Design,synthesis and biological evaluation of estradiol–chlorambucil hybrids as anticancer agents

A series of estradiol–chlorambucil hybrids was synthesized as anticancer drugs for site-directed chemotherapy of breast cancer. The novel compounds were synthesized in good yields through efficient modifications of estrone at position 16α of the steroid nucleus. The newly synthesized compounds were evaluated for their anticancer efficacy in different hormone-dependent and hormone-independent breast cancer cell lines. The novel hybrids showed significant in vitro anticancer activity when compared to chlorambucil. Structure–activity relationship (SAR) reveals the influence of the length of the spacer chain between carrier and drug molecule.     

Click chemistry-assisted synthesis of novel aminonaphthoquinone-1,2,3-triazole hybrids and investigation of their cytotoxicity and cancer cell cycle alterations

A series of 12 novel 1,4-naphthoquinone-1,2,3-triazole hybrids were designed and synthesized through copper-catalyzed click reaction of 2-(prop-2-ynylamino)naphthalene-1,4-dione (3) and different azidomethyl-benzene derivatives. The synthesized compounds were assessed for their anticancer activity against three cancer cell lines (MCF-7, HT-29 and MOLT-4) by MTT assay. The results showed that the majority of the synthesized compounds displayed cytotoxic activity. Derivatives 6f and 6h, bearing 4-trifluoromethyl-benzyl and 4-tert-butyl-benzyl groups, respectively, as well as intermediate 3 demonstrated good cytotoxic potential against all tested cancer cell lines, among which compound 6f showed the highest activity. Flow cytometric analysis revealed that compounds 3, 6f and 6h arrested cell cycle at G0/G1 phase in MCF-7 cells. Therefore, synthesized aminonaphthoquinone-1,2,3-triazole derivatives can be introduced as promising molecules for further development as potential anticancer agents.     

Synthesis of new conjugated coumarin–benzimidazole hybrids and their anticancer activity

A series of novel coumarin–benzimidazole hybrids, 3-(1H-benzo[d]imidazol-2-yl)-7-(substituted amino)-2H-chromen-2-one derivatives of biological interest were synthesized. Six out of the newly synthesized compounds were screened for in vitro antitumor activity against preliminary 60 tumor cell lines panel assay. A significant inhibition for cancer cells was observed with compound 8 (more than 50% inhibition) compared with other compounds and active known drug 5-fluorouracil (in some cell lines) as positive control. Compound 8 displayed appreciable anticancer activities against leukemia, colon cancer and breast cancer cell lines.     

Synthesis and antitumoral activity of novel 3-(2-substituted-1,3,4-oxadiazol-5-yl) and 3-(5-substituted-1,2,4-triazol-3-yl) beta-carboline derivatives

Several novel 1-substituted-phenyl beta-carbolines bearing the 2-substituted-1,3,4-oxadiazol-5-yl and 5-substituted-1,2,4-triazol-3-yl groups at C-3 were synthesized and evaluated for their in vitro anticancer activity. The assay results pointed thirteen compounds with growth inhibition effect (GI(50)<100 microM) for all eight different types of human cancer cell lines tested. The beta-carbolines 7a and 7h, bearing the 3-(2-metylthio-1,3,4-oxadiazol-5-yl) group, displayed high selectivity and potent anticancer activity against ovarian cell line with GI(50) values lying in the nanomolar concentration range (GI(50)=10 nM for both compounds). The 1-(N,N-dimethylaminophenyl)-3-(5-thioxo-1,2,4-triazol-3-yl) beta-carboline (8g) was the most active compound, showing particular effectiveness on lung (GI(50)=0.06 microM), ovarian and renal cell lines. The potent anticancer activity presented for synthesized compounds 7a, 7h, and 8g, together with their easiness of synthesis, makes these compounds promising anticancer agents.     

