Cytotoxic and genotoxic effects of (R)- and (S)-ricinoleic acid derivatives

(R)-ricinoleic acid is the main component of castor oil from Ricinus communis L. Due to the presence of the hydroxyl group in homoallylic position and asymmetrically substituted carbon atom, it may undergo a number of chemical and biochemical transformations resulting in the products with some specific bioactivities. Conversion of (R)-ricinoleic acid into its (S)-enantiomer enables synthesis of both (R)- and (S)-ricinoleic acid derivatives and comparison of their biological activities. In the present research, (R)- and (S)-ricinoleic acid amides synthesized from methyl ricinoleates and ethanolamine or pyrrolidine as well as acetate derivatives of ethanolamine amides were studied to demonstrate their biological activities using HT29 cancer cells. Double staining of cells with fluorochromes (Hoechst 33258/propidium iodide) as well as 2,′7′-dichlorodihydrofluorescein (DCF) and comet assays were performed. Both the tested amides and acetates caused DNA damage and induced apoptotic and necrotic cell death. In the case of (R)- and (S)-enantiomers of one of the tested acetates, significant difference in the ability to induce DNA damage was observed, which showed the impact of the stereogenic center on the activities of these compounds.     

Chiral Recognition of N‐Phthaloyl,N‐Tetrachlorophthaloyl,and N‐Naphthaloyl α‐Amino Acids and Their Esters on Polysaccharide‐Derived Chiral Stationary Phases

Enantiomeric separations of N‐phthaloyl (N‐PHT), N‐tetrachlorophthaloyl (N‐TCPHT), and N‐naphthaloyl (N‐NPHT) α‐amino acids and their esters were examined on several kinds of polysaccharide‐derived chiral stationary phases (CSPs). Resolution capability of CSPs was greater Chiralcel OF than the others for N‐PHT and N‐NPHT α‐amino acids and their esters. In N‐TCPHT α‐amino acids and their esters, good enantioselectivities showed Chiralcel OG for N‐TCPHT α‐amino acids, Chiralpak AD for N‐TCPHT α‐amino acid methyl esters, and Chiralcel OD for N‐TCPHT α‐amino acid ethyl esters, respectively. From the results of liquid chromatography and computational chemistry, it is concluded that l ‐form is preferred and more retained with electrostatic interaction in case of interaction between N‐PHT α‐amino acid derivatives and Chiralcel OF, N‐TCPHT α‐amino acid derivatives and Chiralcel OD, and N‐NPHT α‐amino acid derivatives and Chiracel OF. On the other hand, d ‐form is preferred and more retained with van der Waals interaction in case of interaction between N‐TCPHT α‐amino acid ester derivatives and Chiralcel OG and Chiralpak AD. Chirality 24:1037–1046, 2012. © 2012 Wiley Periodicals, Inc.     

Novel amides of 1,1‐bis‐(carboxymethylthio)‐1‐arylethanes: Synthesis,characterization, acetylcholinesterase,butyrylcholinesterase, and carbonic anhydrase inhibitory properties

The thiolation reaction was carried out in a benzene solution at 80°C and p‐substituted ketones and mercaptoacetic acid in a molar ratio (1:4) of in the presence of a catalytic amount of toluene sulfonic acids. The enzyme inhibition activities of the novel amides of 1,1‐bis‐(carboxymethylthio)‐1‐arylethanes derivatives were investigated. These novel amides of 1,1‐bis‐(carboxymethylthio)‐1‐arylethanes derivatives showed good inhibitory action against acetylcholinesterase (AChE) butyrylcholinesterase (BChE), and human carbonic anhydrase I and II isoforms (hCA I and II). AChE inhibitors, interacting with the enzyme as their primary target, are applied as relevant drugs and toxins. Many clinically established drugs are carbonic anhydrase inhibitors, and it is highly anticipated that many more will eventually find their way into the market. The novel synthesized compounds inhibited AChE and BChE with K_i values in the range of 0.64–1.47 nM and 9.11–48.12 nM, respectively. On the other hand, hCA I and II were effectively inhibited by these compounds, with K_i values between 63.27–132.34 and of 29.63–127.31 nM, respectively.     

