Synthesis and primary cytotoxicity evaluation of new 5-bromo-3-substituted-hydrazono-1H-2-indolinones

In this study a new series of 5-bromo-3-[(3-substituted-5-methyl-4-thiazolidinone-2-ylidene)-hydrazono]-1H-2-indolinones (3a-i) and 5-bromo-3-[(2-thioxo-3-substituted-4, 5-imidazolidinedione-1-yl)imino]-1H-2-indolinones (4a-f) was synthesized by the cyclization of 5-bromo-3-(N-substituted-thiosemicarbazono)-1H-2-indolinones (2a-i)with ethyl 2-bromopropionate in anhydrous ethanolic medium and oxalyl cloride in anhydrous diethyl ether, respectively. Six compounds chosen as prototypes were evaluated in the 3-cell line, one dose in vitro primary cytotoxicity assay. Four of them were evaluated against the full panel of 60 human tumor cell lines at a minimum of five concentrations at 10-fold dilutions. Among the compounds tested, the 4-fluoro-phenylthiosemicarbazone derivative 2f showed the most favorable cytotoxicity. This compound demonstrated the most marked effects on a breast cancer cell line (BT-549, log(10)GI(50) value -6.40), a non small cell lung cancer cell line (NCI-H23, log(10)GI(50) value -6.10), and an ovarian cancer cell line (IGROV1, log(10)GI(50) value -6.02).     

Synthesis, antibacterial, and cytotoxic evaluation of certain 7-substituted norfloxacin derivatives

We report herein the synthesis and biological evaluation of two series of 7-substituted norfloxacin derivatives. Most compounds tested in this study demonstrated better activity against methicillin-resistant Staphylococcus aureus than norfloxacin. Preliminary in vitro evaluation indicated that the 7-[4-(2-hydroxyiminoethyl)piperazin-1-yl] derivatives 3b-e possess distinct cytotoxicity profiles as compared with their alpha-methylene-gamma-butyrolactone counterparts, 4b,e: i.e., excellent activities against the renal cancer subpanel. Among them, 1-ethyl-6-fluoro-7-?4-[2-(4-chlorophenyl)-2-hydroxyiminoethyl]-1-p ipe razinyl?-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid (3d) demonstrated the most significant activities against renal cancer cell lines, with log GI(50) values of -6.40 against CAK-1, -6.14 against RXF 393, and -7.54 against UO-31, compared with a mean log GI(50) value of -5.03.     

Synthesis of New 6-{[ω-(Dialkylamino(heterocyclyl)alkyl]thio}-3-R-2H-[1,2,4]triazino[2,3-c]quinazoline-2-ones and Evaluation of their Anticancer and Antimicrobial Activities

Several novel 6-thio-3-R-2-oxo-2H-[1,2,4]triazino[2,3-c]quinazoline-based compounds containing an ω-(dialkylamino(heterocyclyl)]alkyl fragment were synthesized to examine their anticancer activity. Some of the 6-{[ω-(hetero-cyclyl)alkyl]thio}-3-R-2H-[1,2,4]triazino[2,3-c]quinazoline-2-ones (3.1-3.10) were obtained by the nucleophilic substitution of 6-[ω-halogenalkyl]thio-3-R-2H-[1,2,4]triazino[2,3-c]quinazoline-2-ones (2.1-2.8) with azaheterocycles. Alternatively, compounds 3.1-3.22 were synthesized by alkylation of 3-R-6-thio-2H-[1,2,4]triazino[2,3-c]quinazoline-2-ones potassium salts (1.1-1.4) with (2-chloroethyl)-N,N-dialkylamine hydrochlorides or 1-(2-chloroethyl)heterocycle hydrochlorides. The structures of compounds were elucidated by (1)H, (13)C NMR, LC-MS and EI-MS analysis. Then anticancer and antibacterial, bioluminescence inhibition of Photobacterium leiognathi Sh1 activities of the substances were tested in vitro. It was found that compound 3.18 possessed a wide range of anticancer activity against 27 cell lines of cancer: non-small cell lung, colon, CNS, ovarian, renal, prostate, breast, melanoma and leukemia (log GI(50) < -5.65). The "structure-activity" relationship was discussed. COMPARE analysis for synthesized anticancer active compounds was performed.     