Synthesis,single crystal and antitumor activities of benzimidazole–quinazoline hybrids

A series of novel regioisomeric hybrids of quinazoline/benzimidazole viz. (3-allyl-2-methyl-3H-benzimidazol-5-yl)-(2-substituted-quinazolin-4-yl)-amine and (1-allyl-2-methyl-1H-benzimidazol-5-yl)-(2-substituted-quinazolin-4-yl)-amine of biological interest were synthesized. All the synthesized compounds were well characterized by ¹H and ¹³C NMR as well as mass spectroscopy. The newly synthesized compounds were screened for in vitro antitumor activities against 60 tumor cell lines panel assay. A significant inhibition for cancer cells were observed with compound 9 and also more active against known drug 5-fluorouracil (5-FU) in some tumor cell lines. Compound 9 displayed appreciable anticancer activity against leukemia, colon, melanoma, renal and breast cancer cell lines.     

Synthesis of a new class of 2-anilino substituted nicotinyl arylsulfonylhydrazides as potential anticancer and antibacterial agents

A series of N'-1-[2-anilino-3-pyridyl]carbonyl-1-benzenesulfonohydrazide derivatives (7a-i) was synthesized and five of them were selected by the National Cancer Institute (NCI) and evaluated for their in vitro anticancer activity. Three of the investigated compounds 7d, 7f and 7g exhibited significant anticancer activity in the primary assay and further tested against a panel of 60 human tumour cell lines. Compound 7g showed 50% growth inhibitory activity in leukaemia, melanoma, lung cancer, colon cancer, renal cancer and breast cancer cells with GI(50) value of 3.2-9.6 microM. The synthesized compounds (7a-i) were also evaluated for their antibacterial activity against various Gram-positive and Gram-negative strains of bacteria. Most of these compounds showed better inhibitory activity in comparison to the standard drugs.     

Synthesis, anticancer and antioxidant activities of some novel N-(benzo[d]oxazol-2-yl)-2-(7- or 5-substituted-2-oxoindolin-3-ylidene) hydrazinecarboxamide derivatives

A series of N-(benzo[d]oxazol-2-yl)-2-(7- or 5-substituted-2-oxoindolin-3-ylidene) hydrazinecarboxamide derivatives were synthesized by treating N-(benzoxazol-2-yl)hydrazinecarboxamide with different isatin derivatives. The newly synthesized compounds were characterized on the basis of spectral analyses. All the synthesized derivatives (Va-l) were screened for anticancer and antioxidant activities. The results showed the anticancer activity of test compounds against HeLa, IMR-32 and MCF-7 cancer cell lines using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. All the synthetic compounds produced a dose-dependant inhibition of growth of the cells. The IC(50) values of some compounds were comparable with standard anticancer agent, cisplatin. All the title compounds effectively scavenged the free radical, α,α-diphenyl-β-picryl hydrazyl. The test compounds having substitution with different halides (electron withdrawing groups) at C5 position showed more potent anticancer and antioxidant activities than those at C7 position. These results indicate that C5-substituted derivatives may be useful for developing antioxidant agents that play a protective role in many pathological conditions such as cancer, diabetes and so on.     

Design and synthesis of 2-(3-alkylaminophenyl)-6-(pyrrolidin-1-yl)quinolin-4-ones as potent antitumor agents

2-(3-Alkylaminophenyl)-6-(pyrrolidin-1-yl)quinolin-4-ones 1–3 were synthesized and screened for anti-proliferative activity against three human cancer cell lines, as well as the normal cell line Detroit 551. All of the synthesized target compounds 1–3 demonstrated potent cytotoxic activity against the cancer cell lines, but weak inhibitory activity toward the normal cell line. 2-(3-Methyl aminophenyl)-6-(pyrrolidin-1-yl)quinolin-4-one (1), one of the potent compounds in vitro, was also tested in an in vivo Hep3B xenograft nude mice model, and its significant anticancer activity was reconfirmed. Therefore, compound 1 merits further investigation as an antitumor clinical trial candidate and potential anticancer agent.     