Design,Synthesis and Bioevaluation of Two Series of 3‐[(1‐Benzyl‐1H‐1,2,3‐triazol‐4‐yl)methyl]quinazolin‐4(3H)‐ones and N‐(1‐Benzylpiperidin‐4‐yl)quinazolin‐4‐amines

Two series of 3‐[(1‐benzyl‐1H‐1,2,3‐triazol‐4‐yl)methyl]quinazolin‐4(3H)‐ones and N‐(1‐benzylpiperidin‐4‐yl)quinazolin‐4‐amines were designed initially as potential acetylcholine esterase inhibitors. Biological evaluation demonstrated that N‐(1‐benzylpiperidin‐4‐yl)quinazolin‐4‐amines significantly inhibited AChE activity. Especially, two compounds of them were found to be the most potent with relative AChE inhibition percentages of 87 % in comparison to donepezil. The docking studies with AChE showed similar interactions between donepezil and four derivatives. N‐(1‐Benzylpiperidin‐4‐yl)quinazolin‐4‐amines also exhibited significant DPPH scavenging effects. The two series of compound also exerted moderate to good cytotoxicity against three human cancer cell lines, including SW620 (human colon cancer), PC‐3 (prostate cancer), and NCI?H23 (lung cancer), with 3‐[(1‐benzyl‐1H‐1,2,3‐triazol‐4‐yl)methyl]quinazolin‐4(3H)‐one being the most cytotoxic agent. 3‐[(1‐Benzyl‐1H‐1,2,3‐triazol‐4‐yl)methyl]quinazolin‐4(3H)‐one significantly induced early apoptosis and arrested the SW620 cells at G2/M phase. From this study, two compounds of N‐(1‐benzylpiperidin‐4‐yl)quinazolin‐4‐amines could serve as new leads for further design and AChE inhibitors, while 3‐[(1‐benzyl‐1H‐1,2,3‐triazol‐4‐yl)methyl]quinazolin‐4(3H)‐one could serve as a new lead for the design and development of more potent anticancer agents.     

Quinazolin‐4(3H)‐one‐Based Hydroxamic Acids: Design,Synthesis and Evaluation of Histone Deacetylase Inhibitory Effects and Cytotoxicity

The present article describes the synthesis and biological activity of various series of novel hydroxamic acids incorporating quinazolin‐4(3H)‐ones as novel small molecules targeting histone deacetylases. Biological evaluation showed that these hydroxamic acids were potently cytotoxic against three human cancer cell lines (SW620, colon; PC‐3, prostate; NCI?H23, lung). Most compounds displayed superior cytotoxicity than SAHA (suberoylanilide hydroxamic acid, Vorinostat) in term of cytotoxicity. Especially, N‐hydroxy‐7‐(7‐methyl‐4‐oxoquinazolin‐3(4H)‐yl)heptanamide ( 5b ) and N‐hydroxy‐7‐(6‐methyl‐4‐oxoquinazolin‐3(4H)‐yl)heptanamide ( 5c ) (IC₅₀ values, 0.10–0.16 μm ) were found to be approximately 30‐fold more cytotoxic than SAHA (IC₅₀ values of 3.29–3.67 μm ). N‐Hydroxy‐7‐(4‐oxoquinazolin‐3(4H)‐yl)heptanamide ( 5a ; IC₅₀ values of 0.21–0.38 μm ) was approximately 10‐ to 15‐fold more potent than SAHA in cytotoxicity assay. These compounds also showed comparable HDAC inhibition potency with IC₅₀ values in sub‐micromolar ranges. Molecular docking experiments indicated that most compounds, as represented by 5b and 5c , strictly bound to HDAC2 at the active binding site with binding affinities much higher than that of SAHA.     

Synthesis of the N‐methyl Derivatives of 2‐Aminothiazol‐4(5H)‐one and Their Interactions with 11βHSD1‐Molecular Modeling and in Vitro Studies

11β‐Hydroxysteroid dehydrogenase type 1 (11β‐HSD1) is an enzyme that affects the body's cortisol levels. The inhibition of its activity can be used in the treatment of Cushing's syndrome, metabolic syndrome and type 2 diabetes. In this study, we synthesized new derivatives of 2‐(methylamino)thiazol‐4(5H)‐one and tested their activity towards inhibition of 11β‐HSD1 and its isoform – 11β‐HSD2. The results were compared with the previously tested allyl derivatives. We found out that methyl derivatives are weaker inhibitors of 11β‐HSD1 in comparison to their allyl analogs. Due to significant differences in the activity of the compounds, molecular modeling was performed, which was aimed at comparing the interactions between 11β‐HSD1 and ligands differing by substituent at the amine group (allyl vs. methyl). Modeling showed that the absence of the allyl group can lead to the rotation of whole ligand molecule which affects its interaction with the enzyme.     