Synthesis and antiproliferative activity of 3-aryl-2-[1H(2H)-benzotriazol-1(2)-yl]acrylonitriles variously substituted: Part 4

A new series of variously substituted 3-aryl-2-[1H(2H)-benzotriazol-1(2)-yl]acrylonitriles was synthesized and tested for antiproliferative and antitubercular activity as part of our continuing research program in the antimicrobial and antitumor fields. The most cytotoxic derivatives (5a,g,i,j,l and 7b) (CC50 < 3.0 microM against MT-4 cells) were evaluated against a panel of human cell lines derived from hematological and solid tumors, using 6-mercaptopurine (6-MP) and etoposide as reference drugs. In particular, E-2-(5,6-dimethyl-1H-benzotriazol-1-yl)-3-(3-nitrophenyl)acrylonitrile (5g) resulted more potent than 6-MP on all cell lines, even if 2-14-fold less potent than etoposide. In the antitubercular screening, the derivatives 5i,j and 7e showed moderate activity against some resistant strains of Mycobacterium tested.     

Synthesis and biological evaluation of 5-formyl-6-arylimidazo(2,1-b)-1,3,4-thiadiazole-2-N-(dimethylaminomethi no) sulfonamides as antitumor agents.

In search for potential anti cancer drug candidates in imidazo (2,1-b)-1,3,4-thiadiazole series, two series of 5-formyl-6-arylimidazo(2,1-b)-1,3,4-thiadiazole-2-N- (dimethylaminomethino) sulfonamides and 5-bromo-6-aryl/ethylacetateimidazo(2,1-b)-1,3,4- thiadiazole-2-sulfonamides were synthesised. All compounds showed significant cytotoxic effects (log10 GI50 < -4.0, log molar drug concentration required to cause 50% growth inhibition) against a variety of human tumor cell lines of the National Cancer Institute in vitro screen, including cells derived from solid tumors such as non-small cell lung, colon, central nervous system, melanoma, ovarian, prostate and breast cancer, and also few cell lines of leukemia and renal cancer. Introduction of a formyl group at the 5- and substituted aromatic group at 6-position generated compounds with potent antitumor activity. Incorporation of a bromo at 5- and ester group at 6-position produced compounds with reduced activity.     

5H-哒嗪并[4,5-b]吲哚类新化合物的合成及 抗肿瘤细胞增殖活性

目的 设计并合成5H-哒嗪并[4,5-b]吲哚类化合物,评价其体外抗肿瘤细胞增殖活性。方法 以7-溴-1-氯-8-(3-氯丙氧基)-5-环丙基-5H-哒嗪并[4,5-b]吲哚为起始原料,经取代、醚化、Mannich 反应、选择性氧化共3步或4步反应合成目标化合物;以吉非替尼(gefitinib)为阳性对照药,采用 MTT 法测定了目标化合物对肿瘤细胞株 Bel-7402 和 HT-1080 的抗增殖活性。结果与结论 合成了13 个化合物,其中12 个是未见文献报道的新化合物,其结构经¹H-NMR、MS 谱确证;8个化合物显示出较好的抗肿瘤细胞增殖活性,其中,化合物4a和5a抗增殖活性突出,分别为吉非替尼的3倍和4倍。     

Synthesis and Anticancer Activity of 2-(Alkyl-, Alkaryl-, Aryl-, Hetaryl-)-[1,2,4]triazolo[1,5-c]quinazolines

