Commercial Anticancer Drug Research Articles

Evaluation of Xanthone and Cinnamoylbenzene as Anticancer Agents for Breast Cancer Cell Lines through In Vitro and In Silico Assays

Breast cancer is a severe global disease for women as the number of deaths increases annually. Therefore, attempts to find new anticancer agents are critical and inevitable. In this work, we report the investigation on the anticancer activity of xanthone and cinnamoylbenzene compounds against two breast cancer cell lines, i.e., T47D and MCF-7, through experimental in vitro and theoretical in silico assays. Xanthone and cinnamoylbenzene exhibit anticancer activity with a half-maximal inhibitory concentration (IC50) of 136.7–194.3 and 235.8–262.4 µg/mL against T47D and MCF-7 cancer cells, respectively. Cinnamoylbenzene generates less cytotoxicity to normal Vero cells with a selectivity index of 1.095–2.102. The molecular docking studies agree with the experimental data in which cinnamoylbenzene is more active against T47D with an IC50 of 136.7 µg/mL due to Topoisomerase II inhibition through π-π stacked interactions with Adenine12 and Guanine13 nitrogen bases. Meanwhile, xanthone is more active against MCF-7 with an IC50 of 235.8 µg/mL due to EGFR inhibition through van der Waals interaction and hydrogen bond with Glutamic acid767 and Methionine769 amino acid residues, respectively. Additionally, the pharmacokinetic parameters of xanthone and cinnamoylbenzene are predicted through absorption, distribution, metabolism, excretion, and toxicity (ADMET) analysis, and they show better suitability than doxorubicin as the commercial anticancer drug.

Chemotherapeutic Activities of New η6-p-Cymene Ruthenium(II) and Osmium(II) Complexes with Chelating SS and Tridentate SNS Ligands.

A series of new chelating bidentate (SS) alkylimidazole-2-thione-Ru(II)/Os(II) complexes (3ai, 3aii, 3aiii, 3bii/4aiii, 4bi, 4bii), and the tridentate (SNS) pyridine-2,6-diylimidazole-2-thione-Ru(II)/Os(II) complexes (5bi, 5civ/6bi, 6ci, 6civ) in the forms [MII(cym)(L)Cl]PF6 and [MII(cym)(L)]PF6 (M = Ru or Os, cym = η6-p-cymene, and L = heterocyclic derivatives of thiourea) respectively, were successfully synthesized. Spectroscopic and analytical methods were used to characterize the complexes and their ligands. Solid-state single-crystal X-ray diffraction analyses revealed a "piano-stool" geometry around the Ru(II) or Os(II) centers in the respective complexes. The complexes were investigated for in vitro chemotherapeutic activities against human cervical carcinoma (HeLa) and the non-cancerous cell line (Hek293) using the MTT assay. The compounds 3aii, 5civ, 5bi, 4aiii, 6ci, 6civ, and the reference drug, 5-fluorouracil were found to be selective toward the tumor cells; the compounds 3ai, 3aiii, 3bii, 4bi, 4bii, and 6bi, which were found not to be selective between normal and tumor cell lines. The IC50 value of the tridentate half-sandwich complex 5bi (86 ± 9 μM) showed comparable anti-proliferative activity with the referenced commercial anti-cancer drug, 5-fluorouracil (87 ± 15 μM). The pincer (SNS) osmium complexes 6ci (36 ± 10 μM) and 6civ (40 ± 4 μM) were twice as effective as the reference drug 5-fluorouracil at the respective dose concentrations. However, the analogous pincer (SNS) ruthenium complex 5civ was ineffective and did not show anti-proliferative activity, even at a higher concentration of 147 ± 1 μM. These findings imply that the higher stability of the chelating (SS) and the pincer (SNS) ligand architectures in the complexes improves the biological (anti-proliferative) activity of the complexes by reducing the chance of ligand dissociation under physiological conditions. In general, the pincer (SNS) osmium complexes were found to be more cytotoxic than their ruthenium analogues, suggesting that the anti-proliferative activity of the imidazole-2-thione-Ru/Os complexes depends on the ligand's spatial coordination, the nature of the metal center, and the charge of the metal complex ions.

Anti-cancer drug axitinib: a unique tautomerism-induced dual-emissive probe for protein analysis.

