Synthesis and antitumor molecular mechanism of agents based on amino 2-(3',4',5'-trimethoxybenzoyl)benzo[b]furan: inhibition of tubulin and induction of apoptosis

Induction of apoptosis is a promising strategy that could lead to the discovery of new molecules active in cancer chemotherapy. This property is generally observed when cells are treated with agents that target microtubules, dynamic structures that play a crucial role in cell division. Small molecules such as benzo[b]furans are attractive as inhibitors of tubulin polymerization. A new class of inhibitors of tubulin polymerization based on the 2-(3',4',5'-trimethoxybenzoyl)benzo[b]furan molecular skeleton, with the amino group placed at different positions on the benzene ring, were synthesized and evaluated for antiproliferative activity, inhibition of tubulin polymerization, and cell-cycle effects. The methoxy substitution pattern on the benzene portion of the benzo[b]furan moiety played an important role in affecting antiproliferative activity. In the series of 5-amino derivatives, the greatest inhibition of cell growth occurred if the methoxy substituent is placed at the C6 position, whereas C7 substitution decreases potency. The most promising compound in this series is 2-(3',4',5'-trimethoxybenzoyl)-3-methyl-5-amino-6-methoxybenzo[b]furan (3 h), which inhibits cancer cell growth at nanomolar concentrations (IC(50) =16-24 nM), and interacts strongly with tubulin by binding to the colchicine site. Sub-G(1) apoptotic cells in cultures of HL-60 and U937 cells were observed by flow cytometric analysis after treatment with 3 h in a concentration-dependent manner. We also show that compound 3 h induces apoptosis by activation of caspase-3, -8, and -9, and this is associated with cytochrome c release from mitochondria. The introduction of an α-bromoacryloyl group increased antiproliferative activity with respect to the parent amino derivatives.     

Discovery of 6-Arylurea-2-arylbenzoxazole and 6-Arylurea-2-arylbenzimidazole Derivatives as Angiogenesis Inhibitors: Design,Synthesis and in vitro Biological Evaluation

We embarked on a structural optimization campaign aimed at the discovery of novel anti-angiogenesis agents with previously reported imidazole kinase inhibitors as a lead compound. A library of 29 compounds was synthesized. Several title compounds exhibited selective inhibitory activities against vascular endothelial growth factor receptor 2 (VEGFR-2) over epidermal growth factor receptor (EGFR) kinase; these compounds also displayed selective and potent antiproliferative activity against three cancer cell lines. The newly synthesized compounds were evaluated for anti-angiogenesis activity by chick chorioallantoic membrane (CAM) assay. Among them, 1-(2-(2-chlorophenyl)benzo[d]oxazol-5-yl)-3-(4-(trifluoromethoxy)phenyl)urea (compound 5 n ) showed the most potent anti-angiogenesis capacity, efficient cytotoxic activities (in vitro against human umbilical vein endothelial cells (HUVEC), H1975, A549, and HeLa cell lines, with respective IC₅₀ values of 8.46, 1.40, 7.61, and 0.28 μm ), and an acceptable level of VEGFR-2 kinase inhibition (IC₅₀=0.25 μm ). Molecular docking analysis revealed 5 n to be a type II inhibitor of VEGFR-2 kinase. In general, these results indicate that these 6-arylurea-2-arylbenzoxazole/benzimidazole derivatives are promising inhibitors of VEGFR-2 kinase for potential development into anti-angiogenesis drugs.     