The combinatorial library of novel potential anticancer agents, namely, 2-(alkyl-, alkaryl-, aryl-, hetaryl-)[1,2,4]triazolo[1,5-c]quinazolines, was synthesized by the heterocyclization of the alkyl-, alkaryl-, aryl-, hetarylcarboxylic acid (3H-quinazoline-4-ylidene)hydrazides by oxidative heterocyclization of the 4-(arylidenehydrazino)quinazolines using bromine, and by the heterocyclization of N-(2-cyanophenyl)formimidic acid ethyl ester. The optimal method for synthesis of the s-triazolo[1,5-c]quinazolines appeared to be cyclocondensation of the corresponding carboxylic acid (3H-quinazoline-4-ylidene)hydrazides. The compounds’ structures were established by ¹H, ¹³C NMR, LC- and EI-MS analysis. The in vitro screening of anticancer activity determined the most active compound to be 3,4,5-trimethoxy-N′-[quinazolin-4(3H)-ylidene]benzohydrazide (3.20) in micromolar concentrations with the GI₅₀ level (MG_MID, GI₅₀ is 2.29). Thus, the cancer cell lines whose growth is greatly inhibited by compound 3.20 are: non-small cell lung cancer (NCI-H522, GI₅₀=0.34), CNS (SF-295, GI₅₀=0.95), ovarian (OVCAR-3, GI₅₀=0.33), prostate (PC-3, GI₅₀=0.56), and breast cancer (MCF7, GI₅₀=0.52), leukemia (K-562, GI₅₀=0.41; SR, GI₅₀=0.29), and melanoma (MDA-MB-435, GI₅₀=0.31; SK-MEL-5, GI₅₀=0.74; UACC-62, GI₅₀=0.32). SAR-analysis is also discussed.     

Substituted 2-[(2-Oxo-2H-[1,2,4]triazino [2,3-c]quinazolin-6-yl)thio]acetamides with Thiazole and Thiadiazole Fragments: Synthesis,Physicochemical Properties,Cytotoxicity, and Anticancer Activity

The series of novel N-R-2-[(3-R-2-oxo-2H-[1,2,4]triazino[2,3-c]quinazolin-6-yl)thio]acetamides with thiazole and thiadiazole fragments in a molecule were obtained by alkylation of potassium salts 1.1–1.4 by N-hetaryl-2-chloroacetamides and by aminolysis of activated acids 2.1–2.4 with N,N’-carbonyldiimidazole (CDI). The structures of compounds were determined by IR, ¹H NMR, MS, and EI-MS analysis. The results of cytotoxicity evaluated by the bioluminescence inhibition of bacterium Photobacterium leiognathi, Sh1 showed that the compounds have considerable cytotoxicity. The synthesized compounds were tested for anticancer activity in NCI against 60 cell lines. Among the highly active compounds 3.1, 3.2, and 6.5, 2-[(3-methyl-2-oxo-2H-[1,2,4]triazino[2,3-c]quinazolin-6-yl)thio]-N-(1,3-thiazol-2-yl)acetamide (3.1) was found to be the most active anticancer agent against the cell lines of colon cancer (GI₅₀ at 0.41–0.69 μM), melanoma (GI₅₀ 0.48–13.50 μM), and ovarian cancer (GI₅₀ 0.25–5.01 μM). The structure-activity relationship (SAR-analysis) was discussed.     

1-苯胺基-5H-哒嗪并[4,5-b]吲哚类化合物的合成及体外抗肿瘤活性

目的设计并合成1-苯胺基-5H-哒嗪并[4,5-b]吲哚类化合物,评价其体外抗肿瘤活性。方法以5-乙酰氧基-6-溴-2-溴甲基-1-环丙基-1H-吲哚-3-羧酸乙酯为起始原料,经8～9步反应合成目标化合物;采用MTT法,测定了目标化合物对肿瘤细胞株Bel-7402和HT-1080的抑制活性。结果与结论合成了12个新化合物,其结构经1H-NMR和MS确证;多个化合物显示出良好的抗肿瘤活性,化合物10a和10d活性突出,对肿瘤细胞株Bel-7402和HT-1080的抑制活性分别是阳性对照药gefitinib的4倍和5倍,值得进一步研究。     

Dichloro-[1-(hydroxyphenyl)-2-phenylethylenediamine]platinum(II) complexes: testing on the human ovarian cancer cell lines NIH: OVCAR3 and SK OV 3.

