First synthesis of 3,16,20-polyoxygenated cholestanes, new cytotoxic steroids from the gorgonian Leptogorgia sarmentosa

Using tigogenin as starting material, (20S)-20-hydroxycholestane-3,6-dione (1), (16S, 20S)-16,20-dihydroxycholestan-3-one (2), (20S)-20-hydroxycholest-1-ene-3,16-dione (3) and (20S)-20-hydroxycholest-4-ene-3,16-dione (4), natural polyoxygenated steroids from the gorgonian, Leptogorgia sarmentosa, were synthesized in four steps. Antitumor activity against three tumor cell lines (breast cancer, MCF7, lung cancer NCI and oral cancer KB) was evaluated. Two compounds (3 and 4) showed strong activity against NCI (IC(50) 6.16 and 10.51 microM) and moderate activity against MCF7 and KB, the IC(50) being in the range 30.65-47.22 microM. Compound 2 showed moderate activity against NCI (IC(50) 42.68 microM) but was inactive against MCF7 and KB whereas compound 1 showed no activity against all tested cells.     

Further study on synthesis and evaluation of 3,16,20-polyoxygenated steroids of marine origin and their analogs as potent cytotoxic agents

A series of new polyoxygenated steroid derivatives with various steroid skeleton moieties were synthesized. Antitumor activity of the compounds against three tumor cell lines (Breast cancer MCF7, lung cancer NCI and oral cancer KB) were evaluated. Compounds with aromatic A ring of this series exhibited the most potent cytotoxicities in all tested cells. The absence of OH at C-16 or lack of cholesterol like side chain at C-20 in the steroid skeleton apparently result in decreased cytotoxicity. The compound became inactive when the side chain contains double bond at C-24-C-25. When hydroxyl group at C-3 was protected no cytotoxicities against MCF7 and NCI and considerable low cytotoxicity against KB cell lines were observed.     

Combined Fourier transform infrared and Raman spectroscopic approach for identification of multidrug resistance phenotype in cancer cell lines

Cancer cells escape cytotoxic effects of anticancer drugs by a process known as multidrug resistance (MDR). Identification of cell status by less time-consuming methods can be extremely useful in patient management and treatment. This study aims at evaluating the potentials of vibrational spectroscopic methods to perform cell typing and to differentiate between sensitive and resistant human cancer cell lines, in particular those that exhibit the MDR phenotype. Micro-Raman and Fourier transform infrared (FTIR) spectra have been acquired from the sensitive promyelocytic HL60 leukemia cell line and two of its subclones resistant to doxorubicin (HL60/DOX) and daunorubicin (HL60/DNR), and from the sensitive MCF7 breast cancer cell line and its MDR counterpart resistant to verapamil (MCF7/VP). Principal components analysis (PCA) was employed for spectral comparison and classification. Our data show that cell typing was feasible with both methods, giving two distinct clusters for HL60- and MCF7-sensitive cells. In addition, phenotyping of HL60 cells, i.e., discriminating between the sensitive and MDR phenotypes, was attempted by both methods. FTIR could not only delineate between the sensitive and resistant HL60 cells, but also gave two distinct clusters for the resistant cells, which required a two-step procedure with Raman spectra. In the case of MCF7 cell lines, both the sensitive and resistant phenotypes could be differentiated very efficiently by PCA analysis of their FTIR and Raman point spectra. These results indicate the prospective applicability of FTIR and micro-Raman approaches in the differentiation of cell types as well as characterization of the cell status, such as the MDR phenotype exhibited in resistant leukemia cell lines like HL60 and MCF7.     

