Preparation of Dearomatized p-Coumaric Acid Derivatives as DNA Damage Response Inhibitors with Potent In Vitro Antitumor Effect.

Our research group previously identified graviquinone (1) as a promising antitumor metabolite that is formed in situ when the antioxidant methyl caffeate scavenges free radicals. Furthermore, it exerted a DNA damaging effect on cancer cells and a DNA protective effect on normal keratinocytes. To expand and explore chemical space around qraviquinone, in the current work we synthesized 9 new alkyl-substituted derivatives and tested their in vitro antitumor potential.

Seleno-vs. thioether triazine derivatives in search for new anticancer agents overcoming multidrug resistance in lymphoma.

Lymphomas are still difficult to treat even with modern therapies as, among others, multidrug resistance (MDR) is often counteracting a successful cancer therapy. P-gp/ABC-transporters are well-known for their crucial role in the main tumour MDR mechanism, eliminating drugs and cytotoxic substances from the cancer cell by efflux, and their modulators are promising for innovative therapy, but none has been approved in the pharmaceutical market yet. Herein, we have designed, synthesised and analysed 30 novel seleno- and thioether 1,3,5-triazine derivatives conducting comprehensive studies to evaluate their potential application in human JURKAT lymphoma cells.

Diversity-Oriented Synthesis Catalyzed by Diethylaminosulfur-Trifluoride-Preparation of New Antitumor Ecdysteroid Derivatives.

Fluorine represents a privileged building block in pharmaceutical chemistry. Diethylaminosulfur-trifluoride (DAST) is a reagent commonly used for replacement of alcoholic hydroxyl groups with fluorine and is also known to catalyze water elimination and cyclic Beckmann-rearrangement type reactions. In this work we aimed to use DAST for diversity-oriented semisynthetic transformation of natural products bearing multiple hydroxyl groups to prepare new bioactive compounds.

Cyano- and Ketone-Containing Selenoesters as Multi-Target Compounds against Resistant Cancers.

Fifteen selenocompounds, comprising of eight ketone-containing selenoesters (-, also known as oxoselenoesters) and seven cyano-containing selenoesters (-, known also as cyanoselenoesters), have been designed, synthesized, and evaluated as novel anticancer agents. These compounds are derivatives of previously reported active selenoesters and were prepared following a three-step one-pot synthetic route. The following evaluations were performed in their biological assessment: cytotoxicity determination, selectivity towards cancer cells in respect to non-cancer cells, checkerboard combination assay, ABCB1 inhibition and inhibition of ABCB1 ATPase activity, apoptosis induction, and wound healing assay.

In vitro adjuvant antitumor activity of various classes of semi-synthetic poststerone derivatives.

Various classes of semi-synthetic analogs of poststerone, the product of oxidative cleavage of the C20-C22 bond in the side chain of the phytoecdysteroid 20-hydroxyecdysone, were synthesized. The analogs were obtained by reductive transformations using L-Selectride and H-Pd/C, by molecular abeo-rearrangements using the DAST reagent or ultrasonic treatment in the NaI-Zn-DMF system, and by acid-catalyzed reactions of poststerone derivatives with various aldehydes (o-FCHCHO, m-CFCHCHO, COMe(CH)CHO). The products were tested on a mouse lymphoma cell line pair, L5178 and its ABCB1-transfected multi-drug resistant counterpart, L5178, for their in vitro activity alone and in combination with doxorubicin, and for the ability to inhibit the ABCB1 transporter.

Alkylated monoterpene indole alkaloid derivatives as potent P-glycoprotein inhibitors in resistant cancer cells.

Aiming at generating a series of monoterpene indole alkaloids with enhanced multidrug resistance (MDR) reversing activity in cancer, two major epimeric alkaloids isolated from Tabernaemontana elegans, tabernaemontanine (1) and dregamine (2), were derivatized by alkylation of the indole nitrogen. Twenty-six new derivatives (3-28) were prepared by reaction with different aliphatic and aromatic halides, whose structures were elucidated mainly by NMR, including 2D NMR experiments. Their MDR reversal ability was evaluated through a functional assay, using as models resistant human colon adenocarcinoma and human ABCB1-gene transfected L5178Y mouse lymphoma cells, overexpressing P-glycoprotein (P-gp), by flow cytometry.