The diastereoisomeric dichloro-[1-(2-, 3- and 4-hydroxyphenyl)-2-phenylethylenediamine]platinum(II) complexes were tested on two human ovarian cancer cell lines NIH: OVCAR-3 and SK-OV-3, both resistant against cisplatin. Dichloro-[threo-1-(3-hydroxyphenyl)-2-phenylethylenediamine]platinum(II) (threo-5-PtCl2) proved to be the most active representative of the new series, producing cytocidal effects at a concentration range of 2.5 to 5.0 microM on the NIH: OVCAR-3 cell line. On the more resistant SK-OV-3 cell line, threo-5-PtCl2 was only moderately active, while in combination with BSO, a GSH level lowering compound, threo-5-PtCl2 showed a strong synergistic effect.     

Synthesis and antibacterial evaluation of certain quinolone derivatives.

A number of 7-substituted quinolone derivatives were synthesized and evaluated for antibacterial and cytotoxic activities. Preliminary results indicated that most compounds tested in this study demonstrated better activity against methicillin-resistant Staphylococcus aureus than norfloxacin. Among them, 1-(4-amino-2-fluorophenyl)-6-fluoro-1,4-dihydro-7-[4-[2-(4-methoxyphenyl)-2-hydroxyiminoethyl]-1-piperazinyl]-4-oxo-3-quinolinecarboxylic acid (11d) and its ketone precursor 10d exhibited significant activities against Klebsiella pneumoniae, methicillin-resistant S. aureus, erythromycin- and ampicillin-resistant Streptococcus pneumoniae, and vancomycin-resistant Enterococcus faecalis. Due to strong cytotoxicities of 11d (a mean log GI(50) of -5.40), compound 10d, with good antibacterial activities and low cytotoxicities (a mean log GI(50) of -4.67), is a more potential drug candidate.     

Synthesis and antitumor cytotoxicity evaluation of pyrido[4,3,2-de]quinolines and isoquinolino[6,5,4,3-cde]quinolines

A series of novel pyrido[4,3,2-de]quinoline and isoquinolino[6,5,4,3-cde] quinoline compounds was synthesized and evaluated for cytotoxicity in the National Cancer Institute developmental therapeutics program. The tricyclic compound 7 was synthesized by the cyclization of 3,4-diamino-1,2dimethoxybenzene with diethyl 1,3-acetonedicarboxylate. Oxidation of monochloropyrido[4,3,2-de]quinoline 8 selectively produced 2,3-diketopyrido[4,3,2-de]quinoline 9 as deep violet crystals. Compound 9, when treated with acetone or acetophenone, affords the tetracyclic isoquinolino[6,5,4,3-cde]quinolines 13 and 14, respectively. 2,3-Diketopyrido[4,3,2-de]quinolines 9 and 10 exhibit higher cytotoxic potency than isoquinolino[6,5,4,3-cdelquinolines 13, 14, 15 and 16. Compound 9 selectively affects the cell growth against leukemia CCRF-CEM and HL-60 cell lines, the non-small cell lung cancer HOP-92 cell line, and breast cancer MDA-MB231/ ATCC and MDA-MB- 435 cell lines with GI(50) values of <2.0 microM. Modification of compound 9 with an ester group at the N-1 position afforded compound 10, which exhibits a wide spectrum of anticancer activities with a mean graph midpoint value of 1.8 microM against the 60 cancer cell lines.     