Anticancer and superoxide scavenging activities of p-alkylaminophenols having various length alkyl chains

A series of p-alkylaminophenols including 3, p-butylaminophenol; 4, p-hexylaminophenol; 5, p-octylaminophenol; and 6, N-(p-methoxybenzyl)aminophenol were synthesized based on the structure of fenretinide, N-(4-hydroxyphenyl)retinamide (1). This latter agent is a synthetic amide of all-trans-retinoic acid (RA), which is a cancer chemopreventive and antiproliferative agent. It was found that elongation of the alkyl chain length in these compounds increased antioxidative activity and inhibition of lipid peroxidation. These findings led us to investigate whether antiproliferative activity against cancer cells was effected by the length of alkyl chains linked to the aminophenol residue. All p-alkylaminophenols inhibited growth of HL60 and HL60R cells in a dose-dependent manners. The HL60R line is a resistant clone against RA. Growth of various cancer cell lines (HL60, HL60R, MCF-7, MCF-7/Adr(R), HepG2, and DU-145) was suppressed by p-alkylaminophenols in a fashion dependent on the aminophenol alkyl chain length (5>4>3>p-methylaminophenol (2)), with 5 being the most potent inhibitor of cell growth against HL60R, MCF-7/Adr(R), and DU-145 cells among p-alkylaminophenols tested, including 1. In particular, with the exception of compound 2, antiproliferative activity against DU-145 cells by these p-alkylaminophenols was greater than by 1. In HL60 cells, growth inhibition was associated with apoptosis. On the other hand, elongation of the alkyl chain length reduced superoxide trapping capability (2>3>4>5) in contrast to the effects on inhibition of lipid peroxidation. These results indicate that anticancer activity of p-alkylaminophenols correlated with the inhibitory activity of lipid peroxidation, but not with the superoxide scavenging activity.     

Synthesis of 4β-carbamoyl epipodophyllotoxins as potential antitumour agents

A series of new 4β-carbamoyl epipodophyllotoxin analogues have been synthesized and evaluated for their anticancer activity against eleven cancer cell lines including Zr-75-1, MCF7, KB, Gurav, DWD, Colo 205, A-549, Hop62, PC3, SiHa and A-2780. Most of the compounds exhibited better growth-inhibition activities against tested cell lines than that of etoposide. Further, compounds 6g and 6i are also evaluated for their DNA topoisomerase-II (topo-II) inhibition activity and they exhibited significant inhibition of topo-II catalytic activity comparable to etoposide.     

Synthesis,Cytotoxicity and Antimicrobial Evaluation of New Coumarin‐Tagged β‐Lactam Triazole Hybrid

A series of coumarin‐tagged β‐lactam triazole hybrids ( 10a – 10o ) were synthesized and tested for their cytotoxic activity against MDA‐MB‐231 (triple negative breast cancer), MCF‐7 (estrogen receptor positive breast cancer (ER+)) and A549 (human lung carcinoma) cancer cell lines including one normal cell line, HEK‐293 (human embryonic kidney). Two compounds 10b and 10d exhibited substantial cytotoxic effect against MCF‐7 cancer cell lines with IC₅₀ values of 53.55 and 58.62 μm , respectively. More importantly, compounds 10b and 10d were non‐cytotoxic against HEK‐293 cell lines. Structure–activity relationship (SAR) studies suggested that the nitro and chloro group at the C‐3 position of phenyl ring are favorable for anticancer activity, particularly against MCF‐7 cell lines. Furthermore, antimicrobial evaluation of these compounds revealed modest inhibition of examined pathogenic strains with compounds 10c and 10i being the most promising antimicrobial agents against Pseudomonas aeruginosa and Candida albicans, respectively.     

民族药四数九里香的化学成分及其细胞毒活性研究

为了阐明民族药四数九里香Murraya tetramera Huang的药效物质基础,课题组使用色谱技术从其醇提取物中分离得14个化合物;运用~1H NMR、¹³C NMR波谱方法和文献数据对比鉴定为正24烷酸(1)、9,13,17,21-tetramethyl-5-docosenoic acid(2)、3-O-β-D-吡喃葡萄糖基-山奈酚甙(3)、补骨脂素(4)、紫苏醛(5)、槲皮素(6)、methyl salicylate glucoside(7)、(9S,10R,11E,13R,15Z)-9,10,13-trihydroxyoctadeca-11,15-dienoic Acid(8)、2-isopropyl-5-methylphenol(9)、β-胡萝卜甘(10)、7-羟基香豆素(11)、七叶内酯(12)、β-谷甾醇醋酸酯(13)、山奈酚(14)。除了化合物4、6外,其他化合物为首次从该植物中分离得到。同时,研究各化合物对5株肿瘤细胞的体外生长抑制作用。与阳性对照组比较,结果表明:化合物3、4、5、6、7、8、10、11、12、13、14对白血病HL60显现良好的细胞毒活性;化合物1～14对肺腺癌A549的的细胞毒活性低于阳性对照组;化合物6、13、14对肝癌SMMC7721显现良好的细胞毒活性;化合物1、2、3、6、7、9、11、12对乳腺癌MCF7显现良好的细胞毒活性;化合物1～14对结肠癌SW480的细胞毒活性低于阳性对照组。     