A commercial anti-cancer drug, axitinib, exhibits very stable dual emissions for discrimination of human serum albumin.

Multitarget Mechanisms of 5‐hydroxy Ferulic Acid for Cancer Prevention: A Computational Chemistry Study

AbstractThis study used computational methods to investigate the multitarget mechanisms of 5‐hydroxy ferulic acid in preventing cancer. The antiradical activity of 5‐hydroxy ferulic acid was systematically studied by using the M06‐2X/6‐311++G(d,p) method in both pentyl ethanoate (lipid‐like) and water media. The results show that 5‐hydroxy ferulic acid is more effective at scavenging the HOO• radical (koverall=5.2×108 M−1s−1) than Trolox (koverall=1.3×105 M−1s−1) in aqueous solution. The complexation ability of 5‐hydroxy ferulic acid with Cu(II) ions was investigated at the M06/6‐311++G(d,p) level of theory under physiological pH conditions. The most thermodynamically stable complexes can slow down about 107 times the Haber‐Weiss cycle's first reaction (from 4.2×109 M−1s−1 to 3.8×102 M−1s−1) and mitigate the potential damage caused by ⋅OH radical production. Furthermore, by performing molecular docking simulations on protein‐ligand adducts and comparing their activity to that of 5‐fluorouracil (a commercial anticancer drug), the existing forms of 5‐hydroxy ferulic acid at physiological pH were extremely effective at inhibiting the thymidylate synthase enzyme. Based on these findings, 5‐hydroxy ferulic acid may be an effective cancer treatment.

Synthesis, structure-activity relationship, and biological evaluation of quinolines for development of anticancer agents.

Tetrahydro-β-carbolines (THβCs) are a kind of natural alkaloids with multiple pharmaceutical activities. Herein, a focused compound library derived from THβCs was synthesized and their anticancer activities were studied in several cancer cell lines. Among them, three compounds showed considerable anticancer activities with low micromolar to submicromolar IC50 values. The abilities to induce apoptosis and alter mitochondrial membrane potential levels, which are comparable to those of the commercial anticancer drug adriamycin, were confirmed by one representative compound (21) on the B16/F10 cell line. Our preliminary structure-activity relationship studies indicated that alkylamines with suitable lengths are very important for potency improvement.

Near-Infrared Light-Activated Ruthenium Complex-based Photocage for Cancer Phototherapy.

Conventional photocages only respond to short wavelength light, which is a significant obstacle to developing efficient phototherapy in vivo. The development of photocages activated by near-infrared (NIR) light at wavelengths from 700 to 950 nm is important for in vivo studies but remains challenging. Herein, we describe the synthesis of a photocage based on a ruthenium (Ru) complex with NIR light-triggered photocleavage reaction. The commercial anticancer drug, tetrahydrocurcumin (THC), was coordinated to the Ru(II) center to create the Ru-based photocage that is readily responsive to NIR light at 760 nm. The photocage inherited the anticancer properties of THC. As a proof-of-concept, we further engineered a self-assembled photocage-based nanoparticle system with amphiphilic block copolymers. Upon exposure to NIR light at 760 nm, the Ru complex-based photocages were released from the polymeric nanoparticles and efficiently inhibited tumor proliferation in vivo.

A Near‐Infrared Light‐Activated Photocage Based on a Ruthenium Complex for Cancer Phototherapy

AbstractConventional photocages only respond to short wavelength light, which is a significant obstacle to developing efficient phototherapy in vivo. The development of photocages activated by near‐infrared (NIR) light at wavelengths from 700 to 950 nm is important for in vivo studies but remains challenging. Herein, we describe the synthesis of a photocage based on a ruthenium (Ru) complex with NIR light‐triggered photocleavage reaction. The commercial anticancer drug, tetrahydrocurcumin (THC), was coordinated to the RuII center to create the Ru‐based photocage that is readily responsive to NIR light at 760 nm. The photocage inherited the anticancer properties of THC. As a proof‐of‐concept, we further engineered a self‐assembled photocage‐based nanoparticle system with amphiphilic block copolymers. Upon exposure to NIR light at 760 nm, the Ru complex‐based photocages were released from the polymeric nanoparticles and efficiently inhibited tumor proliferation in vivo.

Synthesis and Antiproliferative Activity of Novel Dehydroabietic Acid-Chalcone Hybrids.