Isolation and characterization of fatty acid methyl ester (FAME)‐producing Streptomyces sp. S161 from sheep (Ovis aries) faeces

An actinomycete producing oil‐like mixtures was isolated and characterized. The strain was isolated from sheep faeces and identified as Streptomyces sp. S161 based on 16S rRNA gene sequence analysis. The strain showed cellulase and xylanase activities. The ¹H nuclear magnetic resonance (NMR) spectra of the mixtures showed that the mixtures were composed of fatty acid methyl esters (52·5), triglycerides (13·7) and monoglycerides (9·1) (mol.%). Based on the gas chromatography–mass spectrometry (GC‐MS) analysis, the fatty acid methyl esters were mainly composed of C14‐C16 long‐chain fatty acids. The results indicated that Streptomyces sp. S161 could produce fatty acid methyl esters (FAME) directly from starch. To our knowledge, this is the first isolated strain that can produce biodiesel (FAME) directly from starch.

Significance and Impact of the Study

Nowadays, production of biodiesel is based on plant oils, animal fats, algal oils and microbial oils. Lipid mostly consists of triacylglycerols (TAG), and conversion of these lipids into fatty acid short‐chain alcohol esters (methanol or ethanol) is the final step in biodiesel production. In this study, an oil‐producing Streptomyces strain was isolated from sheep faeces. The oil was composed of C₁₄‐C₁₆ long‐chain fatty acid methyl esters, triglycerides and monoglycerides. This is the first isolated strain‐producing biodiesel (FAME) directly from starch. Due to showing cellulase and xylanase activities, the strain would be helpful for converting renewable lignocellulose into biodiesel directly.     

New Derivatives from Microbial Transformation of ent‐Kaur‐16‐en‐19‐oic Acid by Cunninghamella echinulata

Biotransformation of ent‐kaur‐16‐en‐19‐oic acid using fungus Cunninghamella echinulata resulted in two novel hydroxylated metabolites together with five known compounds. Their structures were elucidated by means of extensive NMR and HR‐ESI‐MS data analysis. The eight compounds were measured for their cytotoxicity against the human breast carcinoma (MCF‐7) and human hepatoblastoma (HepG‐2) cell lines. Seven compounds showed no cytotoxicity to the two cell lines. One compound displayed moderate cytotoxicity against HepG‐2 and MCF‐7 with the IC₅₀ values of 12.6 and 27.1 μM, respectively.     

Lewis acid catalysed methylation of N‐(9H‐fluoren‐9‐yl)methanesulfonyl (Fms) protected lipophilic α‐amino acid methyl esters

This work reports an efficient Lewis acid catalysed N‐methylation procedure of lipophilic α‐amino acid methyl esters in solution phase. The developed methodology involves the use of the reagent system AlCl₃/diazomethane as methylating agent and α‐amino acid methyl esters protected on the amino function with the (9H‐fluoren‐9‐yl)methanesulfonyl (Fms) group. The removal of Fms protecting group is achieved under the same conditions to those used for Fmoc removal. Thus the Fms group can be interchangeable with the Fmoc group in the synthesis of N‐methylated peptides using standard Fmoc‐based strategies. Finally, the absence of racemization during the methylation reaction and the removal of Fms group were demonstrated by synthesising a pair of diastereomeric dipeptides. Copyright © 2015 European Peptide Society and John Wiley & Sons, Ltd.     

Synthesis and Antioxidant Ability of Novel Derivatives Based on para‐Coumaric Acid Containing Isobornyl Groups

A series of novel esters and amides was synthesized on the basis of para‐coumaric acid containing isobornyl groups in ortho‐positions relative to the phenolic hydroxy group. Antioxidant properties of the obtained compounds were evaluated and compared on in vitro models: radical‐scavenging ability, antioxidant activity on a substrate containing the lipids of animal brain, cytotoxicity of red blood cells, antioxidant and membrane‐protective properties on the model of oxidative red blood cells hemolysis. Statistically significant relationship was established between the antioxidant activity of the studied compounds in model system containing animal lipids and the parameters reflecting their antioxidant properties on the model of H₂O₂‐induced hemolysis of red blood cells. It was determined that an amide with a morpholine fragment has the highest antioxidant activity. The specified derivative significantly surpassed the reference substances (parent acid, BHT) and was not inferior to the effective antioxidant 2,6‐diisobornyl‐4‐methylphenol in terms of its properties.     