Design,Synthesis, and Cytotoxic Activity of 3‐Aryl‐N‐hydroxy‐2‐(sulfonamido)propanamides in HepG2, HT‐1080, KB,and MCF‐7 Cells

A new series of (sulfonamido)propanamides ( 6a1 – 6a13 , 6b1 – 6b15 , 7c1 – 7c5 , 6d1 – 6d5 , 6e1 – 6e6 ) was designed and synthesized. All the synthesized compounds were characterized by NMR and mass spectrometry. The target compounds were evaluated for their in vitro cytotoxic activity against hepatocellular carcinoma (HepG2), fibrosarcoma (HT‐1080), mouth epidermal carcinoma (KB), and breast adenocarcinoma (MCF‐7) cell lines with the sulforhodamine B (SRB) assay, with gemcitabine and mitomycin C as positive controls. Most of these compounds exhibit a more potent cytotoxic effect than the positive control group on various cancer cell lines and the most potent compound, 6a7 , shows the IC₅₀ values of 29.78±0.516 μm , 30.70±0.61 μm , and 64.89±3.09 μm in HepG2, HT‐1080, KB, and MCF‐7 cell lines, respectively. Thus, these compounds with potent cytotoxic activity have potential for development as new chemotherapy agents.     

Synthesis and biological evaluation of ethacrynic acid derivatives bearing sulfonamides as potent anti-cancer agents

A series of ethacrynic acid (2-[2,3-dichloro-4-(2-methylidenebutanoyl)phenoxy]acetic acid) (EA, Edecrin) containing sulfonamides linked via three types of linkers namely 1,2-ethylenediamine, piperazine and 4-aminopiperidine was synthesized and subsequently evaluated in vitro against HL60 and HCT116 cancer cell lines. All the EA analogs, excluding 6a and 6c, showed anti-proliferative activity with IC_50s in the micromolar range (less than 4 uM). Three derivatives 6b, 7b and 7e were selected for their interesting dual activity on HL60 cell line in order to be further evaluated against a panel of cancer cell lines (HCT116, A549, MCF7, PC3, U87-MG and SKOV3) as well as on MRC5 as a normal cell line. These compounds displayed IC₅₀ values in nanomolar range against A549, MCF7, PC3 and HCT116 cell lines, deducing the discovery that piperazine or 4-aminopiperidine is the linker’s best choice to develop EA analogs with highly potent anti-proliferative activities own up to 24 nM. Besides, in terms of selectivity, those linkers are more suitable offering safety ratios of up to 63.8.     

Synthesis and Evaluation of Piperazine-Tethered Derivatives of Alepterolic Acid as Anticancer Agents

Alepterolic acid is a natural diterpenoid isolated from Aleuritopteris argentea with potential anti-cancer activity. In this study, alepterolic acid was modified to construct a series of arylformyl piperazinyl derivatives ( 3a – 3p ). The synthesized derivatives were fully characterized with HRMS, NMR, and IR. Four compounds with inhibition rate higher than 30 % at 10 μM ( 3f , 3n , 3g and 3k ) were further measured to obtain the IC₅₀ values against four cancer cell lines, including hepatoma cell lines HepG2, lung cancer cell lines A549, estrogen receptor-positive cell lines MCF7, and triple-negative breast cancer (TNBC) cell lines MDA-MB-231 by MTT assay. It was found that these compounds were more effective to HepG2 and MDA-MB-231 cells, while less toxic to A549 and MCF7 cells, and compound 3n as the most toxic derivatve against MDA-MB-231 cell lines, with IC₅₀ value of 5.55±0.56 μM. Trypan blue staining and colony formation assay showed that compound 3n inhibited the growth of MDA-MB-231 cells and prevented colony formation. Hoechst staining, flow cytometry and western blot analysis revealed that compound 3n induced caspase-dependent apoptosis in MDA-MB-231 cells. Conclusively, compound 3n was demonstrated to be a potential anti-cancer lead compound for further investigation.     