Dehydroabietic Acid (DHA, 1) derivatives are known for their antiproliferative properties, among others. In the context of this work, DHA was initially modified to two key intermediates bearing a C18 methyl ester, a phenol moiety at C12, and an acetyl or formyl group at C13 position. These derivatives allowed us to synthesize a series of DHA-chalcone hybrids, suitable for structure–activity relationship studies (SARS), following their condensation with a variety of aryl-aldehydes and methyl ketones. The antiproliferative evaluation of the synthesized DHA-chalcone hybrids against three breast cancer cell lines (the estrogen-dependent MCF-7 and the estrogen-independent MDA-MB-231 and Hs578T) showed that eight derivatives (33, 35, 37, 38, 39, 41, 43, 44) exhibit low micromolar activity levels (IC50 2.21–11.5 μΜ/MCF-7). For instance, some of them showed better activity compared to the commercial anticancer drug 5-FU against MCF-7 cells (33, 41, 43, 44) and against MDA-MB231 (33 and 41). Hybrid 38 is a promising lead compound for the treatment of MCF-7 breast cancer, exhibiting comparable activity to 5-FU and being 12.9 times less toxic (SI = 22.7). Thus, our findings suggest that DHA-chalcone hybrids are drug candidates worth pursuing for further development in the search for novel breast cancer therapies.

Triphenylphosphonium-linked derivative of allobetulin: preparation, anticancer properties and their mechanism of inhibiting SGC-7901 cells proliferation

As a very important lipophilic cation, the triphenylphosphonium moiety has been extensively studied in the development of anticancer agents. In this work, we adopted 1,2,3-triazole as the linking group to prepare triphenylphosphine salt-natural triterpenoid conjugates. We chose the rarely studied natural triterpenoid allobetulin as the lead compound and prepared three 1,2,3-triazole derivatives of allobetulin by the triazolization reaction which was developed by our group. The hydroxyl group was then replaced by bromination, and the target triphenylphosphonium-linked derivative of allobetulin 5 was obtained by reacting with triphenylphosphine. The cytotoxicity screening showed that the target compound 5 displayed same antiproliferative activity against tested cancer cells as the commercial anticancer drug doxorubicin but more active than cisplatin. Further studies on the mechanism of action indicated that compound 5 could obviously induce SGC-7901 cells apoptosis through the mitochondrial pathway, inducing cell cycle arrest. Moreover, compound 5 also could reduce the expression of Vimentin and increase the expression of E-cadherin to hinder Epithelial–mesenchymal transition (EMT). Since compound 5 has excellent anticancer activity, further research and development should be done.

Transport Behavior of Commercial Anticancer Drug Protein-Bound Paclitaxel (Paclicad) in a Micron-Sized Channel.

Protein-bound paclitaxel has been developed clinically as one of the most successful chemotherapy drugs for the treatment of a wide variety of cancers. However, these medications, due to their nanoscale properties, may often induce capillary blocking while migrating through minute blood vessels. Considering the detrimental impact of this restriction, we investigated the transport of protein-bound paclitaxel, Paclicad, in a 7 μm microchannel mimicking the identical mechanical confinement of the blood capillaries. The drug was reported to migrate through a constricted microchannel without obstruction at a solution flow rate of 20-50 μL/h. The onset of an agglomeration site was observed at higher flow rates of 70-90 μL/h, while complete capillary obstruction was observed at 100 μL/h. The mobility of the particles was also calculated, and the results suggested that the presence of varying cross-sections affects the mobility of the drug particles. The trajectory of the particle migration was observed to be less tortuous at the higher flow rate, but the tortuous nature appeared to increase with the presence of agglomeration sites in the flow field. The experimental results were also compared with the computational model of the drug particle. The drug particle was modeled both as Newtonian and as an FENE-P viscoelastic drop. The drop interface tracking was done by the VOF method using the open source software Basilisk. The particle displacement was better estimated by both the FENE-P and Newtonian model at a flow rate of 30 μL/h, while deviation was observed at a flow rate of 50 μL/h. The FENE-P model was observed to show higher deformation than the Newtonian model at both flow rates. The experimental results provided better insight into the agglomeration tendency of Paclicad, migrating through a constricted microchannel at higher flow rates. The numerical model could be further employed to understand the more complex intravenous transport of drugs.