Novel 5-(2-hydroxyphenyl)-3-substituted-2,3-dihydro-1,3,4-oxadiazole-2-thione derivatives: promising anticancer agents

A series of 5-(2-hydroxyphenyl)-3-substituted-2,3-dihydro-1,3,4-oxadiazole-2-thione derivatives was synthesized and 13 of them were selected by the National Cancer Institute (NCI) and evaluated for their in vitro anticancer activity. Seven of the investigated compounds, 3i, 3j, 3k, 3o, 3p, 3q, and 3r, displayed high anticancer activity in the primary assay. These compounds have been selected for a full anticancer screening against a 60-cell panel assay where they showed non-selective broad spectrum and promising activity against all cancer cell lines. Compounds 3j and 3k proved to be the active members in this study compared to 5-fluorouracil and cyclophosphamide as reference drugs, respectively. Compounds 3j and 3k were identified as promising lead compounds.     

Synthesis,anticancer and antioxidant activities of some novel N-(benzo[d]oxazol-2-yl)-2-(7- or 5-substituted-2-oxoindolin-3-ylidene) hydrazinecarboxamide derivatives

A series of N-(benzo[d]oxazol-2-yl)-2-(7- or 5-substituted-2-oxoindolin-3-ylidene) hydrazinecarboxamide derivatives were synthesized by treating N-(benzoxazol-2-yl)hydrazinecarboxamide with different isatin derivatives. The newly synthesized compounds were characterized on the basis of spectral analyses. All the synthesized derivatives (Va-l) were screened for anticancer and antioxidant activities. The results showed the anticancer activity of test compounds against HeLa, IMR-32 and MCF-7 cancer cell lines using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. All the synthetic compounds produced a dose-dependant inhibition of growth of the cells. The IC₅₀ values of some compounds were comparable with standard anticancer agent, cisplatin. All the title compounds effectively scavenged the free radical, α,α-diphenyl-β-picryl hydrazyl. The test compounds having substitution with different halides (electron withdrawing groups) at C5 position showed more potent anticancer and antioxidant activities than those at C7 position. These results indicate that C5-substituted derivatives may be useful for developing antioxidant agents that play a protective role in many pathological conditions such as cancer, diabetes and so on.     

Synthesis,photophysical properties,anticancer evaluation,and molecular docking studies of new pyrimidine linked 4-arylidene-thiazolidin-4-ones as potent anticancer agents

The reaction of 4-(chloroacetamido)pyrimidine (1) with ammonium thiocyanate gave 2-(pyrimidin-4-ylimino)thiazolidin-4-one (2) , which, when condensed with four substituted benzaldehyde analogues, gave the consequent 5-arylidine-2-(pyrimidin-4-ylimino)thiazolidin-4-ones 3a–d . In addition, the absorbance and fluorescence behaviours of pyrimidinylimino-thiazolidin-4-one hybrids 3a–d in various organic solvents were investigated. The emphasis was on studying UV absorption capacities and the effect of various structural components on photophysical qualities such as the 5-arylidene-2-(pyrimidin-4-ylimino)thiazolidin-4-ones and N,N-dimethylamino tail. The cytotoxic effect of four pyrimidinylimino-thiazolidin-4-one hybrids 3a–d on tumour cell lines (HepG2, HCT-116, PC3, MCF-7) and a normal cell line (WI38) is investigated in this work. The cytotoxicity was measured by comparing the half-maximal inhibitory concentration (IC₅₀) to the reference medication, 5-fluorouracil. The findings indicate that these hybrid compounds had varying cytotoxic effects on the cell lines examined; hybrids 3b and 3c demonstrated significant anticancer activity against MCF-7 with IC₅₀ values of 7.53 ± 0.43 and 9.17 ± 0.31 μM, respectively. The inhibitory efficacy of various synthesized hybrids on the epidermal growth factor receptor (EGFR) kinase was investigated. EGFR is a crucial target in cancer treatment because inhibiting it may reduce tumour development and proliferation. The IC₅₀ value was used to calculate the inhibitory activity, which is the concentration of inhibitor necessary to induce half-maximal inhibition of EGFR kinase activity. In addition, the predicted ADME results show that pyrimidinylimino-thiazolidin-4-one hybrids have good pharmacokinetic properties; hybrid 3d is more lipophilic than the other compounds. It has a medium molecular weight, a small number of hydrogen bond acceptors and donors, and a large number of aromatic heavy atoms. Moreover, molecular docking simulations revealed precise information on the interactions of pyrimidinylimino-thiazolidin-4-one hybrids 3a–d and 5-Fu with their respective protein targets. These interactions point to possible pathways for their biological activities and call for more testing to establish their effectiveness as bioactive molecules or therapeutic candidates.     

