Synthesis,Antiproliferative, and Antiplatelet Activities of Oxime‐Containing 3,4‐Dihydroquinolin‐2(1H)‐One Derivatives

Some oxime‐containing 3,4‐dihydroquinolin‐2(1H)‐one derivatives were synthesized and evaluated for their antiplatelet and antiproliferative activities. These compounds were synthesized via alkylation of hydroxyl precursors followed by the reaction with NH₂OH. The preliminary assays indicated that (Z)‐7‐[2‐(4‐fluorophenyl)‐2‐(hydroxyimino)ethoxy]‐3,4‐dihydroquinolin‐2(1H)‐one (13c) is the most active against U46619 induced platelet aggregation with an IC₅₀ value of 3.51 μM. For the inhibition of AA‐induced aggregation, (E)‐6‐[2‐(hydroxyimino)propoxy]‐3,4‐dihydroquinolin‐2(1H)‐one (15 ) is the most potent with an IC₅₀ value of 1.85 μM. These oxime‐containing 3,4‐dihydroquinolin‐2(1H)‐one derivatives were inactive against thrombin induced platelet aggregation with an IC₅₀ value of greater than 26.78 μM. For the antiproliferative activity, most of these oxime‐containing 3,4‐dihydroquinolin‐2(1H)‐one derivatives were inactive while (Z)‐7‐[2‐(hydroxyimino)‐2‐(naphthalen‐2‐yl)ethoxy]‐3,4‐dihydroquinolin‐2(1H)‐one (13a) exhibited only marginal activities with GI₅₀ value of 7.63, 7.34 and 6.36 μM against the growth of NPC‐TW01, NCI‐H661, and Jurkat respectively.     

Novel 5‐Methyl‐2‐[(un)substituted phenyl]‐4‐{4,5‐dihydro‐ 3‐[(un)substituted phenyl]‐5‐(1,2,3,4‐tetrahydroisoquinoline‐2‐yl)pyrazol‐1‐yl}‐oxazole Derivatives: Synthesis and Anticancer Activity

Eleven novel 5‐methyl‐2‐[(un)substituted phenyl]‐4‐{4,5‐dihydro‐3‐[(un)substituted phenyl]‐5‐(1,2,3,4‐tetrahydroisoquinoline‐2‐yl)pyrazol‐1‐yl}‐oxazole derivatives were synthesized and characterized by elemental analysis, ESI‐MS, ¹H NMR and ¹³C NMR. All of the compounds have been screened for their antiproliferative activities against PC‐3 cell (human prostate cancer) and A431 cell (human epidermoid carcinoma cancer) lines in vitro. The results revealed that compounds 4g , 4j and 4k exhibited the strong inhibitory activities against the PC‐3 cell lines (with IC₅₀ values of 2.8±0.11, 3.1±0.10 and 3.0±0.06 μg/mL, respectively).     

Design,Synthesis, and Anticancer Activity of 3H–benzo[f]chromen‐3‐one Derivatives

A series of substituted aminomethylbenzocoumarin derivatives 8a–i have been synthesized, characterized, and structure of compound 8g was confirmed by X‐ray single crystal analysis. All the synthesized compounds were tested for their anticancer activity against cancer cell lines A549 (lung carcinoma cell line), MCF7 (breast cancer cell line), and A375 (melanoma cell line). Compounds 8a , 8f , and 8h showed excellent growth inhibitory activity against all three cell lines, respectively. Compounds 8a and 8f were also found to be quite promising at very low concentration as an anticancer agent against MCF7 and A549 cell lines. Compounds 8g and 8i showed excellent antimitotic activity with IC₅₀ 0.32 and19.98 nM for A549 cell line.     

Synthesis of novel xanthone and acridone carboxamides with potent antiproliferative activities

Several new amino-substituted acridone and xanthone derivatives have been designed and synthesized, using an efficient methodology from suitable acridone- or xanthone-carboxylic acid intermediates. The antiproliferative activity of the target compounds has been evaluated against four cancer cell lines, namely breast adenocarcinoma MCF-7, acute lymphocytic leukemia CCRF-CEM, and its doxorubicin-resistant variant CEM/ADR5000 and prostate cancer PC-3 cell lines. Selected derivatives have also been tested against the urinary bladder T24 and metastatic melanoma WM266-4 cancer cell lines. Two nitro substituted acridones, bearing a basic side chain as well, were endowed with a remarkable profile against the majority of the cell lines tested, with IC₅₀ values in the low micromolar range. Both compounds cause accumulation at G0/G1 phase, induce apoptosis, and act as potent autophagy inhibitors in PC-3 cells, suggesting their further evaluation in various pathophysiological environments, conditions, and regimens.     