Terpene Conjugates of the Nigella sativa Seed‐Oil Constituent Thymoquinone with Enhanced Efficacy in Cancer Cells

Thymoquinone (TQ; 1 ) is a weak anticancer constituent of black seed oil. Derivatives bearing terpene‐terminated 6‐alkyl residues were tested in cells of human HL‐60 leukemia, 518A2 melanoma, multidrug‐resistant KB‐V1/Vbl cervix, and MCF‐7/Topo breast carcinomas, as well as in non‐malignant human foreskin fibroblasts. Derivatives with a short four‐atom spacer between quinone and cyclic monoterpene moieties were more antiproliferative than analogues with longer spacers. 6‐(Menthoxybutyryl)thymoquinone ( 3a ) exhibited single‐digit micromolar IC₅₀ (72 h) values in all four cell lines. It was seven times more active than TQ ( 1 ) in 518A2 melanoma cells and four times in KB‐V1/Vbl cervix carcinoma cells, while only half as toxic in the fibroblasts. Compound 3a was also not a substrate for the P‐gp and BCRP drug transporters of the resistant cancer cells. The caryophyllyl and germacryl conjugates 3e and 3f specifically inhibited the growth of the resistant MCF‐7 breast carcinoma cells. Conjugation of TQ with the triterpene betulinic acid via the OH group as in 3g led to a loss in activity, while conjugation via the carboxylic acid afforded compound 4 with nanomolar IC₅₀ (72 h) activity against HL‐60 cells. All anticancer‐active derivatives of TQ ( 1 ) induced apoptosis associated with DNA laddering, a decrease in mitochondrial membrane potential and a slight increase in reactive oxygen species.     

Synthesis of novel substituted pyrimidine derivatives bearing a sulfamide group and their in vitro cancer growth inhibition activity

The synthesis of two series of novel substituted pyrimidine derivatives bearing a sulfamide group have been described and their in vitro cancer growth inhibition activities have been evaluated against three human tumour cell lines (HT-29, M21, and MCF7). In general, growth inhibition activity has been enhanced by the introduction of a bulky substituent on the aromatic ring with the best compound having GI₅₀ < 6 μM for all the human tumour cell lines. The MCF7 selective compounds were evaluated on four additional human invasive breast ductal carcinoma cell lines (MDA-MB-231, MDA-MB-468, SKBR3, and T47D) and were selective against T47D cell line in all cases except one, suggesting a potential antiestrogen activity.     

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.     

Development of novel chromeno[4,3-c]pyrazol-4(2H)-one derivates containing piperazine as inhibitors of PI3Kα

PI3K pathway has been heavily studied and is one of the most potential targets for various cancer treatment. Herein, we designed and synthesized a series of novel chromeno[4,3-c]pyrazol-4(2H)-one derivates contained piperazine based on our previous research. They were evaluated for their PI3Kα wild-type and H1047R mutant inhibitory activities and anticancer effects in vitro. Most of these compounds displayed the potential antiproliferative activities against four cancer cell lines (HCT-116, A549, Huh7 and HL60). Among them, Compound 4p revealed the remarkable antiproliferative activity and was selected for further biological evaluation. Compound 4p displayed the potent activity against both PI3Kα wild-type and H1047R mutant, and a certain degree of selectivity for PI3Kα over PI3Kβ, γ and δ, and meanwhile it can remarkable down-regulate the phosphorylation of Akt. In addition, compound 4p was found to induce cell apoptosis via upregulation of Bax and cleaved-caspase 3/9, and downregulation of Bcl-2. The above results suggested that compound 4p could be considered as a promising PI3Kα inhibitor.     