Microwave‐Assisted Syntheses of Benzimidazole‐Containing Selenadiazole Derivatives That Induce Cell‐Cycle Arrest and Apoptosis in Human Breast Cancer Cells by Activation of the ROS/AKT Pathway

The use of selenium‐containing heterocyclic compounds as potent cancer chemopreventive and chemotherapeutic agents has been well documented by a large number of clinical studies. In this study we developed a new approach to synthesize four benzimidazole‐containing selenadiazole derivatives (BSeDs). The method uses a combination of peptide coupling reagents and microwave irradiation. This strategy features milder reaction conditions, higher yields, and shorter reaction times. The synthetic BSeDs were identified as potent antiproliferative agents against the human MCF‐7 and MDA‐MB‐231 breast cancer cell lines. Compounds 1 b (5‐(6‐methyl‐1H‐benzo[d]imidazol‐2‐yl)benzo[c][1,2,5]selenadiazole), 1 c (5‐(6‐chloro‐1H‐benzo[d]imidazol‐2‐yl)benzo[c][1,2,5]selenadiazole), and 1 d (5‐(6‐bromo‐1H‐benzo[d]imidazol‐2‐yl)benzo[c][1,2,5]selenadiazole) were found to show greater cytotoxicity against the triple‐negative breast cancer cell line MDA‐MB‐231 than MCF‐7, and to exhibit dose‐dependent inhibition of cell migration, in which a significant decrease in the zone of cell monolayer wound closure was observed relative to untreated controls. Our results demonstrate that BSeDs can cause cell‐cycle arrest and apoptosis in MDA‐MB‐231 cells by inducing DNA damage, inhibiting protein kinase B (AKT), and activating mitogen‐activated protein kinase (MAPK) family members through the overproduction of reactive oxygen species (ROS). Taken together, the results of this study provide a facile microwave‐assisted strategy for the synthesis of selenium‐containing organic compounds that exhibit a high level of anticancer efficacy.     

Semisynthetic Ursolic Acid Fluorolactone Derivatives Inhibit Growth with Induction of p21(waf1) and Induce Apoptosis with Upregulation of NOXA and Downregulation of c-FLIP in Cancer Cells

A series of ursolic acid ((1S,2R,4aS,6aR,6aS,6bR,8aR,10S,12aR,14bS)‐10‐hydroxy‐1,2,6a,6b,9,9,12a‐heptamethyl‐2,3,4,5,6,6a,7,8,8a,10,11,12,13,14b‐tetradecahydro‐1H‐picene‐4a‐carboxylic acid) derivatives with a 12‐fluoro‐13,28β‐lactone moiety were synthesized using the electrophilic fluorination reagent Selectfluor. The antiproliferative effects of these novel compounds were evaluated in AsPC‐1 pancreatic cancer cells, and the structure–activity relationships (SARs) were evaluated. Of the compounds synthesized, ursolic acid derivatives carrying a heterocyclic ring, such as imidazole or methylimidazole, and cyanoenones were among the more potent inhibitors of AsPC‐1 pancreatic cancer cell growth. 2‐Cyano‐3‐oxo‐12α‐fluoro‐urs‐1‐en‐13,28β‐olide, compound 20 , was the most effective inhibitor with IC₅₀ values of 0.7, 0.9 and 1.8 μM in pancreatic cancer cell lines AsPC‐1, MIA PaCa‐2 and PANC‐1, respectively. This compound also exhibited better antiproliferative activities against breast (MCF7), prostate (PC‐3), hepatocellular (Hep G2) and lung (A549) cancer cell lines, with IC₅₀ values lower than 1 μM . The mechanism of action by which these compounds exert their biological effect was evaluated in AsPC‐1 cells using the most potent inhibitor synthesized, compound 20 . At 1 μM , the cell cycle arrested at the G1 phase with upregulation of p21^waf1. Apoptosis was induced at an inhibitor concentration of 8 μM with upregulation of NOXA and downregulation of c‐FLIP. These data indicate that fluorolactone derivatives of ursolic acid have improved antiproliferative activity, acting through arrest of the cell cycle and induction of apoptosis.     