β-Cyclodextrin modified Pt(II) metallacycle-based supramolecular hyperbranched polymer assemblies for DOX delivery to liver cancer cells

Despite the widespread clinical application of chemotherapeutic anticancer drugs, their adverse side effects and inefficient performances remain ongoing issues. A drug delivery system (DDS) designed for a specific cancer may therefore overcome the drawbacks of single chemotherapeutic drugs and provide precise and synergistical cancer treatment by introducing exclusive stimulus responsiveness and combined chemotherapy properties. Herein, we report the design and synthesis of a supramolecular drug delivery assembly 1 constructed by orthogonal self-assembly technique in aqueous media specifically for application in liver cancer therapy. Complex 1 incorporates the β-cyclodextrin host molecule-functionalized organoplatinum(II) metallacycle 2 with two specific stimulus-responsive motifs to the signaling molecule nitric oxide (NO), in addition to the three-armed polyethylene glycol (PEG) functionalized ferrocene 3 with redox responsiveness. With this molecular design, the particularly low critical aggregation concentration (CAC) of assembly 1 allowed encapsulation of the commercial anticancer drug doxorubicin (DOX). Controlled drug release was also achieved by morphological transfer via a sensitive response to the endogenous redox and NO stimuli, which are specifically related to the microenvironment of liver tumor cells. Upon combination of these properties with the anticancer ability from the platinum acceptor, in vitro studies demonstrated that DOX-loaded 1 is able to codeliver anticancer drugs and exhibit therapeutic effectiveness to liver tumor sites via a synergistic effect, thereby revealing a potential DDS platform for precise liver cancer therapeutics.

Mitochondria-localizing dicarbohydrazide Ln complexes and their mechanism of in vitro anticancer activity.

In this study, two novel organic ligands, bis(salicylaldehyde)pyrazino-1,10-phenanthroline-7,10-dicarbohydrazide (L) and bis(salicylaldehyde)-1,10-phenanthroline-7,10-dicarbohydrazide (L1), were synthesized. These ligands were used to react with lanthanide(iii) acetate to obtain complexes 1-6, namely, [Dy5(L)2(CH3COO)5(CH3OH)(μ3-OH)(μ2-OH)(H2O)]·2CH3OH (1), [Tb5(L)2(CH3COO)5(CH3OH)(μ3-OH)(μ2-OH)(H2O)]·3CH3OH (2), [Gd5(L)2(CH3COO)5(CH3OH)(μ3-OH)(μ2-OH)(H2O)]·3CH3OH (3), [Dy5(L1)2(μ2-OH)(μ3-OH)(CH3COO)5(CH3OH)(H2O)2]·2H2O (4), [Dy5(L1)2(μ3-OH)(CH3COO)6(CH3OH)3]·CH3OH (5), and [Dy5(L1)2(μ2-OH)2(μ3-OH)(CH3COO)4(CH3OH)(H2O)2]·CH3OH (6). Fluorescence studies demonstrated that complexes 1-6 show appreciable fluorescence in the yellow-green region. In vitro antitumor screening revealed that complex 1 exhibits better inhibitory activities than the commercial anticancer drug cisplatin against SK-OV-3 and A549 tumor cell lines, with IC50 values of 8.09 ± 1.25 and 13.26 ± 0.39 μM, respectively. All six complexes showed low cytotoxicity toward normal human liver HL-7702 cells compared with cisplatin. Complexes 1 and 3 induced the highest apoptosis rate of SK-OV-3/DDP cells. They also bind to DNA via an intercalative mode with the binding constant Kq values of 1.6 × 104 and 1.19 × 104 L mol-1, respectively. Confocal fluorescence imaging ascertained that complexes 1 and 3 are primarily localized in the mitochondria. Further studies revealed that these complexes trigger SK-OV-3/DDP cell apoptosis via a mitochondrial dysfunction pathway, which is probably caused by the reduction of the mitochondrial membrane potential and the induction of reactive oxygen species production.

