Exploration of some indole-based hydroxamic acids as histone deacetylase inhibitors and antitumor agents

In our search for novel small molecules targeting histone deacetylases, we have designed and synthesized a series of novel hydroxamic acids incorporating indole moiety as a cap group (3a–l). Biological evaluation showed that these hydroxamic acids potently inhibited HDAC2 with IC₅₀ values in submicromolar range and up to tenfold (compound 3j) better than that of SAHA (also known as suberoylanilide hydroxamic acid). In four human cancer cell lines [SW620 (colon), PC-3 (prostate), AsPC-1 (pancreatic), NCI-H23 (lung)], the synthesized compounds that exhibited potent cytotoxicity with several compounds (3k, 3l) were found to be 12- to 77-fold more cytotoxic than SAHA. Docking experiments indicated that the compounds tightly bound to HDAC2 at the active binding site with binding affinities much higher than that of SAHA. Our present results demonstrate that these novel hydroxamic acids are potential for further development as anticancer agents.     

Synthesis,cytotoxicity, apoptosis and molecular docking studies of novel phenylbutyrate derivatives as potential anticancer agents

Phenylbutyrate (PB), a small aromatic fatty acid, has been known as an interesting compound with the ability of anti-proliferation and cell growth inhibition in cancer cells. In the present study, a series of PB derivatives were synthesized by Passerini multicomponent reaction and their cytotoxic activities against various human cancer cell lines including A549 (non-small cell lung cancer), MDA-MB-231 (breast cancer), and SW1116 (colon cancer) were evaluated. The results revealed that B9, displayed significantly higher in vitro cytotoxicity with IC₅₀ of 6.65, 8.44 and 24.71 μM, against A549, MDA-MB-231 and, SW1116, respectively, in comparison to PB. The effects of these compounds on the proliferation of MCF-10A as non-tumoral breast cell line, showed good selectivity of the compounds between tumorigenic and non-tumorigenic cell lines. Moreover, B9 has indicated apoptosis-inducing activities to MDA-MB-231 cancer cell line in a dose-dependent manner. The molecular docking studies of the synthesized compounds on pyruvate dehydrogenase kinase 2 (PDK2; PDB ID: 2BU8) and histone deacetylase complex (HDAC; PDB ID: 1C3R), as the main targets of PB were applied to predict the binding sites and binding orientation of the compounds to these targets.     

Antioxidant and Antitumor Activities of Newly Synthesized Hesperetin Derivatives

Hesperetin is a class of natural products with a wide range of sources and remarkable biological activities. In this study, we described the synthesis of a series of novel hesperetin derivatives and evaluated the in vitro antioxidant and antitumor activity of these compounds. Eleven novel compounds were synthesized in moderate yields. The compounds synthesized in this work exhibited antioxidant activities against DPPH and ABTS free radicals in a dose-dependent manner. Among them, compound 3f had the best antioxidant activity, with IC₅₀ of 1.2 μM and 24 μM for DPPH and ABTS, respectively. The antitumor activity of the compounds against human cancer cell lines, such as breast MCF-7, liver HepG2, and cervical Hela, was determined by a standard 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assay. Three compounds had moderate IC₅₀ values. Interestingly, compound 3f had better biological activity than hesperetin, which matches the prediction by Maestro from Schrödinger. Therefore, the new hesperidin derivative is a promising drug for the treatment of cancer due to its effective antitumor activity. The results also suggested that the antitumor activities of hesperetin derivatives may be related to their antioxidant activities.     

New Hybrids Based on Curcumin and Resveratrol: Synthesis,Cytotoxicity and Antiproliferative Activity against Colorectal Cancer Cells

We synthesized twelve hybrids based on curcumin and resveratrol, and their structures were elucidated by spectroscopic analysis. The chemopreventive potential of these compounds was evaluated against SW480 human colon adenocarcinoma cells, its metastatic derivative SW620, along with the non-malignant CHO-K1 cell line. Among the tested compounds, hybrids 3e and 3i (for SW480) and 3a, 3e and 3k (for SW620) displayed the best cytotoxic activity with IC₅₀ values ranging from 11.52 ± 2.78 to 29.33 ± 4.73 µM for both cell lines, with selectivity indices (SI) higher than 1, after 48 h of treatment. Selectivity indices were even higher than those reported for the reference drug, 5-fluorouracil (SI = 0.96), the starting compound resveratrol (SI = 0.45) and the equimolar mixture of curcumin plus resveratrol (SI = 0.77). The previous hybrids showed good antiproliferative activity.     