Synthesis and Anticancer Activity of Mitotic-Specific 3,4-Dihydropyridine-2(1H)-thiones

Most anticancer drugs target mitosis as the most crucial and fragile period of rapidly dividing cancer cells. However the limitations of classical chemotherapeutics drive the search for new more effective and selective compounds. For this purpose structural modifications of the previously characterized pyridine analogue (S1) were incorporated aiming to obtain an antimitotic inhibitor of satisfactory and specific anticancer activity. Structure-activity relationship analysis of the compounds against a panel of cancer cell lines allowed to select a compound with a thiophene ring at C5 of a 3,4-dihydropyridine-2(1H)-thione (S22) with promising antiproliferative activity (IC₅₀ equal 1.71 ± 0.58 µM) and selectivity (SI = 21.09) against melanoma A375 cells. Moreover, all three of the most active compounds from the antiproliferative study, namely S1, S19 and S22 showed better selectivity against A375 cells than reference drug, suggesting their possible lower toxicity and wider therapeutic index. As further study revealed, selected compounds inhibited tubulin polymerization via colchicine binding site in dose dependent manner, leading to aberrant mitotic spindle formation, cell cycle arrest and apoptosis. Summarizing, the current study showed that among obtained mitotic-specific inhibitors analogue with thiophene ring showed the highest antiproliferative activity and selectivity against cancer cells.     

Synthesis of New Biscoumarin Derivatives,In Vitro Cholinesterase Inhibition,Molecular Modelling and Antiproliferative Effect in A549 Human Lung Carcinoma Cells

A series of novel C4-C7-tethered biscoumarin derivatives (12a–e) linked through piperazine moiety was designed, synthesized, and evaluated biological/therapeutic potential. Biscoumarin 12d was found to be the most effective inhibitor of both acetylcholinesterase (AChE, IC₅₀ = 6.30 µM) and butyrylcholinesterase (BChE, IC₅₀ = 49 µM). Detailed molecular modelling studies compared the accommodation of ensaculin (well-established coumarin derivative tested in phase I of clinical trials) and 12d in the human recombinant AChE (hAChE) active site. The ability of novel compounds to cross the blood–brain barrier (BBB) was predicted with a positive outcome for compound 12e. The antiproliferative effects of newly synthesized biscoumarin derivatives were tested in vitro on human lung carcinoma cell line (A549) and normal colon fibroblast cell line (CCD-18Co). The effect of derivatives on cell proliferation was evaluated by MTT assay, quantification of cell numbers and viability, colony-forming assay, analysis of cell cycle distribution and mitotic activity. Intracellular localization of used derivatives in A549 cells was confirmed by confocal microscopy. Derivatives 12d and 12e showed significant antiproliferative activity in A549 cancer cells without a significant effect on normal CCD-18Co cells. The inhibition of hAChE/human recombinant BChE (hBChE), the antiproliferative activity on cancer cells, and the ability to cross the BBB suggest the high potential of biscoumarin derivatives. Beside the treatment of cancer, 12e might be applicable against disorders such as schizophrenia, and 12d could serve future development as therapeutic agents in the prevention and/or treatment of Alzheimer’s disease.     

Discovery of Potent Inhibitors of Cyclin-Dependent Kinases 7 and 9: Design,Synthesis, Structure-Activity Relationship Analysis and Biological Evaluation

Cyclin-dependent kinases (CDKs) 7 and 9 are deregulated in various types of human cancer and are thus viewed as therapeutic targets. Accordingly, small-molecule inhibitors of both CDKs are highly sought-after. Capitalising on our previous discovery of CDKI-73, a potent CDK9 inhibitor, medicinal chemistry optimisation was pursued. A number of N-pyridinylpyrimidin-2-amines were rationally designed, chemically synthesised and biologically assessed. Among them, N-(6-(4-cyclopentylpiperazin-1-yl)pyridin-3-yl)-4-(imidazo[1,2-a]pyrimidin-3-yl)pyrimidin-2-amine was found to be one of the most potent inhibitors of CDKs 7 and 9 as well as the most effective anti-proliferative agent towards multiple human cancer cell lines. The cellular mode of action of this compound was investigated in MV4-11 acute myeloid leukaemia cells, revealing that the compound dampened the kinase activity of cellular CDKs 7 and 9, arrested the cell cycle at sub-G1 phase and induced apoptosis.     