Synthesis,Biological Evaluation,and Molecular Docking Studies of Novel 4‐[4‐Arylpyridin‐1(4H)‐yl]benzoic Acid Derivatives as Anti‐HIV‐1 Agents

The structural similarities between N1 substituted 1,4‐dihydropyridines and the known gp41 inhibitors, NB ‐2 and NB ‐64 , were considered in the current research for the design of some novel anti‐HIV‐1 agents. A series of novel 4‐[4‐arylpyridin‐1(4H)‐yl]benzoic acid derivatives were synthesized and after a comprehensive structural elucidation were screened for in vitro anti‐HIV‐1 activity. Most of the tested compounds displayed moderate to good inhibitory activity against HIV‐1 growth and were evaluated for in vitro cytotoxic activity using XTT assay at the concentration of 100 μm . Among the tested compounds, 1c , 1d and 1e showed potent anti‐HIV‐1 activity against P24 expression at 100 μm with inhibition percentage of 84.00%, 76.42% and 80.50%, respectively. All the studied compounds possessed no significant cytotoxicity on MT‐2 cell line. The binding modes of these compounds to gp41 binding site were determined through molecular docking study. Docking studies proved 1a as the most potent compound and binding maps exhibited that the activities might be attributed to the electrostatic and hydrophobic interactions and additional H‐bonds with the gp41 binding site. The Lipinski's ‘rule of five’ and drug‐likeness criteria were also calculated for the studied compounds. All derivatives obeyed the Lipinski's ‘rule of five’ and had drug‐like features. The findings of this study suggest that novel 4‐[4‐arylpyridin‐1(4H)‐yl]benzoic acid might be a promising scaffold for the discovery and development of novel anti‐HIV‐1 agents.     

Synthesis and Anticancer Activity of 3‐(Substituted Aroyl)‐4‐(3,4,5‐trimethoxyphenyl)‐1H‐pyrrole Derivatives

A series of 3‐(substituted aroyl)‐4‐(3,4,5‐trimethoxyphenyl)‐1H‐pyrrole derivatives were synthesized and determined for their anticancer activity against eleven cancer cell lines and two normal tissue cell lines using MTT assay. Among the synthesized compounds, compound 3f was the most potent compound against A375, CT‐26, HeLa, MGC80‐3, NCI‐H460 and SGC‐7901 cells (IC₅₀ = 8.2 – 31.7 μm ); 3g , 3n and 3a were the most potent compounds against CHO (IC₅₀ = 8.2 μm ), HCT‐15 (IC₅₀ = 21 μm ) and MCF‐7 cells (IC₅₀ = 18.7 μm ), respectively. Importantly, all the target compounds showed no cytotoxicity towards the normal tissue cell (IC₅₀ > 100 μm ). Thus, these compounds with the potent anticancer activity and low toxicity have potential for the development of new anticancer chemotherapy agents.     

Synthesis and in Vitro Antimicrobial Activity Screening of New 3‐Acetyl‐2,5‐disubstituted‐1,3,4‐oxadiazoline Derivatives

Thirteen new 3‐acetyl‐2,5‐disubstituted‐1,3,4‐oxadiazoline derivatives were synthesized from corresponding hydrazide‐hydrazones of isonicotinic acid in the reaction with acetic anhydride. The obtained compounds were identified with the use of spectral methods (IR, ¹H‐NMR, ¹³C‐NMR, MS). In vitro antimicrobial activity screening of synthesized compounds against a panel of bacteria and fungi revealed interesting antibacterial and antifungal activity of tested 1,3,4‐oxadiazoline derivatives, which is comparable to that of commonly used antimicrobial agents.     