Antitumor Activity of Cyclodextrin-based Supramolecular Platinum Prodrug In vitro and In vivo

Background: Considering the limitations of cisplatin in clinical application, there is ongoing research to fabricate new platinum-containing prodrug which are highly effective to tumor cells and have low toxicity to normal cells. Methods: In this study, a cyclodextrin-based supramolecular platinum prodrug that is 6,6’-ophenylenediseleno- bridged bis (β-cyclodextrin)s (CD) and its potassium tetrachloroplatinate(II) complex was reported. The cytotoxicity experiments were performed to evaluate the anticancer activities of supramolecular prodrug in vitro by means of MTT assay. The practical application of supramolecular prodrug in tumor treatment in vivo were evaluated using BALB/c nude mice model bearing Hela cancer cells. Results: Compared with commercial anticancer drug cisplatin, the resultant cyclodextrin-based platinum prodrug exhibited comparative anticancer effect but with much lower toxicity side effects in vitro and in vivo. Conclusion: The cyclodextrin-based supramolecular platinum prodrug displayed antitumor activity comparable to the commercial antitumor drug cisplatin but with lower side effects both in vitro and in vivo, implying that the two adjacent cyclodextrin cavities not merely act as desired solubilizer, but also endowed the prodrug with cell permeability through the interaction of cyclodextrin with phospholipids and cholesterol on cell membrane.

Biochemical characterization of Momordica charantia (leaf and fruit) and effect of soluble extract on MCF-7 breast cancer cell lines

Abstract. Ansari AA, Singh J, Aminuddin M. 2019. Biochemical characterization of Momordica charantia (leaf and fruit) and effect of soluble extract on MCF-7 breast cancer cell lines. Cell Biol Dev 3: 1-5. Cancer is a serious worldwide problem targeted by various treatments, including traditional medicinal plants. One known medicinal plant is bitter gourd (Momordica charantia), which has been investigated for its anti-cancerous properties. This study was carried out to explore the biochemical analysis of different components of M. charantia (leaf and fruit) and the effect of alcoholic extract of M. charantia to investigate their potential effect on MCF-7 breast cancer cell line in comparison to cisplatin, a commercial anti-cancer drug. The different components (leaf and fruit) were separated, dried, and converted to powdered form. MCF-7 (human mammary primary epithelial cancer cells) breast cancer cell line was treated with different concentrations (8 - 800 µg/mL) of the soluble extract and cisplatin (all dissolved in DMSO and diluted in the incubating medium) for 48 hours. Initial time course experiments established that maximal cell death occurred between 24-48 hours. Cell viability (cell death) was measured using an established method. The results have shown that with the MCF-7 cell line, the extract at a high concentration (800 µg/mL) was more effective in killing the cancer cells when compared to cisplatin. The present results have clearly shown that the soluble ethanol extract of M. charantia, especially at high doses, can be used effectively to treat breast cancer.

Four Ni(II), Co(III), Cd(II) complexes based on 5-(pyrazol-1-yl)nicotinic acid: synthesis, X-ray single crystal structure, in vitro cytotoxicity, apoptosis and molecular docking studies

We have developed complexes [Ni2(L)2(H2O)4]n (1), [Co2(L)2(H2O)4]n (2), [Cd2(L)2(H2O)2Cl2]n (3) and [Cd2(L)2(H2O)2]n (4), where HL = 5-(pyrazol-1-yl) nicotinic acid. All complexes were characterized by elemental analysis, IR spectroscopy and single crystal X-ray diffraction, showing monoclinic crystal lattice with space group P21/c (1), P21/c (2), P21/c (3), and triclinic crystal lattice with space group P-1 (4), separately. In vitro antitumor screening (MTT method) revealed that 3 exhibited better inhibitory activities than the commercial anticancer drug cisplatin against HeLa tumor cell lines, with IC50 values 9 ± 2. The bindings of these complexes with Fish Sperm DNA were measured by electronic absorption spectra and fluorescence spectroscopy, showing Ksq 0.1867 (1), 0.1589 (2), 0.2332 (3), and 0.1411 (4), with the binding affinities ranked 3 > 1 > 2 > 4. The experimental result showed that these complexes could bind DNA via intercalation. The ability of 1–4 to cleave the pBR322 plasmid DNA was demonstrated by gel electrophoresis assay. The experiment verified that these complexes could induce DNA damage. In addition, flow cytometric analysis showed that 1–4 induced apoptosis of HeLa tumor cell lines; as time increases, the apoptotic impact becomes increasingly significant. The potential of 1–4 as anticancer agents were examined using molecular docking of the complexes with DNA.