Antiproliferative Efficacy of N-(3-chloro-4-fluorophenyl)-6,7-dimethoxyquinazolin-4-amine,DW-8, in Colon Cancer Cells Is Mediated by Intrinsic Apoptosis

A novel series of 4-anilinoquinazoline analogues, DW (1–10), were evaluated for anticancer efficacy in human breast cancer (BT-20) and human colorectal cancer (CRC) cell lines (HCT116, HT29, and SW620). The compound, DW-8, had the highest anticancer efficacy and selectivity in the colorectal cancer cell lines, HCT116, HT29, and SW620, with IC₅₀ values of 8.50 ± 2.53 µM, 5.80 ± 0.92 µM, and 6.15 ± 0.37 µM, respectively, compared to the non-cancerous colon cell line, CRL1459, with an IC₅₀ of 14.05 ± 0.37 µM. The selectivity index of DW-8 was >2-fold in colon cancer cells incubated with vehicle. We further determined the mechanisms of cell death induced by DW-8 in SW620 CRC cancer cells. DW-8 (10 and 30 µM) induced apoptosis by (1) producing cell cycle arrest at the G2 phase; (2) activating the intrinsic apoptotic pathway, as indicated by the activation of caspase-9 and the executioner caspases-3 and 7; (3) nuclear fragmentation and (4) increasing the levels of reactive oxygen species (ROS). Overall, our results suggest that DW-8 may represent a suitable lead for developing novel compounds to treat CRC.     

Design,Synthesis, and Biological Evaluation of 5,6,7,8-Tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidines as Microtubule Targeting Agents

A series of eleven 4-substituted 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidines were designed and synthesized and their biological activities were evaluated. Synthesis involved the Gewald reaction to synthesize ethyl 2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate ring, and S_NAr reactions. Compound 4 was 1.6- and ~7-fold more potent than the lead compound 1 in cell proliferation and microtubule depolymerization assays, respectively. Compounds 4, 5 and 7 showed the most potent antiproliferative effects (IC₅₀ values < 40 nM), while compounds 6, 8, 10, 12 and 13 had lower antiproliferative potencies (IC₅₀ values of 53–125 nM). Additionally, compounds 4–8, 10 and 12–13 circumvented Pgp and βIII-tubulin mediated drug resistance, mechanisms that diminish the clinical efficacy of paclitaxel (PTX). In the NCI-60 cell line panel, compound 4 exhibited an average GI₅₀ of ~10 nM in the 40 most sensitive cell lines. Compound 4 demonstrated statistically significant antitumor effects in a murine MDA-MB-435 xenograft model.     

Design,Sonosynthesis, Quantum‐Chemical Calculations,and Evaluation of New Mono‐ and Bis‐pyridine Dicarbonitriles as Antiproliferative Agents

A highly efficient, simple, and clean single‐step sonosynthetic procedure has been sophisticated for assembling new series of mono‐ and bis‐pyridine dicarbonitriles from ketones, HCl, and tetracyanoethylene. The presented protocol is applicable for the preparation of a broad range of uniquely substituted pyridine dicarbonitriles and seems to be superior in comparison with other previously reported methods. The antiproliferative impact of the newly synthesized derivatives was screened towards three representative cancer cell lines (MCF‐7, A549, and HCT116). Most of the evaluated derivatives showed a moderate to excellent anti‐proliferative activity towards the selected cell lines. Of these, compounds 4h , 4k , 10 , 12a , and 12b showed both potent anticancer activity (IC₅₀<10 μM) and lower cytotoxic effect (IC₅₀ > 58 μM) on non‐tumorigenic cells (MCF‐10A and NCM460), suggesting their promising potential to be lead molecules for future antitumor drug discovery. The structure‐activity relationships have been also discussed. Moreover, quantum chemical studies based on Density Functional Theory (DFT) of the synthesized compounds were investigated and found to be consistent with the in vitro inhibitory activities.     