Pyrrolizine/Indolizine-NSAID Hybrids: Design,Synthesis, Biological Evaluation,and Molecular Docking Studies

In the current study, eight new hybrids of the NSAIDs, ibuprofen and ketoprofen with five pyrrolizine/indolizine derivatives were designed and synthesized. The chemical structures of these hybrids were confirmed by spectral and elemental analyses. The antiproliferative activities of these hybrids (5 μM) was investigated against MCF-7, A549, and HT-29 cancer cell lines using the cell viability assay, MTT assay. The results revealed 4–71% inhibition of the growth of the three cancer cell lines, where 8a,e,f were the most active. In addition, an investigation of the antiproliferative activity of 8a,e,f against MCF-7 cells revealed IC₅₀ values of 7.61, 1.07, and 3.16 μM, respectively. Cell cycle analysis of MCF-7 cells treated with the three hybrids at 5 μM revealed a pro-apoptotic increase in cells at preG1 and cell cycle arrest at the G1 and S phases. In addition, the three hybrids induced early apoptotic events in MCF-7 cells. The results of the molecular docking of the three hybrids into COX-1/2 revealed higher binding free energies than their parent compounds 5a,c and the co-crystallized ligands, ibuprofen and SC-558. The results also indicated higher binding free energies toward COX-2 over COX-1. Moreover, analysis of the binding modes of 8a,e,f into COX-2 revealed partial superposition with the co-crystallized ligand, SC-558 with the formation of essential hydrogen bonds, electrostatic, or hydrophobic interactions with the key amino acid His90 and Arg513. The new hybrids also showed drug-likeness scores in the range of 1.06–2.03 compared to ibuprofen (0.65) and ketoprofen (0.57). These results above indicated that compounds 8a,e,f deserve additional investigation as potential anticancer candidates.     

Synthesis,Antiproliferative, and c‐Src Kinase Inhibitory Activities of 4‐Oxo‐4H‐1‐benzopyran Derivatives

A new class of 4‐oxo‐4H‐1‐benzopyran derivatives were synthesized and their antiproliferative activity examined against a panel of three human cancer cell lines, that is, breast carcinoma (MDA‐MB‐468), ovarian adenocarcinoma (SK‐OV‐3), and colorectal adenocarcinoma (HT‐29). Two compounds, that is, 3‐hexyl‐7,8‐dihydroxy‐4‐oxo‐4H‐1‐benzopyran and (E)‐ethyl 3‐(7‐methoxy‐4‐oxo‐4H‐1‐benzopyran‐3‐yl)acrylate were found to be potent against all three cancer cell lines studied at 50 μM concentration. Also, the inhibitory potency of the compounds was evaluated against active Src kinase. A few of these compounds exhibited modest Src kinase inhibitory activity (IC₅₀ = 52–57 μM). Structure‐activity relationship studies with respect to the nature and position of substituents on the lead compounds could be further exploited for the design and development of more potent antiproliferative agents and/or Src kinase inhibitors.     

Design,Synthesis and Anticancer Evaluation of Substituted Cinnamic Acid Bearing 2-Quinolone Hybrid Derivatives

A new series of hybrid molecules containing cinnamic acid and 2-quinolinone derivatives were designed and synthesized. Their structures were confirmed by ¹H-NMR, ¹³C-NMR and mass analyses. All the synthesized hybrid molecules were assessed for their in vitro antiproliferative activity against more than one cancer cell lines. Compound 3-(3,5-dibromo-7,8-dihydroxy-4-methyl-2-oxoquinolin-1(2H)-ylamino)-3-phenylacrylic acid (5a) with IC₅₀ = 1.89 μM against HCT-116 was proved to the most potent compound in this study, as compared to standard drug staurosporin. DNA flow cytometry assay of compound 5a revealed G2/M phase arrest and pre-G1 apoptosis. Annexin V-FITC showed that the percentage of early and late apoptosis was increased. The results of topoisomerase enzyme inhibition activity showed that the hybrid molecule 5a displays potent inhibitory activity compared with control.     