Synthesis,In Vitro and In Silico Anticancer Activity of New 4-Methylbenzamide Derivatives Containing 2,6-Substituted Purines as Potential Protein Kinases Inhibitors

A novel class of potential protein kinase inhibitors 7–16 was synthesized in high yields using various substituted purines. The most promising compounds, 7 and 10, exhibited inhibitory activity against seven cancer cell lines. The IC₅₀ values for compounds 7 and 10 were 2.27 and 2.53 μM for K562 cells, 1.42 and 1.52 μM for HL-60 cells, and 4.56 and 24.77 μM for OKP-GS cells, respectively. In addition, compounds 7 and 10 dose-dependently induced the apoptosis and cell cycle arrest at G2/M phase, preventing the cell division of OKP-GS cells. Compounds 7, 9, and 10 showed 36–45% inhibitory activity against PDGFRα and PDGFRβ at the concentration of 1 μM. Molecular modeling experiments showed that obtained compounds could bind to PDGFRα as either type 1 (compound 7, ATP-competitive) or type 2 (compound 10, allosteric) inhibitors, depending on the substituent in the amide part of the molecule.     

Design,Synthesis, and in vitro Evaluation of Tubulin-Targeting Dibenzothiazines with Antiproliferative Activity as a Novel Heterocycle Building Block

We prepared a series of free NH and N-substituted dibenzonthiazines with potential anti-tumor activity from N-aryl-benzenesulfonamides. A biological test of synthesized compounds (59 samples) was performed in vitro measuring their antiproliferative activity against a panel of six human solid tumor cell lines and its tubulin inhibitory activity. We identified 6-(phenylsulfonyl)-6H-dibenzo[c,e][1,2]thiazine 5,5-dioxide and 6-tosyl-6H-dibenzo[c,e][1,2]thiazine 5,5-dioxide as the best compounds with promising values of activity (overall range of 2–5.4 μM). Herein, we report the dibenzothiazine core as a novel building block with antiproliferative activity, targeting tubulin dynamics.     

Synthesis and Biological Evaluation of Benzo[b]furans as Inhibitors of Tubulin Polymerization and Inducers of Apoptosis

A series of benzo[b]furans was synthesized with modification at the 5‐position of the benzene ring by introducing C‐linked substituents (aryl, alkenyl, alkynyl, etc.). These compounds were evaluated for their antiproliferative activities, inhibition of tubulin polymerization, and cell‐cycle effects. Some compounds in this series displayed excellent activity in the nanomolar range against lung cancer (A549) and renal cell carcinoma (ACHN) cancer cell lines. (6‐Methoxy‐5‐((4‐methoxyphenyl)ethynyl)‐3‐methylbenzofuran‐2‐yl)(3,4,5‐trimethoxyphenyl)methanone ( 26 ) and (E)‐3‐(6‐methoxy‐3‐methyl‐2‐(1‐(3,4,5‐trimethoxyphenyl)vinyl)benzofuran‐5‐yl)prop‐2‐en‐1‐ol ( 36 ) showed significant activity in the A549 cell line, with IC₅₀ values of 0.08 and 0.06 μM , respectively. G₂/M cell‐cycle arrest and subsequent apoptosis was observed in the A549 cell line after treatment with these compounds. The most active compound in this series, 36 , also inhibited tubulin polymerization with a value similar to that of combretastatin A‐4 (1.95 and 1.86 μM , respectively). Furthermore, detailed biological studies such as Hoechst 33258 staining, DNA fragmentation and caspase‐3 assays, and western blot analyses with the pro‐apoptotic protein Bax and the anti‐apoptotic protein Bcl‐2 also suggested that these compounds induce cell death by apoptosis. Molecular docking studies indicated that compound 36 interacts and binds efficiently with the tubulin protein.     