Design,synthesis, and evaluation of novel combretastatin A-4 based chalcone derivatives as anticancer agents

A series of combretastatin A-4 based chalcones ( 14a-l ) were designed, synthesized and these compounds examined for inhibitory effects on the proliferation of human lung (A549), breast (MCF-7), melanoma (A375), and colon (HT-29) carcinoma cells. Compounds 14b , 14c , 14e , 14h , and 14i (tri/dimethoxy, methyl, and mono/dinitro derivatives) have exhibited the most potent antiproliferative activity with IC₅₀ < 2 μM and the hexa methoxy derivative 14b , the most promising one, which displayed the potent inhibitory activities in MCF-7 (IC₅₀: 10 nM), A375 (IC₅₀: 12 nM), and A549 (IC₅₀: 65 nM) cell lines, and is 18 times more potent than the CA-4. Compound 14b represents a new scaffold and the results provide insights into further development of anticancer agents.     

Synthesis and Biological Activity of Ferrocenyl and Ruthenocenyl Analogues of Etoposide: Discovery of a Novel Dual Inhibitor of Topoisomerase II Activity and Tubulin Polymerization

Two series of the ferrocenyl and ruthenocenyl analogues of etoposide bearing 1,2,3-triazolyl or aminoalkyl linker were synthesized and evaluated for their cytotoxic properties, influence on the cell cycle, ability to induce tubulin polymerization, and inhibition of topoisomerase II activity. We found that the replacement of the etoposide carbohydrate moiety with a metallocenyl group led to organometallic conjugates exhibiting differentiated antiproliferative activity. Biological studies demonstrated that two ferrocenylalkylamino conjugates were notably more active than etoposide, with submicromolar or low-micromolar IC₅₀ values towards SW620, etoposide-resistant SW620E, and methotrexate-resistant SW620M cancer cell lines. Moreover, the simplest ferrocenylmethylamino conjugate exerted dual inhibitory action against tubulin polymerization and topoisomerase II activity while other studied compounds affected only topoisomerase II activity.     

HRMS Characterization,Antioxidant and Cytotoxic Activities of Polyphenols in Malus domestica Cultivars from Costa Rica

There is increasing interest in research into fruits as sources of secondary metabolites because of their potential bioactivities. In this study, the phenolic profiles of Malus domestica Anna and Jonagold cultivars from Costa Rica were determined by Ultra Performance Liquid Chromatography coupled with High Resolution Mass Spectrometry (HRMS) using a quadrupole-time-of-flight analyzer (UPLC-QTOF-ESI MS), on enriched-phenolic extracts from skins and flesh, obtained through Pressurized Liquid Extraction (PLE). In total, 48 different phenolic compounds were identified in the skin and flesh extracts, comprising 17 flavan-3-ols, 12 flavonoids, 4 chalcones, 1 glycosylated isoprenoid and 14 hydroxycinnamic acids and derivatives. Among extracts, the flesh of Jonagold exhibits a larger number of polyphenols and is especially rich in procyanidin trimers, tetramers and pentamers. Evaluating total phenolic content (TPC) and antioxidant activities using ORAC and DPPH procedures yields higher values for this extract (608.8 mg GAE/g extract; 14.80 mmol TE/g extract and IC₅₀ = 3.96 µg/mL, respectively). In addition, cytotoxicity evaluated against SW620 colon cancer cell lines and AGS gastric cancer cell lines also delivered better effects for Jonagold flesh (IC₅₀ = 62.4 and 60.0 µg/mL, respectively). In addition, a significant negative correlation (p < 0.05) was found between TPC and cytotoxicity values against SW620 and AGS adenocarcinoma (r = −0.908, and −0.902, respectively). Furthermore, a significant negative correlation (p < 0.05) was also found between the number of procyanidins and both antioxidant activities and cytotoxicity towards SW620 (r = −0.978) and AGS (r = −0.894) cell lines. These results align with Jonagold flesh exhibiting the highest abundance in procyanidin oligomers and yielding better cytotoxic and antioxidant results. In sum, our findings suggest the need for further studies on these Costa Rican apple extracts—and particularly on the extracts from Jonagold flesh—to increase the knowledge on their potential benefits for health.     

