoglycero-triazole-oxadiazoles, mainly the compounds 5a,j,k, 5e and 7 (10-47 µM), were the most active against TB.•Insilico studies supported the anti-TB compounds complexed with proteins DprE1 and InhA have stable association.
Cutaneous secretions of toad species are an important source of bufadienolides, compounds that exhibit interesting structural features and biopharmacological properties. Here we describe the ...isolation of bufadienolides from the Brazilian toad
Rhinella schneideri parotoid glands secretion, including: marinobufagin (
1), bufalin (
2), telocinobufagin (
3), hellebrigenin (
4), and the atypical 20
S,21
R-epoxymarinobufagin (
5) besides the widespread
β-sitosterol (
6). Starting from natural bufadienolides four derivatives were prepared: 3
β-acetoxy-marinobufagin (
7), 3
β-acetoxy-bufalin (
8), 3
β-acetoxy-telocinobufagin (
9), and 3
β-acetoxy-20
S,21
R-epoxymarinobufagin (
10). The cytotoxic evaluation showed that all natural bufadienolides and their derivatives exhibited moderate to strong activity against human HL-60, SF-295, MDA-MB-435, and HCT-8 cancer cell strains without hemolysis of mouse erythrocytes. The acetylated bufadienolides (
7–9) and the epoxide
10 showed lesser peripheral blood lymphocytes (PBLs) inhibitory activity than their precursors, suggesting that chemical modifications on such compounds can play an important role on the modulation of their cytotoxic profile.
Piplartine (piperlongumine, 5,6-dihydro-1-(2E)-1-oxo-3-(3,4,5-trimethoxyphenyl)-2-propenyl-2(1H)-pyridinone) is a biologically active alkaloid/amide from peppers, as from long pepper (Piper longum L. ...– Piperaceae). Long pepper is one of the most widely used in Ayurvedic medicine, which is used to treat many diseases, including tumors. The purpose of the current paper is to address to the chemical structure establishment and to systematically survey the published articles and highlight recent advances in the knowledge of the therapeutic potential of piplartine, establishing new goals for future research. The reported pharmacological activities of piplartine include cytotoxic, genotoxic, antitumor, antiangiogenic, antimetastatic, antiplatelet aggregation, antinociceptive, anxiolytic, antidepressant, anti-atherosclerotic, antidiabetic, antibacterial, antifungal, leishmanicidal, trypanocidal, and schistosomicidal activities. Among the multiple pharmacological effects of piplartine, its anticancer property is the most promising. Therefore, the preclinical anticancer potential of piplartine has been extensively investigated, which recently resulted in one patent. This compound is selectively cytotoxic against cancer cells by induction of oxidative stress, induces genotoxicity, as an alternative strategy to killing tumor cells, has excellent oral bioavailability in mice, inhibits tumor growth in mice, and presents only weak systemic toxicity. In summary, we conclude that piplartine is effective for use in cancer therapy and its safety using chronic toxicological studies should be addressed to support the viability of clinical trials.
This work describes the multigram-scale synthesis of the building-block N1 -(7-chloroquinolin4-yl)ethane-1,2-diamine via sonochemistry and its use in the synthesis of seven new quinoline-thiazole ...hybrids endowed with interesting anticancer activity. Target compounds were planned based on the drugs chloroquine and primaquine and the desired thiazoles were obtained through the Hantzsch thiazole synthesis, without the use of catalysts, by reacting key intermediate 1-(2-((7-chloroquinolin-4-yl)amino)ethyl)thiourea, obtained in two-steps from N1-(7-chloroquinolin-4-yl)ethane-1,2-diamine, with different 2-bromoacetophenones. The novel molecules were assessed against four different leukemia cell lines (HL60, K562, KASUMI-1, and KG-1) plus normal fibroblasts (L929), using the 3-(4,5-dimethyl-2-thiazol)-2,5-diphenyl2H-tetrazolium bromide (MTT) assay, and showed, overall, a high cytotoxic profile, but with interesting selectivity index, especially against K562 cells (1.89 to 5.50), when compared to standard doxorubicin (3.51). Docking studies suggest that all tested derivatives are able to interact with BCR-ABL1 tyrosine kinase enzyme, and, therefore, these molecules may be promising leads against chronic myeloid leukemia.
Disruption of the epigenetic program of gene expression is a hallmark of cancer that initiates and propagates tumorigenesis. Altered DNA methylation, histone modifications and ncRNAs expression are a ...feature of cancer cells. The dynamic epigenetic changes during oncogenic transformation are related to tumor heterogeneity, unlimited self-renewal and multi-lineage differentiation. This stem cell-like state or the aberrant reprogramming of cancer stem cells is the major challenge in treatment and drug resistance. Given the reversible nature of epigenetic modifications, the ability to restore the cancer epigenome through the inhibition of the epigenetic modifiers is a promising therapy for cancer treatment, either as a monotherapy or in combination with other anticancer therapies, including immunotherapies. Herein, we highlighted the main epigenetic alterations, their potential as a biomarker for early diagnosis and the epigenetic therapies approved for cancer treatment.
The present study evaluated the use of a pressurized method to extract phycobiliproteins from the cyanobacterium
Arthrospira platensis
using sodium phosphate buffer as an extracting solution. ...Phycobiliprotein extracts were characterized and their antioxidant and anticancer activities (on different cancer cell lines) were determined. A high extraction yield was obtained when high pressure was used, without any alteration of the molecules’ biofunctionality. Maximum phycocyanin and allophycocyanin concentrations obtained (at 100 bar after 360 min) were 4.44 g L
−1
and 1.63 g L
−1
, respectively. The purity indexes of extract were 3.59 (A
615
/A
280
) for phycocyanin and 1.72 (A
652
/A
280
) for allophycocyanin. The purified phycobiliprotein extract showed high antioxidant activity, with 98% in the reduction of 2,2-diphenyl-1-picryl-hydrazil (DPPH) radicals and 100% in the chelation of ferrous ions, and it presented in vitro anticancer activity for HL60 leukemic cells.
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