Ferrocenyl‐Coupled N‐Heterocyclic Carbene Complexes of Gold(I): A Successful Approach to Multinuclear Anticancer Drugs

Four gold(I) carbene complexes featuring 4‐ferrocenyl‐substituted imidazol‐2‐ylidene ligands were investigated for antiproliferative and antivascular properties. They were active against a panel of seven cancer cell lines, including multidrug‐resistant ones, with low micromolar or nanomolar IC₅₀ (72 h) values, according to their lipophilicity and cellular uptake. The delocalized lipophilic cationic complexes 8 and 10 acted by increasing the reactive oxygen species in two ways: through a genuine ferrocene effect and by inhibiting the thioredoxin reductase. Both complexes gave rise to a reorganization of the F‐actin cytoskeleton in endothelial and melanoma cells, associated with a G1 phase cell cycle arrest and a retarded cell migration. They proved antiangiogenic in tube formation assays with endothelial cells and vascular‐disruptive on real blood vessels in the chorioallantoic membrane of chicken eggs. Biscarbene complex 10 was also tolerated well by mice where it led to a volume reduction of xenograft tumors by up to 80 %.     

Synthesis and antiproliferative evaluation of some novel quinazolin-4(3H)-one derivatives

A series of novel quinazolinone derivatives was designed and synthesized. The antiproliferative activities were evaluated in vitro using MTT assay against hepatocellular carcinoma (HepG-2) and mammary gland breast cancer (MCF-7). The preliminary bioassay results demonstrated that tested compounds exhibited antiproliferation with various degrees. Triazole moiety enhanced the activity against the two cell lines when incorporating with quinazolinone moiety in a single molecular framework. Acetohydrazide-quinazolinone derivative showed strong activity against the two cancer cells comparable to that of doxorubicin. Biological evaluation indicated that all the tested compounds possessed antiproliferative activity with certain degrees.     

Bioguided Isolation and Antiproliferative Activity of Constituents from Smilax korthalsii A.D.C. Leaves

Ethyl acetate extract of Smilax korthalsii A.D.C. leaves exhibited antiproliferative activity on leukaemia carcinoma K562, hepatic liver cancer cells WRL and colorectal carcinoma with IC₅₀ of 125.20, 46.10 and 160.00 μM respectively. Isolation of the bioactive ethyl acetate extract of Smilax korthalsii A.D.C. leaves gave eight compounds; 3β‐hydroxyspirost‐5‐ene (diosgenin), 1 , β‐sitosterol, 2 , lup‐5,11,20‐trien‐23‐ol, 3 , uneicos‐9‐enoic acid, 4 , ethylheptadecan‐17‐oic‐9‐enoate, 5 , cis‐octadec‐9‐enoic acid, 6 , hexadec9‐enoic acid, 7 and 11‐methyltridec‐12‐en‐1‐ol, 8 . The isolated compounds were tested against four human cancer cell lines: leukaemia carcinoma, K‐562; hepatic liver cancer cells, WRL; colorectal carcinoma, COLO; and breast carcinoma, MCF‐7 using the MTT assay. Diosgenin 1 exhibited significant antiproliferative activity against all four cell lines (IC₅₀; K562=6.25, WRL=14.34, COLO=38.00, MCF‐7=12.40 μM), while compounds 3, 6 and 7 inhibited the growth of K‐562 at 20, 50 and 100 μM concentrations with IC₅₀ of 90.20, 75.92 and 50.72 μM respectively. Other isolated compounds also showed cytotoxic properties against K‐562, WRL and COLO, but showed low inhibition of MCF‐7.     

Synthesis and Anti‐proliferative Activity of Novel Polysubstitued Indazole Derivatives

A simple and efficient process is developed for the synthesis of new N‐(1‐alkyl‐3‐chloro‐4‐ethoxy‐1H‐indazol‐5‐yl)‐arylsulfonamides 4a – d and N‐(1‐alkyl‐3‐chloro‐1H‐indazol‐5‐yl)‐arylsulfonamides 5a – d through the reduction of 1‐alkyl‐3‐chloro‐5‐nitroindazoles 2a , b with SnCl₂ in ethanol followed by coupling the corresponding amine with arylsulfonyl chlorides in pyridine. All the newly synthesized compounds have been characterized by elemental analysis and spectroscopic data. Some compounds were tested for their in vitro antiproliferative activities against two selected human cancer cell lines A2780 and A549. Among all of these derivatives, compound 5d showed the most potent antiproliferative activity against A2780 (IC₅₀ = 5.47 ± 1.45 μM) and A549 (IC₅₀ = 7.73 ± 1.66 μM) cell lines.     