3-methyl-2-(4-substituted phenyl)-4,5-dihydronaphtho[1,2-c]-pyrazoles: synthesis and in-vitro biological evaluation as antitumour agents

The synthetic strategies and characterization of some novel derivatives of 3-methyl-2-(4-substituted phenyl)-4,5-dihydronaphtho[1,2-c]pyrazoles carrying different pharmacophores and heterocyclic rings that are relevant to potential antitumour and cytotoxic activities are described. The antitumour activities of the newly synthesized compounds were evaluated according to the protocol of the National Cancer Institute (NCI) in-vitro disease-oriented human cells screening panel assay. The results revealed that six compounds, namely 6, 8, 11, 15, 17 and 18; displayed promising in-vitro antitumour activity in the 60-cell lines assay. The sulfonylthioureido group emerged as the most favourable pharmacophore. Incorporating such thioureido counterpart into the 6-membered 1,3-thiazinan-5-one resulted in better antitumour activities than those displayed by the 5-membered thiazoles and the 6-membered 1,3-thiazinan-4-one ring systems. Further ring expansion led to a total loss of the antitumour activity. The analog 18, 3-benzyl-2-[4-(3-methyl-4,5-dihydronaphtho-[1,2-c]pyrazol-2-yl)-benzenesulfonylimino]-1,3-thiazinan-5-one, proved to be the most active member identified in this series of compounds (GI(50), TGI, and LC(50) MG-MID values of 34.7, 85.1 and 97.7 microM, respectively). The differential cytotoxicity of the six active compounds to cancer and normal cells was studied utilizing the standard MTT cell viability assay. Compounds 17 and 18 were totally selective for the breast cancer cell line MCF7 (IC(50 )8.5 and 4.7 microM), without exerting any inhibitory effect on the normal breast cell line MCF-10A at the concentration level used (25 microM).     

Synthesis of N-[4-[1-ethyl-2-(2,4-diaminofuro[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-L-glutamic acid as an antifolate

N-[4-[1-Ethyl-2-(2,4-diaminofuro[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-L-glutamic acid 3 was designed and synthesized to investigate the effect of homologation of a C9-methyl to an ethyl on dihydrofolate reductase (DHFR) inhibition and on antitumor activity. Compound 3 was obtained via a concise seven step synthesis starting from palladium-catalyzed carbonylation of 4-propionylphenol, followed by a Wittig reaction with 2,4-diamino-5-(chloromethyl)furo[2,3-d]pyrimidine (6), catalytic hydrogenation, hydrolysis, and standard peptide coupling with diethyl L-glutamate. The biological results indicated that extending the C9-methyl group to an ethyl on the C8-C9 bridge region (analogue 3) doubled the inhibitory potency against recombinant human (rh) DHFR (IC(50) = 0.21 microM) as compared to the C9-methyl analogue 1 and was 4-fold more potent than the C9-H analogue 2. As compared to 1, compound 3 demonstrated increased growth inhibitory potency against several human tumor cell lines in culture with GI(50) values < 1.0 x 10(-8) M. Compound 3 was also a weak inhibitor of rh thymidylate synthase. Compounds 1 and 3 were efficient substrates of human folylpolyglutamate synthetase (FPGS). Further evaluation of the cytotoxicity of 3 in methotrexate-resistant CCRF-CEM cell sublines and metabolite protection studies implicated DHFR as the primary intracelluar target. Thus, alkylation of the C9 position in the C8-C9 bridge of the classical 5-substituted 2,4-diaminofuro[2,3-d]pyrimidine is highly conducive to DHFR and tumor inhibitory activity as well as FPGS substrate efficiency.     

Cytotoxic effects of pyridino[2,3-f]indole-4,9-diones on human tumor cell lines

The cytotoxicities of pyridino[2,3-f]indole-4,9-dione derivatives were examined against human lung tumor cell lines (A 549), human ovarian tumor cell lines (SK-OV-3), human melanoma tumor cell lines (SK-MEL-2), human CNS tumor cell lines (XF 498) and human colon tumor cell lines (HCT 15) in vitro using a Sulforhodamine B assay. 3-Ethoxycarbonyl-1-(2-methoxyethyl)-2-methyl-1H-pyridino[2,3-f]ind ole-4,9-dione (5) showed excellent cytotoxicity against XF 498 and HCT 15. The ED50 values of 5 were 0.006 microg/ml against XF 498 and 0.073 microg/ml against HCT 15, while those of doxorubicin were 0.012 and 0.264 microg/ml, respectively. 1-Benzyl-3-ethoxycarbonyl-2-methyl-1H-pyridino[2,3-f]indole-4,9-di one (7) (ED50 value 0.065 microg/ml) was also significantly more cytotoxic against HCT 15 compared with doxorubicin.     