Synthesis and antitumor activity of cholest-4 alpha-methyl-7-en-3beta-ol derivatives

Cholest-4 alpha-methyl-7-en-3beta-ol (1) has potent inhibitory activity against pc 12 tumor with 0.5043 ratio (10 microg/mL). This paper describes a series of structural modification of this compound, which focus on 3beta-hydroxyl group and 7(8)-double bond. The synthesized derivatives of 1 were tested for human cancer cell lines including colon cancer (HCT-8), liver cancer (BEL-7402) and nasopharyngeal cancer (KB) cells. The results showed that cholest-4 alpha-methyl-8-en-3beta,7 alpha-diol 6a inhibits KB cell significantly with IC(50) 1.32 x 10(-9)microg/mL. In addition, the cytotoxic properties of this compound against HCT-8 and BEL-7402 are excellent with IC(50) 1.2 microg/mL.     

Synthesis and antiproliferative potency of 9-beta-D-arabinofuranosyl-2-fluoroadenine phospholipid adducts.

Three novel alkylphospholipid and four novel O-alkylglycerophospholipid derivatives of fludarabine (F-ara-AMP), known as a drug for the clinical treatment of chronic lymphocytic leukemia, were synthesized. The antiproliferative activity was determined in comparison to the parent nucleoside fludarabine in an immortalized but nontumorigenic human mammary epithelial cell line (H 184 A1N4), in two human breast tumor cell lines (MaTu and MCF7), and in two leukemic cell lines (HL 60 and Daudi). Fludarabine inhibited the growth of the leucemic cell lines very effectively. The breast tumor cell lines responded with much less sensitivity. The antiproliferative potency of the new compounds strongly depended on the chemical structure of the lipid component, and derivatives with a high effectiveness against one or both of the breast tumor cell lines were described.     

Acetonic extract of Buxus sempervirens induces cell cycle arrest, apoptosis and autophagy in breast cancer cells

Plants are an invaluable source of potential new anti-cancer drugs. Here, we investigated the cytotoxic activity of the acetonic extract of Buxus sempervirens on five breast cancer cell lines, MCF7, MCF10CA1a and T47D, three aggressive triple positive breast cancer cell lines, and BT-20 and MDA-MB-435, which are triple negative breast cancer cell lines. As a control, MCF10A, a spontaneously immortalized but non-tumoral cell line has been used. The acetonic extract of Buxus sempervirens showed cytotoxic activity towards all the five studied breast cancer cell lines with an IC(50) ranging from 7.74 μg/ml to 12.5 μg/ml. Most importantly, the plant extract was less toxic towards MCF10A with an IC(50) of 19.24 μg/ml. Fluorescence-activated cell sorting (FACS) analysis showed that the plant extract induced cell death and cell cycle arrest in G0/G1 phase in MCF7, T47D, MCF10CA1a and BT-20 cell lines, concomitant to cyclin D1 downregulation. Application of MCF7 and MCF10CA1a respective IC(50) did not show such effects on the control cell line MCF10A. Propidium iodide/Annexin V double staining revealed a pre-apoptotic cell population with extract-treated MCF10CA1a, T47D and BT-20 cells. Transmission electron microscopy analyses indicated the occurrence of autophagy in MCF7 and MCF10CA1a cell lines. Immunofluorescence and Western blot assays confirmed the processing of microtubule-associated protein LC3 in the treated cancer cells. Moreover, we have demonstrated the upregulation of Beclin-1 in these cell lines and downregulation of Survivin and p21. Also, Caspase-3 detection in treated BT-20 and T47D confirmed the occurrence of apoptosis in these cells. Our findings indicate that Buxus sempervirens extract exhibit promising anti-cancer activity by triggering both autophagic cell death and apoptosis, suggesting that this plant may contain potential anti-cancer agents for single or combinatory cancer therapy against breast cancer.     