2-Amino-4-aryl-5-oxo-4,5-dihydropyrano[3,2-c]chromene-3-carbonitriles with Microtubule-Disruptive,Centrosome-Declustering,and Antiangiogenic Effects in vitro and in vivo

A series of fifteen 2-amino-4-aryl-5-oxo-4,5-dihydropyrano[3,2-c]chromene-3-carbonitriles ( 1 a – o ) were synthesized via a three-component reaction of 4-hydroxycoumarin, malononitrile, and diversely substituted benzaldehydes or pyridine carbaldehydes. The compounds were tested for anticancer activities against a panel of eight human tumor cell lines. A few derivatives with high antiproliferative activities and different cancer cell specificity were identified and investigated for their modes of action. They led to microtubule disruption, centrosome de-clustering and G2/M cell cycle arrest in 518 A2 melanoma cells. They also showed anti-angiogenic effects in vitro and in vivo.     

Synthesis,Biological Evaluation of 1,1‐Diarylethylenes as a Novel Class of Antimitotic Agents

The cytotoxic activities of 23 new isocombretastatin A derivatives with modifications on the B‐ring were investigated. Several compounds exhibited excellent antiproliferative activity at nanomolar concentrations against a panel of human cancer cell lines. Compounds isoFCA‐4 ( 2 e ), isoCA‐4 ( 2 k ) and isoNH₂CA‐4 ( 2 s ) were the most cytotoxic, and strongly inhibited tubulin polymerization with IC₅₀ values of 4, 2 and 1.5 μM , respectively. These derivatives were found to be 10‐fold more active than phenstatin and colchicine with respect to growth inhibition but displayed similar activities as tubulin polymerization inhibitors. In addition, cell cycle arrest in the G₂/M phase and subsequent apoptosis was observed in three cancer cell lines when treated with these compounds. The disruptive effect of 2 e , 2 k and 2 s on the vessel‐like structures formed by human umbilical vein endothelial cells (HUVEC) suggest that these compounds may act as vascular disrupting agents. Both compounds 2 k and 2 s have the potential for further prodrug modification and development as vascular disrupting agents for treatment of solid tumors.     

Milk-Derived Exosomes as Nanocarriers to Deliver Curcumin and Resveratrol in Breast Tissue and Enhance Their Anticancer Activity

Dietary (poly)phenols are extensively metabolized, limiting their anticancer activity. Exosomes (EXOs) are extracellular vesicles that could protect polyphenols from metabolism. Our objective was to compare the delivery to breast tissue and anticancer activity in breast cancer cell lines of free curcumin (CUR) and resveratrol (RSV) vs. their encapsulation in milk-derived EXOs (EXO-CUR and EXO-RSV). A kinetic breast tissue disposition was performed in rats. CUR and RSV were analyzed using UPLC-QTOF-MS and GC-MS, respectively. Antiproliferative activity was tested in MCF-7 and MDA-MB-231 breast cancer and MCF-10A non-tumorigenic cells. Cell cycle distribution, apoptosis, caspases activation, and endocytosis pathways were determined. CUR and RSV peaked in the mammary tissue (41 ± 15 and 300 ± 80 nM, respectively) 6 min after intravenous administration of EXO-CUR and EXO-RSV, but not with equivalent free polyphenol concentrations. Nanomolar EXO-CUR or EXO-RSV concentrations, but not free CUR or RSV, exerted a potent antiproliferative effect on cancer cells with no effect on normal cells. Significant (p < 0.05) cell cycle alteration and pro-apoptotic activity (via the mitochondrial pathway) were observed. EXO-CUR and EXO-RSV entered the cells primarily via clathrin-mediated endocytosis, avoiding ATP-binding cassette transporters (ABC). Milk EXOs protected CUR and RSV from metabolism and delivered both polyphenols to the mammary tissue at concentrations compatible with the fast and potent anticancer effects exerted in model cells. Milk EXOs enhanced the bioavailability and anticancer activity of CUR and RSV by acting as Trojan horses that escape from cancer cells’ ABC-mediated chemoresistance.     