ANALYSIS OF THE ANTIOXIDANT PROPERTY, CYTOTOXICITY AND ANTI-TUMOUR EFFICIENCY OF BAUHINIA PHOENICEA.

Objective: Bauhinia phoenicea Wight and Arn. is a medicinal plant endemic to Southern Western Ghats. In the traditional systems of medicine, it is using against various ailments including some oxidative disorders. Detailed studies on the pharmacological activities of this plant are not yet reported. Hence, this paper aimed to prove the efficacy of this plant as a natural antioxidant source.Methods: The sequential extracts of the dried leaf powder were assayed for an antioxidant property using 2,2 diphenyl 1-picrylhydrazyl free radical scavenging assay, in vitro cytotoxicity of the extracts was screened using Trypan blue exclusion method. The antitumor activity of the selected fractions was studied using ascites tumor affected mice and noted the percentage of increase in lifespan.Results: The free radical scavenging activity of all extracts was increasing with increasing concentration of the drug, the least IC50 value was showed by ethanol fraction (41 μg/ml). The plant drug was not toxic to the normal cells and was highly toxic to tumor cell lines. Maximum in vitro cytotoxicity was observed in chloroform fraction (98% cell death at 100 mg/ml) and the least IC50 value was exhibited by the aqueous fraction (34 mg/ml). Both the aqueous and chloroform fractions increased the lifespan of ascites tumor bearing mice, aqueous fraction in 100 mg/ml concentration shows 71.9% increase in lifespan which is near to the result showed by the commercial anticancer drug cyclophosphamide (72.5%).Conclusion: According to our results, it is concluded that leaf of B. phoenicea has significant antioxidant, cytotoxic, and antitumor properties supporting the folk medicinal use of this species. The further procedures of identification of pharmacological active principles are in progress.

Synthesis and Biological Evaluation of Novel Dehydroabietic Acid-Oxazolidinone Hybrids for Antitumor Properties.

Novel representatives of the important group of biologically-active, dehydroabietic acid-bearing oxazolidinone moiety were synthesized to explore more efficacious and less toxic antitumor agents. Structures of all the newly target molecules were confirmed by IR, 1H-NMR, 13C-NMR, and HR-MS. The inhibitory activities of these compounds against different human cancer cell lines (MGC-803, CNE-2, SK-OV-3, NCI-H460) and human normal liver cell line LO2 were evaluated and compared with the commercial anticancer drug cisplatin, using standard MTT (methyl thiazolytetrazolium) assay in vitro. The pharmacological screening results revealed that most of the hybrids showed significantly improved antiproliferative activities over dehydroabietic acid and that some displayed better inhibitory activities compared to cisplatin. In particular, compound 4j exhibited promising cytotoxicity with IC50 values ranging from 3.82 to 17.76 µM against all the test cell lines and displayed very weak cytotoxicity (IC50 > 100 µM) on normal cells, showing good selectivity between normal and malignant cells. Furthermore, the action mechanism of the representative compound 4j was preliminarily investigated by Annexin-V/PI dual staining, Hoechst 33258 staining, which indicated that the compound can induce cell apoptosis in MGC-803 cells in a dose-dependent manner and arrest the cell cycle in G1 phase. Therefore, 4j may be further exploited as a novel pharmacophore model for the development of anticancer agents.

Discovery of 18β-glycyrrhetinic acid conjugated aminobenzothiazole derivatives as Hsp90-Cdc37 interaction disruptors that inhibit cell migration and reverse drug resistance

A series of 18β-glycyrrhetinic acid (GA) conjugated aminobenzothiazole derivatives were designed, synthesized and evaluated for disruption activity of Hsp90-Cdc37 as well as the effects of in vitro cell migration. These compounds exhibited relatively good disruption activity against Hsp90-Cdc37 with IC50 values in low micromolar range. A docking study of the most active compound 11g revealed key interactions between 11g and Hsp90-Cdc37 complex in which the benzothiazole moiety and the amine chain group were important for improving activity. It is noteworthy that further antitumor activity screening revealed that some compounds exhibited better inhibitory activity than the commercial anticancer drug 5-FU and showed potent suppression activity against drug-resistant cancer cells. In particular, compound 11 g appeared to be the most potent compound against the A549 cell line, at least partly, by inhibition of the activity of Hsp90 and apoptosis induction. The treatment of A549 cells with compound 11g resulted in inhibition of in vitro cell migration through wound healing assay and S phase of cell cycle arrested. In addition, 11g-induced apoptosis was significantly facilitated in A549 cells. Thus, we conclude that GA aminobenzothiazole derivatives may be the potential Hsp90-Cdc37 disruptors with the ability to suppress cells migration and reversed drug-resistant.