Antioxidant and anticancer activities of novel p-alkylaminophenols and p-acylaminophenols (aminophenol analogues)

Novel compounds were designed based on fenretinide, N-(4-hydroxyphenyl)retinamide (2), which is a synthetic amide of all-trans-retinoic acid (1) that is a potent antioxidant and anticancer agent. Our recent findings indicated that antioxidant and anticancer activities were due to p-methylaminophenol moiety (8) in 2, and that p-octylaminophenol (7), which has an elongated alkyl chain, was more potent than 8. This finding lets us to investigate whether compounds containing alkyl or acyl chains linked to an aminophenol residue as long as 2 and 1, would show activities greater than 2. For this purpose, we prepared p-dodecanoylaminophenol (3), p-decanoylaminophenol (4), p-dodecylaminophenol (5), and p-decylaminophenol (6). The p-alkylaminophenols, 5 and 6, exhibited superoxide scavenging activities, but not p-acylaminophenols, 3 and 4. Elongation of the alkyl chain length reduced superoxide trapping capability (8>7>6>5). In contrast, lipid peroxidation in rat liver microsomes was reduced by 5 and 6 in dose-dependent manner. Compounds 3 and 4 were poor lipid peroxidation inhibitors, being approximately 400- to 1300-fold lower than 5 and 6. In addition, all compounds inhibited cell growth of human leukemia cell lines, HL60 and HL60R, in dose-dependent manners (5>6>3=4). The HL60R cell line is resistant against 1. Growth of both cell lines was suppressed by 5 and 6 in a fashion dependent on the length of the aminophenol alkyl chain, but not by 3 and 4. These results indicate that 5, a potent anticancer agent greater than 2, may potentially have clinical utility, and that its anticancer activity is correlated with inhibitory potency against lipid peroxidation, but not with superoxide scavenging activity.     

Differences in the biological activity of TNF alpha and TNF beta correlate with their different abilities for binding to the target cells.

TNF alpha and TNF beta were compared regarding their binding to different types of target cells, cytotoxic/cytostatic activity against murine and human tumor cell lines as well as human capillary endothelial cells, their ability to induce differentiation in myeloid leukemia cell lines, and induction of hemorrhagic tumor necrosis and tumor regression as well as lethal toxicity in tumor-bearing mice. The results show considerable quantitative differences in the biological activity between TNF alpha and TNF beta depending on the type of target cell which has been used. TNF beta was 3 fold more cytotoxic than TNF alpha against murine L929 fibroblasts and 3-5 times more active concerning the induction of hemorrhagic tumor necrosis, complete tumor regression and more toxic in tumor-bearing mice. In contrast to this, TNF beta was markedly less cytotoxic against human capillary endothelial cells and the human mammary carcinoma cell line MCF7 and much less cytostatic against the human myeloid leukemia cell lines HL60 and U937. The lesser antiproliferative effect of TNF beta correlated with a lower ability for induction of differentiation in these cell lines. Competitive radioligand binding assays showed that TNF beta was about 4 fold more effective than TNF alpha in competing with 125I-labeled TNF alpha for the binding to murine L929 fibroblasts. But it was 15-20 times less effective in binding to the human MCF7 cells and the human myeloid leukemia cell lines HL60 and U937. This revealed that, at least for these targets, the differences in the biological activity between TNF alpha and TNF beta are due to different abilities for binding to the target cells. Possible mechanisms for these different binding abilities are discussed.     

Design and synthesis of anti-breast cancer agents from 4-piperazinylquinoline: A hybrid pharmacophore approach

A novel class of 4-piperazinylquinoline derivatives based on the isatin scaffold were designed by molecular hybridization approach and synthesized for biological evaluation. Subsequently, the compounds were examined for their cytotoxic effects on two human breast tumor cell lines, MDA-MB468 and MCF7, and two non-cancer breast epithelial cell lines, 184B5 and MCF10A. Although all compounds examined were quite effective on the breast cancer cell lines examined, the compound 4-bromo-1-[4-(7-chloro-quinolin-4-yl)-piperazin-1-ylmethyl]-1H-indole-2,3-dione (5b) and N¹-[4-(7-trifluoromethyl-quinolin-4-yl)]-piperazin-1-ylmethyl-4-chloro-1H-indole-2,3-dione-3-thiosemicarbazone (8a) emerged as the most active among this series. It appeared that both 5b and 8a caused apoptosis to MCF7 cancer cells, but not MCF10A non-cancer cells. Thus, 4-piperazinylquinoline linked isatin analog can serve as the prototype molecule for further development of a new class of anti-breast cancer agents.