Enzymatic Synthesis of β-Lactam Antibiotics and N-Fatty-Acylated Amino Compounds by the Acyl-Transfer Reaction Catalyzed by Penicillin V Acylase from Streptomyces mobaraensis

Penicillin V acylase from Streptomyces mobaraensis (Sm-PVA) showed high acyl-transfer activity in reactions using methyl esters of carboxylic acid (acyl donor) and amino compounds (nucleophile), to produce the corresponding amides. Moreover, Sm-PVA had broad substrate specificity, as indicated by the fact that it catalyzed the efficient synthesis of β-lactam antibiotics, capsaicin derivatives, and N-fatty-acyl-amino acid/N-fatty-acyl-peptide derivatives.     

Caffeoylquinic Acids: Separation Method,Antiradical Properties and Cytotoxicity

Twelve chlorogenic acid derivatives and two flavones were isolated from Moquiniastrum floribundum (Asteraceae, other name: Gochnatia floribunda). Compounds were evaluated in relation to their cytotoxicity and antiradical properties. Cytotoxicity was not observed for compounds, however, chlorogenic acid derivatives showed antiradical activity and were more active than the Trolox standard. Quinic acid esterified with caffeoyl group at C‐4 position showed higher antiradical activity compared to acylation at C‐3 or C‐5 positions. Additional caffeoyl groups esterified in quinic acid increase the antiradical activity observed for 4‐caffeoylquinic acid. Excepted to 3,4‐dicaffeoylquinic acid methyl ester, methyl ester derivatives show higher capacity of trapping radicals than their respective acids. Consequently, the presence of caffeoyl group at C‐4 position of quinic acid is suggested as fundamental to obtain the highest antiradical activity.     

Application of NMR spectroscopy for assignment of the absolute configuration of 8‐tert‐butyl‐2‐hydroxy‐7‐methoxy‐8‐methyl‐9‐oxa‐6‐azaspiro[4.5]dec‐6‐en‐10‐one

In order to assign the absolute configurations of 8‐tert‐butyl‐2‐hydroxy‐7‐methoxy‐8‐methyl‐9‐oxa‐6‐azaspiro[4.5]dec‐6‐en‐10‐one ( 2a , 2b ), their esters ( 5a , 5b , 5c , 5d ) with (R)‐ or (S)‐2‐methoxyphenylacetic acid ( 4a , 4b ) have been synthesized. The absolute configurations of these compounds have been determined on the basis of NOESY correlations between the protons of the tert‐butyl group and the cyclopentane fragment of the molecules. The crucial part of this analysis was assignment of the absolute configuration at C‐5. Additionally, by calculation of the chemical shift anisotropy, δ^RS, for the relevant protons, it was also possible to confirm the absolute configurations at the C‐2 centres of compounds 2a , 2b and 5a , 5b , 5c , 5d . Chirality, 25:422–426, 2013.© 2013 Wiley Periodicals, Inc.     

Syntheses and Antitumor Evaluation of C(6)‐Isobutyl‐ and C(6)‐Isobutenyl‐Substituted Pyrimidines,and Dihydropyrrolo[1,2‐c]pyrimidine‐1,3‐diones

A growing body of evidence supports that pyrimidine derivatives, in which the sugar residues have been replaced by acyclic side chains, might be developed as promising anticancer agents that interfere with tumor cell proliferation, survival, and metastatic formation. In this work, we prepared novel pyrimidines bearing i‐Bu (i.e., 3, 4 , and 7 – 9 ) and isobutenyl (i.e., 5 and 10 ) side chains at C(6) and examined their in vitro effects on tumor cell lines. The dihydropyrrolo[1,2‐c]pyrimidine‐1,3‐diones 6 and 11 were obtained as products of intramolecular cyclization, which occurred during the removal of Bn in 5 or MeO protecting groups in 10 . Fluorination of 3 with diethylaminosulfur trifluoride (DAST) and then dehydrohalogenation of the resulting fluorinated derivative 4 afforded 6‐isobut‐2′‐enyl pyrimidine derivative 5 with a C(2′)C(3′) bond. For the preparation of 6‐isobut‐1′‐en‐1‐yl pyrimidine 10 , a synthetic strategy involving acetylation of the 1,3‐diols was applied. Antitumor evaluation of compounds 3 – 11 showed that 2,4‐dimethoxypyrimidine containing 6‐[(1,3‐dibenzyloxy)‐2‐hydroxy]methyl side chain, 3 , exerted a strong antiproliferative effect on the studied tumor cell lines. Additionally, it was shown that the mechanism of antiproliferative effect of 3 in HeLa cells include early G2/M arrest and apoptosis, as well as a p53‐independent S‐phase arrest upon prolonged treatment.     