Baicalin induces apoptosis in SW620 human colorectal carcinoma cells in vitro and suppresses tumor growth in vivo

In the United States, colorectal cancer (CRC) is the second most frequent malignancy and the fourth most common cause of cancer death. Baicalin, a flavone derivative isolated and purified from the dry root of Scutellaria, was assessed for its antitumor effects in human SW620 CRC cells. Baicalin (200 μM) inhibited proliferation of SW620 cells. Baicalin (200 μM) increased activities of caspase-3, -8, and -9 in SW620 cells. Furthermore, flow cytometric analysis of baicalin-treated SW620 cells showed an increase in sub-G1 cells, and the dihydroethidium assay showed significant enhancement of intracellular peroxide production in baicalin-treated cells. Addition of N-acetylcysteine prevented most of the baicalin-induced apoptosis, which in turn mediated cytotoxicity in human SW620 cells. In vivo, baicalin (50 mg/kg/day, i.p.) treatment inhibited 55% of tumor growth in xenografted nude mice by 4 weeks, compared to that of the vehicle control (p < 0.05). Baicalin had no noteworthy influence on body weight. Thus, we suggest the development of baicalin as a potential leading antitumor agent in CRC.     

N9位芳基取代嘌呤-8-酮类衍生物的合成及抗肿瘤活性

合成了一系列N9位芳基取代嘌呤-8-酮类衍生物, 利用核磁共振氢谱(¹H NMR)、 核磁共振碳谱(¹³C NMR)和高分辨质谱(HRMS)进行了结构确证. 采用四甲基偶氮唑盐(MTT)法测定了目标化合物的体外抗肿瘤细胞增殖活性. 结果表明, 嘌呤酮环的C2位及N9位的取代对活性有较大影响, C2位引入对位由含氮六元环取代的苯胺, N9位引入对三氟甲基苯均有利于提高抗肿瘤活性. 化合物12c对人白血病细胞(K562)、 人前列腺癌细胞(PC-3)、 人乳腺癌细胞(MDA-MB-231)及人结肠癌细胞(HCT116)的抑制效果明显优于阳性对照药R-Roscovitine.     

Synthesis and antitumor activities of a new series of 4,5-dihydro-1H-thiochromeno[4,3-d]pyrimidine derivatives

A new series of 4,5-dihydro-1H-thiochromeno[4,3-d]pyrimidine derivatives have been designed and synthesized.The antitumor activities of the target compounds have been evaluated in vitro against two human cancer cell lines including A549 (human alveolar adenocarcinoma cell) and H460 (human lung cancer) by MTT assay.Most of the target compounds exhibited significant antitumor activities against A549 and H460 cancer cell lines.The most potent compound 4-(benzo[d][1,3]dioxol5-yl)-8,9-difluoro-2-(4-methylpiperazin-1-yl)-4,5-dihydro-1H-thiochromeno[4,3-d]pyrimidine (CH05) (IC50=0.44 M,3.07 M) was 2.0 and 8.4 times more active than gefitinib (IC50=0.89 M,16.81 M) against A549 and H460 cell lines,respectively.     

Design,Synthesis, and Antitumor Activity of Olmutinib Derivatives Containing Acrylamide Moiety

Two series of olmutinib derivatives containing an acrylamide moiety were designed and synthesized, and their IC₅₀ values against cancer cell lines (A549, H1975, NCI-H460, LO2, and MCF-7) were evaluated. Most of the compounds exhibited moderate cytotoxic activity against the five cancer cell lines. The most promising compound, H10, showed not only excellent activity against EGFR kinase but also positive biological activity against PI3K kinase. The structure–activity relationship (SAR) suggested that the introduction of dimethylamine scaffolds with smaller spatial structures was more favorable for antitumor activity. Additionally, the substitution of different acrylamide side chains had different effects on the activity of compounds. Generally, compounds H7 and H10 were confirmed as promising antitumor agents.     

Derivatives of 5-nitro-1H-benzo[de]isoquinoline-1,3(2H)-dione: design, synthesis, and biological activity

Abstract  

A series of mono and bis-2-(2-(dimethylamino)-ethyl)-5-nitro-1H-benzo[de]isoquinoline-1,3(2H)-diones with different amino side chains, a novel family of antitumor agents, has been designed and synthesized. Their antitumor activity was evaluated against HeLa, A549, P388, HL-60, MCF-7, HCT-8, and A375 cancer cell lines in vitro. Preliminary results showed that most of the derivatives had antitumor activity comparable with that of mitonafide, with IC ₅₀ values of 10⁻⁶–10⁻⁵ M. More importantly, the derivatives had distinct antitumor selectivity against different cancer cell lines. This work provided a novel class of mitonafide-based lead compounds with improved antitumor selectivity against cancer cell lines for further optimization.     