Ruthenium(II)–Arene Thiocarboxylates: Identification of a Stable Dimer Selectively Cytotoxic to Invasive Breast Cancer Cells

Ru^II-arene complexes provide a versatile scaffold for novel anticancer drugs. Seven new Ru^II-arene-thiocarboxylato dimers were synthesized and characterized. Three of the complexes ( 2 a , b and 5 ) showed promising antiproliferative activities in MDA-MB-231 (human invasive breast cancer) cells, and were further tested in a panel of fifteen cancerous and noncancerous cell lines. Complex 5 showed moderate but remarkably selective activity in MDA-MB-231 cells (IC₅₀=39±4 μm Ru). Real-time proliferation studies showed that 5 induced apoptosis in MDA-MB-231 cells but had no effect in A549 (human lung cancer, epithelial) cells. By contrast, 2 a and b showed moderate antiproliferative activity, but no apoptosis, in either cell line. Selective cytotoxicity of 5 in aggressive, mesenchymal-like MDA-MB-231 cells over many common epithelial cancer cell lines (including noninvasive breast cancer MCF-7) makes it an attractive lead compound for the development of specifically antimetastatic Ru complexes with low systemic toxicity.     

Development and Biological Evaluation of a Novel Aurora A Kinase Inhibitor

Stop dividing : In the quest for antitumorigenic compounds, aurora A kinase has recently emerged as a potential drug target. In this paper three novel aurora inhibitors (shown in the illustration) have been tested for their biological activity in cultured cells. One of them (TC‐28) appears to be a promising specific aurora A inhibitor in vivo.

     

Design and Synthesis of Oligopeptidic Parvulin Inhibitors

Pin1 catalyzes the cis-trans isomerization of pThr-Pro or pSer-Pro amide bonds of various proteins involved in several physio/pathological processes. In this framework, recent research activity is directed toward the identification of new selective Pin1 inhibitors. Here, we developed a set of peptide-based Pin1 inhibitors. Direct-binding experiments allowed the identification of the peptide-based inhibitor 5 k (methylacetyl-l -alanyl-l -histidyl-l -prolyl-l -phenylalaninate) as a potent ligand of Pin1. Notably, 5 k binds Pin1 with higher affinity than Pin4. The comparative analysis of molecular models of Pin1 and Pin4 with the selected compound gave a rational explanation of the biochemical activity and pinpointed the chemical elements that, if opportunely modified, may further improve inhibitory potency, pharmacological properties, and selectivity of future peptide-based parvulin inhibitors. Since 5 k showed limited cell penetration and no antiproliferative activity, it was conjugated to a polyarginine stretch (R8), known to promote cell penetration of peptides, to obtain the R8–5 k derivative, which displayed antiproliferative effects on cancer cell lines over non-tumor cells. The effect of R8 on cell proliferation was also investigated. This work warrants caution about applying the R8 strategy in the development of cell-penetrating antiproliferative peptides, as it is not inert.     

Structure–Activity Relationship (SAR) Study of Spautin-1 to Entail the Discovery of Novel NEK4 Inhibitors