Synthesis and Solid State Conformation of Tetrapeptide Amides Containing two Aib and two (αMe)Phe Residues – Use of Enantiomerically Pure 2‐Benzyl‐2‐methyl‐2H‐azirin‐3‐amines as (αMe)Phe‐Synthons

A series of tetrapeptide amides containing two aminoisobutyric acids (Aib) and two α‐methylphenylalanine ((αMe)Phe) units were prepared through the ‘azirine/oxazolone method’. New 2‐benzyl‐2‐methyl‐2H‐azirin‐3‐amines have been used for the selective introduction of (S)‐ and (R)‐(αMe)Phe, respectively. The solid‐state conformations of five tetrapeptide amides were determined by X‐ray crystallography. In all cases, two β‐turns stabilize 3₁₀‐helical conformations and it was confirmed that, in contrast to proteinogenic amino acids, the configuration of (αMe)Phe does not determine the screw sense of the helix.     

Investigation of acetylcholinesterase and mammalian DNA topoisomerases,carbonic anhydrase inhibition profiles,and cytotoxic activity of novel bis(α‐aminoalkyl)phosphinic acid derivatives against human breast cancer

The aim of this study was to evaluate biologically active novel molecules having potentials to be drugs by their antitumor properties and by activities of apoptotic caspase and topoisomerase. Following syntheses of novel eight bis(α‐aminoalkyl)phosphinic acid derivatives ( 4a–h ) as a result of array of reactions, compounds were evaluated by cytotoxic effects in vitro on human breast cancer (MCF‐7) and normal endothelial (HUVEC) cell lines. All phosphinic acid derivatives were effective for cytotoxicity on both MCF‐7 and HUVEC lines, while 4c , 4e , and 4f compounds were found significantly more effective. For the evaluation of antitumor properties of compounds in a highly sensitive method, their effects on inhibiting topoisomerases I and II were investigated. Also, some of the bis(α‐aminoalkyl)phosphinic acid derivatives ( 4a, 4e–h ) showed nice inhibitory action against acetylcholinesterase and human carbonic anhydrase isoforms I and II.     

Synthesis of 3‐Methylidene‐1‐tosyl‐2,3‐dihydroquinolin‐4(1H)‐ones as Potent Cytotoxic Agents

An efficient synthetic strategy to 3‐methylidene‐2,3‐dihydroquinolin‐4(1H)‐ones variously substituted in position 2 has been developed. The title compounds were synthesized in the reaction sequence involving reaction of diethyl methylphosphonate with methyl 2‐(tosylamino)benzoate, condensation of thus formed diethyl 2‐oxo‐2‐(2‐N‐tosylphenyl)ethylphosphonate with various aldehydes followed by successful application of the obtained 3‐(diethoxyphosphoryl)‐1,2‐dihydroquinolin‐4‐ols as Horner–Wadsworth–Emmons reagents for the olefination of formaldehyde. Also, enantioselective approach to the target compounds has been evaluated using 3‐dimenthoxyphosphoryl group as a chiral auxiliary. Single X‐ray crystal analysis of (2S)‐3‐(dimenthoxyphosphoryl)‐2‐phenyl‐1‐tosyldihydroquinolin‐4‐ol revealed the presence of strong resonance‐assisted hydrogen bond (RAHB). The obtained 3‐methylidene‐2,3‐dihydroquinolin‐4(1H)‐ones were then tested for their cytotoxic activity against two leukemia cell lines NALM‐6 and HL‐60 and a breast cancer MCF‐7 cell line. All compounds showed very high cytotoxic activity with the IC₅₀ values mostly below 1 μm in all three cancer cell lines. The selected analogs were also tested on human umbilical vein endothelial cells (HUVEC) and on human mammary gland/breast cells (MCF‐10A) to evaluate their influence on normal cells. Since one of the most serious problems in cancer chemotherapy is the development of drug resistance, the mRNA levels and activity of ABCB1 transporter considered to be the most important factor engaged in drug resistance, were evaluated in MCF‐7 cells treated with two selected analogs. Both compounds were strong ABCB1 transporter inhibitors that could prevent efflux of anticancer drugs from cancer cells.