Design, synthesis, and evaluation of novel mutual prodrugs (hybrid drugs) of all-trans-retinoic acid and histone deacetylase inhibitors with enhanced anticancer activities in breast and prostate cancer cells in vitro

Novel mutual prodrugs (MPs) of ATRA (all- trans-retinoic acid) and HDIs (histone deacetylase inhibitors) ( 10, 13, 17- 19) connected via glycine acyloxyalkyl carbamate linker (AC linker) or through a benzyl ester linker (1,6-elimination linker) were rationally designed and synthesized. Most of our novel MPs were potent inhibitors of growth of several hormone-insensitive/drug resistant breast cancer cell lines and the hormone-insensitive PC-3 prostate cancer cell line. The novel MPs exhibited differential antiproliferative potencies in both MDA-MB-231 and PC-3 cell lines. Whereas 19 (VNLG/124) [4-(butanoyloxymethyl)phenyl(2 E,4 E,6 E,8 E)-3,7-dimethyl-9-(2,6,6-trimethylcyclohex-1-enyl)nona-2,4,6,8-tetraenoate] with a GI 50 of 10 nM was the most potent MP versus the MDA-MB-231 cells, 13 (VNLG/66) [{ N-[ N-{2-[4-{[3-pyridylmethoxy)carbonyamino]methyl}phenyl) carbonylamino]phenyl} carbamoylcarbamoyloxy}methyl(2 E,4 E,6 E,8 E)-3,7-dimethyl-9-(2,6,6-trimethyl cyclohex-1-enyl)nona-2,4,6,8-tetraenoate] with a GI 50 = 40 nM was the most potent versus the PC-3 cells. MP 19 exhibited the most benefit because its GI 50 of 10 nM versus MDA-MB-231 cells was remarkably 1085-fold lower than that of parent ATRA and over 100000-fold lower than butyric acid (BA).     

Synthesis and antiproliferative activity in vitro of new pyrido[1,4-b]diazepine derivatives and imidazo[4,5-b]pyridine

A novel series of esters 8-10 and hydrazones 4-6 was synthesized from 4-aryl-2-phenacylidene-1,3,4,5-tetrahydropyrido[2,3-b][1,4]diazepine (1-3). Subsequent treatment of hydrazone 4 with p-chlorbenzaldehyde furnished azine 7. Long-standing heating of ester 8 with hydrazine hydrate afforded 3-[1-(p-chlorophenylene)-2-(5-phenyl-1H-pyrazol-3-yl)-ethyl]-1,3-dihydroimidazo[4,5-b]pyridin-2-one (11). The structures of 4-6 and 8-10 were identified by the results of elemental analysis and their IR, 1H-NMR and MS spectra. Additionally, the structure of 11 was confirmed by X-ray diffraction method. Compounds 8-10 and 11 were examined for their antiproliferative activity in vitro against the cells of 5 human cancer cell lines, using SRB or MTT technique. Among tested compounds, only 11 revealed cytotoxic activity in vitro against all cell lines applied with ID50 (inhibitory dose 50%) values lower than 4 microg/mL, which is an international activity criterion for synthetic compounds. All compounds inhibit the proliferation of HL-60 human promyelocytic leukemia cell line.     

A new type of mixed anhydride and its applications to the synthesis of 7-substituted 8-chloro-5,5-dioxoimidazo[1,2-b][1,4,2]benzodithiazines with in vitro antitumor activity.