Lung cancer is one of the most frequently diagnosed cancers accounting for the highest number of cancer-related deaths in the world. Despite significant progress including targeted therapies and immunotherapy, the treatment of advanced lung cancer remains challenging. Targeted therapies are highly efficacious at prolonging life, but not curative. In prior work we have identified Ubiquitin Specific Protease 13 (USP13) as a potential target to significantly enhance the efficacy of mutant EGFR inhibition. The current study aimed to develop lead molecules for the treatment of epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) by developing potent USP13 inhibitors initially starting from Spautin-1, the only available USP13 inhibitor. A SAR study was performed which revealed that increasing the chain length between the secondary amine and phenyl group and introducing a halogen capable of inducing a halogen bond at position 4’ of the phenyl group, dramatically increased the activity. However, we could not confirm the binding between Spautin-1 (or its analogues) and USP13 using isothermal titration calorimetry (ITC) or thermal shift assay (TSA) but do not exclude binding under physiological conditions. Nevertheless, we found that the anti-proliferative activity displayed by Spautin-1 towards EGFR-mutant NSCLC cells in vitro was at least partially associated with kinase inhibition. In this work, we present N-[2-(substituted-phenyl)ethyl]-6-fluoro-4-quinazolinamines as promising lead compounds for the treatment of NSCLC. These analogues are significantly more effective towards EGFR-mutant NSCLC cells than Spautin-1 and act as potent never in mitosis A related kinase 4 (NEK4) inhibitors (IC₅₀~1 µM) with moderate selectivity over other kinases.     

Synthesis and Anticancer Activity of Tertiary Amides of Salinomycin and Their C20-oxo Analogues

The polyether ionophore salinomycin ( SAL ) has captured much interest because of its potent activity against cancer cells and cancer stem cells. Our previous studies have indicated that C1/C20 double-modification of SAL is a useful strategy to generate diverse agents with promising biological activity profiles. Thus, herein we describe the synthesis of a new class of SAL analogues that combine key modifications at the C1 and C20 positions. The activity of the obtained SAL derivatives was evaluated using primary acute lymphoblastic leukemia, human breast adenocarcinoma and normal mammary epithelial cells. One single- [N,N-dipropyl amide of salinomycin ( 5 a )] and two novel double-modified analogues [N,N-dipropyl amide of C20-oxosalinomycin ( 5 b ) and piperazine amide of C20-oxosalinomycin ( 13 b )] were found to be more potent toward the MDA-MB-231 cell line than SAL or its C20-oxo analogue 2 . When select analogues were tested against the NCI-60 human tumor cell line panel, 4 a [N,N-diethyl amide of salinomycin] showed particular activity toward the ovarian cancer cell line SK-OV-3. Additionally, both SAL and 2 were found to be potent ex vivo against human ER/PR⁺, Her2⁻ invasive mammary carcinoma, with 2 showing minimal toxicity toward normal epithelial cells. The present findings highlight the therapeutic potential of SAL derivatives for select targeting of different cancer types.     

1-Cyclohexyl-4-(4-arylcyclohexyl)piperazines: Mixed σ and human Δ(8)-Δ(7) sterol isomerase ligands with antiproliferative and P-glycoprotein inhibitory activity

Many new chemotherapeutic agents are under preclinical investigation and, despite efforts to more selectively target cancer cells, limitations such as toxicity and inherent resistance are often encountered. Therefore, alternative strategies are needed to treat cancer and overcome such limitations. We describe novel cyclohexylpiperazine derivatives, designed as mixed affinity ligands for sigma (σ) receptors and human Δ₈–Δ₇ sterol isomerase (HSI) ligands, which also exhibit P‐glycoprotein (P‐gp) inhibitory activity, with the aim of exploiting the antiproliferative effects mediated by σ and HSI sites while overcoming P‐gp‐mediated resistance. All of the compounds displayed high affinities for σ receptors and HSI sites, P‐gp inhibitory activity, and σ₂ receptor agonist antiproliferative activity. Antiproliferative activity was also tested in PC‐3 cells to establish σ₁ and HSI contribution. Compound cis‐ 11 , which displayed the best antiproliferative and P‐gp inhibitory activities, was co‐administered with 0.1 μM doxorubicin in MDCK‐MDR1 cells. Compound cis‐ 11 caused 70 % and 90 % cell death when co‐administered at 30 μM and 50 μm, respectively. When administered alone, cis‐ 11 resulted in 50 % cell death, demonstrating its single agent antitumor properties in a tumor cell line overexpressing P‐gp.