Synthesis and initial biological evaluation of substituted 1-phenylamino-2-thio-4,5-dimethyl-1H-imidazole derivatives

In this work, some new 2-[(4,5-dimethyl-1-(arylamino)-1H-imidazol-2-yl)thio]-1-(aryl)ethanone derivatives were synthesized and investigated for their antibacterial, antifungal and anticancer activities. Toxicity of the most effective compounds was established by performing Brine-Shrimp lethality assay. Antifungal activity of the compounds was found to be higher than antibacterial and anticancer activities of the compounds.     

Anticancer activity of 3-O-acyl and alkyl-(-)-epicatechin derivatives

By changing the structure or replacing the gallate group of (-)-ECG, 3-O-acyl and alkyl-(-)-epicatechin derivatives were synthesized to be screen as anticancer agents using the MTT assay in vitro against cancer cell lines (PC3, SKOV3, U373MG). 3-O-Acyl and alkyl-(-)-epicatechin derivatives (4-25) exhibited better anticancer activity than (-)-ECG and specially, compounds 6-8, 17-19, which were modified aliphatic chains with moderate sizes (C8-C12) showed strong anticancer activity (IC50=6.4-31.2 microM). The introduction of an alkyloxy group on 3-O-hydroxyl instead of an acyloxy group significantly enhanced inhibitory activity. Consequently, the compound that showed the most potency as anticancer agents were 3-O-decyl-(-)-epicatechin (18) (IC50=8.9, 7.9, 6.4 microM against PC3, SKOV3, U373MG, respectively), which modified the appropriate lipophilic group on the C-3 hydroxyl as an alkyloxy group.     

Synthesis and anticancer activity of new [(Indolyl)pyrazolyl]-1,3,4-oxadiazole thioglycosides and acyclic nucleoside analogs

New [(Indolyl)pyrazolyl]-1,3,4-oxadiazole compounds and their derived thioglycosides as well as the corresponding sugar hydrazones were synthesized. The acyclo C-nucleoside analogs of the oxadiazoline base system were also prepared by reaction of acid hydrazides with aldehydo sugars followed by one pot process encompassing acetylation and cyclization of the synthesized hydrazones. The anticancer activity of the newly synthesized compounds was studied against colorectal carcinoma (HCT116), breast adenocarcinoma (MCF7) and prostate cancer (PC3) human tumor cell lines and a number of compounds showed moderate to high activities.     

1,3,4-oxadiazole/chalcone hybrids: Design,synthesis, and inhibition of leukemia cell growth and EGFR,Src, IL-6 and STAT3 activities

A new series of 1,3,4-oxadiazole/chalcone hybrids was designed, synthesized, identified with different spectroscopic techniques and biologically evaluated as inhibitors of EGFR, Src, and IL-6. The synthesized compounds showed promising anticancer activity, particularly against leukemia, with 8v being the most potent. The synthesized compounds exhibited strong to moderate cytotoxic activities against K-562, KG-1a, and Jurkat leukemia cell lines in MTT assays. Compound 8v showed the strongest cytotoxic activity with IC₅₀ of 1.95 µM, 2.36 µM and 3.45 µM against K-562, Jurkat and KG-1a leukemia cell lines, respectively. Moreover; the synthesized compounds inhibited EGFR, Src, and IL-6. Compound 8v was most effective at inhibiting EGFR (IC₅₀ = 0.24 μM), Src (IC₅₀ = 0.96 μM), and IL-6 (% of control = 20%). Additionally, most of the compounds decreased STAT3 activation.     