A new series of 8-chloro-5,5-dioxoimidazo[1,2-b][1,4,2]benzodithiazine derivatives 8-25 with heteroaryloxycarbonyl or heteroarylcarbamoyl substituents at position 7 have been synthesized as potential antitumor agents. In this procedure a novel type of mixed anhydride 7 was prepared from 8-chloro-5,5-dioxoimidazo[1,2-b][1,4,2]benzodithiazine-7-carboxylic acid 6 and methanesulfonyl chloride, which in turn was condensed either with heteroarylamines or heteroarylhydroxy compounds. All the compounds prepared were screened at the National Cancer Institute (NCI) for their activities against a panel of 60 tumor cell lines, and relationships between structure and antitumor activity in vitro are discussed. The amides 8, 10, 12, 13, 21, and ester 25 were inactive, whereas the other compounds exhibited rather moderate activity against one or more human tumor cell lines. The prominent compound with remarkable activity (log GI(50) < -8) and selectivity for the leukemia HL-60(TB) cell line was 2-methyl-8-quinolyl 8-chloro-5,5-dioxoimidazo[1,2-b][1,4,2]benzodithiazine-7-carboxylate 24.     

Broad-spectrum antiproliferative activity of a series of 6-(4-fluorophenyl)-5-(2-substituted pyrimidin-4-yl)imidazo[2,1-<Emphasis Type="Italic">b</Emphasis>]thiazole derivatives

This article described the synthesis and in vitro antiproliferative activities a series of 6-(4-fluorophenyl)-5-(2-substituted pyrimidin-4-yl)imidazo[2,1-b]thiazole derivatives. The nine target compounds were tested for in vitro antitumor effect against a panel of 55 cell lines of nine different cancer types at the NCI, and their activities were compared with that of Sorafenib as a reference standard drug. Compounds 1d and 1e possessing terminal arylamide moiety exerted superior potencies than Sorafenib against different cancer cell lines. Both compounds were more potent than Sorafenib against UO-31 renal cancer cell line and MCF7 breast cancer cell line. Compound 1d was also more potent than Sorafenib against COLO 205 colon cancer cell line, and compound 1e showed higher potency than Sorafenib against OVCAR-3 ovarian cancer cell line and DU-145 prostate cancel cell line also. For instance, the IC₅₀ value of compound 1e against DU-145 prostate cancer cell line was 1.04 μM, which is threefold more potent than Sorafenib.     

Synthesis and cytotoxic evaluation of some new[1,3]dioxolo[4,5-g]chromen-8-one derivatives

Background

Homoisoflavonoids are naturally occurring compounds belong to flavonoid classes possessing various biological properties such as cytotoxicity. In this work, an efficient strategy for the synthesis of novel homoisoflavonoids, [1,3]dioxolo[4,5-g]chromen-8-ones, was developed and all compounds were evaluated for their cytotoxic activities on three breast cancer cell lines.

Methods

Our synthetic route started from benzo[d][1,3]dioxol-5-ol which was reacted with 3-bromopropanoic acid followed by the reaction of oxalyl chloride to afford 6,7-dihydro-8H-[1,3]dioxolo[4,5-g]chromen-8-one. The aldol condensation of the later compound with aromatic aldehydes led to the formation of the title compounds. Five novel derivatives 4a-e were tested for their cytotoxic activity against three human breast cancer cell lines including MCF-7, T47D, and MDA-MB-231 using the MTT assay.

Results

Among the synthesized compounds, 7-benzylidene-6,7-dihydro-8H-[1,3]dioxolo[4,5-g]chromen-8-one (4a) exhibited the highest activity against three cell lines. Also the analysis of acridine orange/ethidium bromide staining results revealed that 7-benzylidene-6,7-dihydro-8H-[1,3]dioxolo[4,5-g]chromen-8-one (4a) and 7-(2-methoxybenzylidene)-6,7-dihydro-8H-[1,3]dioxolo[4,5-g]chromen-8-one (4b) induced apoptosis in T47D cell line.

Conclusion

Finally, the effect of methoxy group on the cytotoxicity of compounds 4b-4d was investigated in and it was revealed that it did not improve the activity of [1,3]dioxolo[4,5-g]chromen-8-ones against MCF-7, T47D, and MDA-MB-231.