Squalenoylated Nanoparticle Pro-Drugs of Adjuvant Antitumor 11α-Hydroxyecdysteroid 2,3-Acetonides Act as Cytoprotective Agents Against Doxorubicin and Paclitaxel.

Several ecdysteroid acetonides act as adjuvant chemo-sensitizing agents against various cancer cell lines, and they can be formulated to self-assembling nanoparticle (NP) pro-drugs through a hydrolysable conjugation with squalene. In the bloodstream such squalenoylated nanoparticles dissolve into low-density lipoprotein (LDL) that allows targeting tissues containing high levels of LDL-receptors. In this work, ajugasterone C 2,3;20,22-diacetonide () and 11α-hydroxypoststerone 2,3-acetonide () were squalenoylated to obtain two new ecdysteroid pro-drugs ( and ) and their nano-assemblies ( and ).

Phenothiazines and Selenocompounds: A Potential Novel Combination Therapy of Multidrug Resistant Cancer.

Background/aim: Phenothiazines constitute a versatile family of compounds in terms of biological activity, which have also gained a considerable attention in cancer research.

Materials And Methods: Three phenothiazines (promethazine, chlorpromazine and thioridazine) have been tested in combination with 11 active selenocompounds against MDR (ABCB1-overexpressing) mouse T-lymphoma cells to investigate their activity as combination chemotherapy and as antitumor adjuvants in vitro with a checkerboard combination assay.

Results: Seven selenocompounds showed toxicity on mouse embryonic fibroblasts, while three showed selectivity towards tumor cells.

Discovery of phenylselenoether-hydantoin hybrids as ABCB1 efflux pump modulating agents with cytotoxic and antiproliferative actions in resistant T-lymphoma.

Multidrug resistance (MDR) in cancer cells is a crucial aspect to consider for a successful cancer therapy. P-gp/ABCB1, a member of ABC transporters, is involved in the main tumour MDR mechanism, responsible for the efflux of drugs and cytotoxic substances. Herein, we describe a discovery of potent selenium-containing ABCB1 MDR efflux pump modulators with promising anticancer activity.

Search for ABCB1 Modulators Among 2-Amine-5-Arylideneimidazolones as a New Perspective to Overcome Cancer Multidrug Resistance.

Multidrug resistance (MDR) is a severe problem in the treatment of cancer with overexpression of glycoprotein P (Pgp, ABCB1) as a reason for chemotherapy failure. A series of 14 novel 5-arylideneimidazolone derivatives containing the morpholine moiety, with respect to two different topologies (groups A and B), were designed and obtained in a three- or four-step synthesis, involving the Dimroth rearrangement. The new compounds were tested for their inhibition of the ABCB1 efflux pump in both sensitive (parental (PAR)) and ABCB1-overexpressing (MDR) T-lymphoma cancer cells in a rhodamine 123 accumulation assay.

Biofilm Eradication by Symmetrical Selenoesters for Food-Borne Pathogens.

Infections caused by species and represent major health and food industry problems. Bacteria have developed many strategies to resist the antibacterial activity of antibiotics, leading to multidrug resistance (MDR). The over-expression of drug efflux pumps and the formation of biofilms based on quorum sensing (QS) can contribute the emergence of MDR.

The Role of Efflux Pumps and Environmental pH in Bacterial Multidrug Resistance.

Background/aim: One of the most studied bacterial resistance mechanisms is the resistance related to multidrug efflux pumps. In our study the pump activity of the Escherichia coli K-12 AG100 strain expressing the AcrAB-TolC pump system was investigated at pH 7 and pH 5 in the presence of the efflux pump inhibitor (EPI) promethazine (PMZ).

Materials And Methods: The EPI activity was assessed by real-time fluorimetry.

New Chalcone Derivative Inhibits ABCB1 in Multidrug Resistant T-cell Lymphoma and Colon Adenocarcinoma Cells.

Background/aim: Development of new potential drugs to overcome multidrug resistance to chemotherapy is a big challenge for cancer treatment. Attention is also given to the natural compounds and their derivatives. The study aimed at evaluating the impact of a new chalcone derivative (1C) on multidrug resistant cell lines, focusing on P-glycoprotein (P-gp, ABCB1) inhibition, as well as 1C-doxorubicin interaction in vitro.