Novel benzotriazole N-acylarylhydrazone hybrids: Design,synthesis, anticancer activity,effects on cell cycle profile,caspase-3 mediated apoptosis and FAK inhibition

A series of novel benzotriazole N-acylarylhydrazone hybrids was synthesized according fragment-based design strategy. All the synthesized compounds were evaluated for their anticancer activity against 60 human tumor cell lines by NCI (USA). Five compounds: 3d, 3e, 3f, 3o and 3q exhibited significant to potent anticancer activity at low concentrations. Compound 3q showed the most prominent broad-spectrum anticancer activity against 34 tumor cell lines, with mean growth inhibition percent of 45.80%. It exerted the highest potency against colon HT-29 cell line, with cell growth inhibition 86.86%. All leukemia cell lines were highly sensitive to compound 3q. Additionally, compound 3q demonstrated lethal activity to MDA-MB-435 belonging melanoma. Compound 3e exhibited the highest anticancer activity against leukemic CCRF-CEM and HL-60(TB) cell lines, with cell growth inhibition 86.69% and 86.42%, respectively. Moreover, it exerted marked potency against ovarian OVCAR-3 cancer cell line, with cell growth inhibition 78.24%. Four compounds: 3d, 3e, 3f and 3q were further studied through determination of IC₅₀ values against the most sensitive cancer cell lines. The four compounds exhibited highly potent anticancer activity against ovarian cancer OVCAR-3 and leukemia HL-60 (TB) cell lines, with IC₅₀ values in nano-molar range between 25 and 130 nM. They showed 18–2.3 folds more potent anticancer activity than doxorubicin. The most prominent compound was 3e, (IC₅₀ values 29 and 25 nM against OVCAR-3 and HL-60 (TB) cell lines, respectively), representing 10 and 18 folds more potency than doxorubicin. The anti-proliferative activity of these four compounds appeared to correlate well with their ability to inhibit FAK at nano-molar range between 44.6 and 80.75 nM. Compound 3e was a potent, inhibitor of FAK and Pyk2 activity with IC₅₀ values of 44.6 and 70.19 nM, respectively. It was 1.6 fold less potent for Pyk2 than FAK. Additionally, it displayed inhibition in cell based assay measuring phosphorylated-FAK (IC₅₀ = 32.72 nM). Inhibition of FAK enzyme led to a significant increase in the level of active caspase-3, compared to control (11.35 folds), accumulation of cells in pre-G1 phase and annexin-V and propidium iodide staining in addition to cell cycle arrest at G2/M phase indicating that cell death proceeded through an apoptotic mechanism.     

异黄酮衍生物的设计、合成与抗肿瘤活性

为了提高大豆苷元的生物利用度以改善其抗肿瘤活性,利用前药原理对大豆苷元进行修饰。本文根据前药原理成功设计合成了5个新型大豆苷元磺酸酯衍生物（3～7）,所有化合物的结构均经IR、MS、元素分析和。HNMR确证。体外细胞初步活性筛选试验结果表明,部分标题化合物也具有一定的抗肿瘤活性。     

Design, synthesis, and evaluation of novel 6-chloro-/fluorochromone derivatives as potential topoisomerase inhibitor anticancer agents

6-Chloro-2-pyrrolidino-/morpholino-/piperidino-/N-methylpiperazino-3-formyl-chromones (13-16) and 6-fluoro-2,7-di-morpholino-/piperidino-/N-methylpiperazino-3-formylchromones (17-19) have been synthesized as potential topoisomerase inhibitor anticancer agents, and evaluated, in vitro, against Ehrlich ascites carcinoma (EAC) cells, and also in vivo on EAC bearing mice. The compounds displayed promising anticancer activity under these test systems and shall serve as useful 'leads' for further design.     

Synthesis and primary cytotoxicity evaluation of arylmethylenenaphthofuranones derivatives

New series of 2(or 3)-arylmethylenenaphtho[2,1-b]furan-3(or 2)-ones were synthesized, characterized and tested for anticancer properties in vitro. The target compounds were prepared by Knoevenagel coupling between the naphthofuranones 3, 28-30 and formyl derivatives. 2-(4-Oxo-1-benzopyran-3-ylmethylene)naphtho[2,1-b]furan-3-one 36 was the most active compound (IC50 (L1210) = 1.6 microM). These compounds were also evaluated, in an independent manner, as inhibitors of Src protein tyrosine kinase, but only minor activity was observed.