Effects of new derivatives of 2-amino-5-benzylthiazole of genotoxicity and acute toxicity in Allium bioassays

We have found that new derivatives of 2-amino-5-benzylthiazole possess cytotoxic action towards human tumor cells (Finiuk et al., Biopolym. Cell, 2017; Finiuk et al., Ukr. Biochem. J., 2018). A release of the chemotherapeutic drugs into the environment may cause adverse effects towards ecosystems. To promote further these derivatives as potential anticancer agents, it was necessary to evaluate their genotoxicity and acute toxi­city, namely in plants that have an important trophic level in ecosystems. To do that, we used towards plant bioassays for new derivatives of N-(5-benzyl-1,3-thiazol-2-yl)-3,5-dimethyl-1-benzofuran-2-carboxamide (compound 1 ) and 2,8-dimethyl-7-(3-trifluoromethyl-benzyl)pyrazolo[4,3-e]thiazolo[3,2-a]pyrimidin-4-one (compound 2 ). Allium cepa ana-telophase assay was applied to monitor the genotoxicity of the studied compounds. Besides, the acute toxic effects such as inhibition of cell division, seed germination and growth of Allium roots were estimated. The compound 1 (10 mM) in concentration equal to the IC 50 for tumor cells, and compound 2 in 1 mM (1´ concentration, equal to the IC 50 for tumor cells) and 10 mM (10´ concentration) did not possess acute toxicity towards Allium cepa. A significant inhibition of root growth and seed germination effects were detected at using the compound 1 only in dose that is 10 times higher than the IC 50 for tumor cells. The ana-telophase assay did not reveal the genotoxic effect of the compounds 1 (10 mM) and 2 (1 and 10 mM). The compounds 1 (10 mM) and 2 (1 and 10 mM) did not affect the mitotic and phase (prophase, metaphase, anaphase, telophase) indices. A commercial anticancer drug Doxorubicin (0.1 and 1 mM) possessed a significant inhibitory effect on root growth and seed germination, mitotic index and enhanced a level of chromosomal aberrations in Allium cepa . The compound 1 at 10 mM and compound 2 at 1 mM and 10 mM did not possess a significant acute toxicity (inhibition of cell division, seed germination and growth of Allium roots), did not demonstrated the genotoxic effects (induction of chromosomal aberrations) in Allium bioassay. These results give primary evidence about a possibility of using the synthetic 2-amino-5-benzylthiazole derivatives – compounds 1 and 2 – as novel antineoplastic agents that will have no negative side effects in the treated plant organism. Additional experiments should be performed in order to evaluate the adverse effects of new derivatives of 2-amino-5-benzylthiazole in a vide spectrum of the concentrations for the prediction of environmental toxicity and genotoxicity of chemicals.

Discovery of dehydroabietic acid sulfonamide based derivatives as selective matrix metalloproteinases inactivators that inhibit cell migration and proliferation

A series of dehydroabietic acid (DHAA) dipeptide derivatives containing the sulfonamide moiety were designed, synthesized and evaluated for inhibition of MMPs as well as the effects of in vitro cell migration. These compounds exhibited relatively good inhibition activity against MMPs with IC50 values in low micromolar range. A docking study of the most active compound 8k revealed key interactions between 8k and MMP-3 in which the sulfonamide moiety and the dipeptide group were important for improving activity. It is noteworthy that further antitumor activity screening revealed that some compounds exhibited better inhibitory activity than the commercial anticancer drug 5-FU. In particular, compound 8k appeared to be the most potent compound against the HepG2 cell line, at least partly, by inhibition of the activity of MMP-3 and apoptosis induction. The treatment of HepG2 cells with compound 8k resulted in inhibition of in vitro cell migration through wound healing assay and G1 phase of cell cycle arrested. In addition, 8k-induced apoptosis was significantly facilitated in HepG2 cells. Thus, we conclude that DHAA dipeptide derivatives containing the sulfonamide moiety may be the potential MMPs inhibitors with the ability to suppress cells migration.