Antiviral, Antimicrobial and Antibiofilm Activity of Selenoesters and Selenoanhydrides.

Selenoesters and the selenium isostere of phthalic anhydride are bioactive selenium compounds with a reported promising activity in cancer, both due to their cytotoxicity and capacity to reverse multidrug resistance. Herein we evaluate the antiviral, the biofilm inhibitory, the antibacterial and the antifungal activities of these compounds. The selenoanhydride and 7 out of the 10 selenoesters were especially potent antiviral agents in Vero cells infected with herpes simplex virus-2 (HSV-2).

Solution equilibrium, structural and cytotoxicity studies on Ru(η-p-cymene) and copper complexes of pyrazolyl thiosemicarbazones.

Solution chemical properties of two bidentate pyrazolyl thiosemicarbazones 2-((3-methyl-1-phenyl-1H-pyrazol-4-yl)methylene)hydrazinecarbothioamide (Me-pyrTSC), 2-((1,3-diphenyl-1H-pyrazol-4-yl)methylene)hydrazinecarbothioamide (Ph-pyrTSC), stability of their Cu(II) and Ru(η-p-cymene) complexes were characterized in aqueous solution (with 30% DMSO) by the combined use of UV-visible spectrophotometry, H NMR spectroscopy and electrospray ionization mass spectrometry in addition to their solid phase isolation. The solid phase structures of Me-pyrTSC∙HO, [Ru(η-p-cymene)(Me-pyrTSC)Cl]Cl and [Cu(Ph-pyrTSCH)] were determined by single crystal X-ray diffraction. High stability mononuclear Ru(η-p-cymene) complexes with (N,S) coordination mode are formed in the acidic pH range, and increasing the pH the predominating dinuclear [(Ru(η-p-cymene))(L)] complex with μ-bridging sulphur donor atoms is formed (where L is the deprotonated thiosemicarbazone).

Selenoesters and Selenoanhydrides as Novel Agents Against Resistant Breast Cancer.

Background/aim: Selenium-containing compounds are becoming new alternatives in experimental chemotherapy in order to overcome multidrug resistance in cancer. The main goal of this study was to determine whether combined treatment with new Se-compounds would increase the effect of conventional doxorubicin chemotherapy in breast cancer cell lines.

Materials And Methods: Se-compounds were evaluated regarding their cytotoxic and apoptosis-inducing effect on MCF-7 and ATP-binding cassette subfamily B member 1 (ABCB1)-overexpressing KCR breast cancer cell lines.

Novel latonduine derived proligands and their copper(ii) complexes show cytotoxicity in the nanomolar range in human colon adenocarcinoma cells and in vitro cancer selectivity.

Four Schiff bases derived from 7-hydrazin-yl-5,8-dihydroindolo[2,3-d][2]benzazepin-(6H)-one and its bromo-substituted analogue (HL1-HL4) and four copper(ii) complexes 1-4 have been synthesised and fully characterised by standard spectroscopic methods (1H and 13C NMR, UV-vis), ESI mass spectrometry, single crystal X-ray diffraction and spectroelectrochemistry. In addition, two previously reported complexes with paullone ligands 5 and 6 were prepared and studied for comparison reasons. The CuII ion in 1-4 is five-coordinate and adopts a square-pyramidal or slightly distorted square-pyramidal coordination geometry.

Antiproliferative and cytotoxic activities of furocoumarins of Ducrosia anethifolia.

Context: Phytochemical and pharmacological data on Ducrosia anethifolia (DC.) Boiss. (Apiaceae), an Iranian medicinal plant, are scarce; however, furocoumarins are characteristic compounds of D.

Nigella sativa essential oil and its bioactive compounds as resistance modifiers against Staphylococcus aureus.

Nigella sativa essential oil (EO) and its compounds (thymoquinone, carvacrol, and p-cymene) have a broad antimicrobial spectrum. The aim of this study was to investigate the antimicrobial and resistance modifying activity of N. sativa EO, thymoquinone, carvacrol, and p-cymene against one methicillin susceptible and one methicillin resistant Staphylococcus aureus strain.