Synthesis of Phenoxazinone Derivatives and Antiproliferative Activities on Wild-type and Drug-resistant Tumor Cells

Some natural occurring phenoxazinones, such as xanthommatin, actinomycin D (AMD), and questiomycin A (APO), all contain a coplanar tricyclic iminoquinone system (Figure 1). Polycyclic iminoquinone is an important chemical structural moiety of action- mycins and other antitumor drugs. One of the cytostatic mechanisms of coplanar polycyclic compounds, that they can intercalate into human DNA, to cause enzymatic blocking and reading errors during the replication process. AMD is a well known…     

Synthesis and Biological Activities of 1‐Azaaurone Derivatives

A series of 1‐azaaurone derivatives were designed and synthesized from 3,5‐dimethoxyaniline and 2‐chloroacetonitrile. Their structures were characterized by melting point, ¹H NMR, IR, and elemental analysis, as well as ¹³C NMR. The target compounds were evaluated for antitumor activities against human hepatocellular liver carcinoma cell line (HepG‐2) and human cervix carcinoma cell line (Hela) using methyl thiazolyl tetrazolium method. The results revealed that several 1‐azaaurones exhibited strong proliferation inhibition efficacy against HepG‐2 and Hela with an IC₅₀ range of 5.6–8.8 μg/mL without damaging normal cell.     

Synthesis and Antiproliferatory Activities Evaluation of Multi-Substituted Isatin Derivatives

A series of multi-substituted isatin derivatives were synthesized using the powerful Sandmeyer reaction. The structures of these derivatives were confirmed by ¹H-NMR, ¹³C-NMR, and HR-MS. Inhibition of proliferation activities of these derivatives against human leukemia cells (K562), human hepatocellular carcinoma cells (HepG2) and human colon carcinoma cells (HT-29) were evaluated in vitro using the MTT assay. Among the series, compound 4l exhibited strong antiproliferatory activities against K562, HepG2 and HT-29 cells with IC₅₀ values of 1.75, 3.20, and 4.17 μM, respectively. The morphological, growth inhibitory and apoptosic effects of compound 4l in K562 cells, wound healing effect in HepG2 cells, and tube formating effect in matrix gel of HUVEC cells were evaluated consequently. All results indicated that compound 4l could be used as a potential antitumor agent in further investigations.     

Syntheses and cell-based phenotypic screen of novel 7-amino pyrido[2,3-d]pyrimidine-6-carbonitrile derivatives as potential antiproliferative agents

A series of N-3-substituted 7-aminopyrido[2,3-d]pyrimidin-6-carbonitrile derivatives was readily synthesized and their anti-proliferative activities on five types of tumor cells were evaluated through a cell-based phenotypic screening approach. Compound 3k was found to be potent on human colon cancer SW620 cells with an IC(50) value of 12.5 mM. Structural optimization of compound 3k led to compound 4a with improved anti-proliferative potency on SW620 cells with an IC(50) value of 6.9 mM. Further cell-cycle analyses suggested that compound 4a induced apoptosis of SW620 cells in a concentration-dependent manner.     

Facile synthesis of novel bis-derivatives of 2,5-diamino-thiadiazole/<Emphasis Type="Italic">N</Emphasis>,<Emphasis Type="Italic">N</Emphasis>′-thiocarbohydrazide and their biological perspective

A series of new bis derivatives of 2,5-thiadiazole and N,N′-thiocarbohydrazide along with their transition metal complexes were synthesized by green methods (sonochemical and microwave), i.e., energy and time efficient and operationally more simple than existing conventional methods. All the synthesized compounds were fully characterized by routine analytical techniques and subjected to a preliminary biological screening. These novel characterized compounds were screened for antimicrobial activities and showed promising results. A few potent compounds were also tested for antitumor activities against MDA-MB231 (human breast carcinoma cell line) and compound 5 has emerged as a potential antitumor compound followed by compound 2, 10 and 9, with IC₅₀ values of 29.48, 32.25, 32.34 and 34.34 μg/ml, respectively. To understand the binding interactions of these compounds, in silico studies were performed using the AUTODOCK 4.2 suite and found to be supportive of the experimental results.