Two New Prenylated Xanthones from the Pericarp of Garcinia mangostana (Mangosteen)

Two new prenylated xanthones (=9H‐xanthen‐9‐ones), garcimangosxanthones D ( 1 ) and E ( 2 ), together with the six known xanthones 3 – 8 , were isolated from the pericarp of Garcinia mangostana. Their structures were determined by analysis of their spectroscopic data. All of the isolated compounds were biologically evaluated for their in vitro cytotoxic activity against A549, Hep‐G2, and MCF‐7 human‐cancer cell lines and antioxidant activity. Compound 1 exhibited moderate cytotoxicity against Hep‐G2 (IC₅₀=19.2 μM ) and weak cytotoxicity against MCF‐7 (IC₅₀=62.8 μM ) cell lines, and compound 2 showed moderate cytotoxicity against A549, Hep‐G2, and MCF‐7 cell lines with IC₅₀ values of 12.5–20.0 μM (Table 2). Both compounds 1 and 2 demonstrated a weak antioxidant activity with ferric reducing antioxidant power (FRAP) values of 41±7 and 130±4 μmol/g, respectively (Table 3).     

Combined muta- and semisynthesis: a powerful synthetic hybrid approach to access target specific antitumor agents based on ansamitocin P3

Access of four new tumor specific folic acid/ansamitocin conjugates is reported that relies on a synthetic strategy based on the combination of mutasynthesis and semisynthesis. Two bromo‐ansamitocin derivatives were prepared by mutasynthesis or by a modified fermentation protocol, respectively, that served as starting point for the semisynthetic introduction of an allyl amine linker under Stille conditions. A sequence of standard coupling steps introduced the pteroic acid/glutamic acid/cysteine unit to the modified ansamitocins. All new derivatives, including those that are expected to be generated after internalization of the folic acid/ansamitocin conjugates into the cancer cell and reductive cleavage of the disulfide linkage showed good to strong antiproliferative activity (IC₅₀ <10 nM ) for different cancer cell lines. Finally, the four conjugates were exposed to two cancer cell lines [cervix carcinoma, KB‐3‐1 (FR+) and lung carcinoma, A‐459 (FR?)], the latter devoid of the membrane‐bound folic acid receptor (FR?). All four conjugates showed strong antiproliferative activity for the FR+ cancer cell line but were inactive against the FR? cell line. The synthetic strategy pursued is based on the combination of mutasynthesis and semisynthesis and proved to be powerful for accessing new ansamitocin derivatives that are difficult to prepare by total synthesis.     

Design,Synthesis, Molecular Modeling and Antitumor Evaluation of Novel Indolyl-Pyrimidine Derivatives with EGFR Inhibitory Activity

Scaffolds hybridization is a well-known drug design strategy for antitumor agents. Herein, series of novel indolyl-pyrimidine hybrids were synthesized and evaluated in vitro and in vivo for their antitumor activity. The in vitro antiproliferative activity of all compounds was obtained against MCF-7, HepG2, and HCT-116 cancer cell lines, as well as against WI38 normal cells using the resazurin assay. Compounds 1–4 showed broad spectrum cytotoxic activity against all these cancer cell lines compared to normal cells. Compound 4g showed potent antiproliferative activity against these cell lines (IC₅₀ = 5.1, 5.02, and 6.6 μM, respectively) comparable to the standard treatment (5-FU and erlotinib). In addition, the most promising group of compounds was further evaluated for their in vivo antitumor efficacy against EAC tumor bearing mice. Notably, compound 4g showed the most potent in vivo antitumor activity. The most active compounds were evaluated for their EGFR inhibitory (range 53–79%) activity. Compound 4g was found to be the most active compound against EGFR (IC₅₀ = 0.25 µM) showing equipotency as the reference treatment (erlotinib). Molecular modeling study was performed on compound 4g revealed a proper binding of this compound inside the EGFR active site comparable to erlotinib. The data suggest that compound 4g could be used as a potential anticancer agent.     

Synthesis and anticancer activity of benzotriazole derivatives

A series of benzotriazole (BTA) derivatives were synthesized as tyrosine protein kinase inhibitors using fragment-based design strategy. All desired compounds were synthesized with the reaction of benzotriazole, chloroacetonitrile and aromatic aldehyde using Ultrasonic-Microwave method and characterized by IR, ¹H and ¹³C-NMR, mass spectrometry (MS) and elemental analysis. The anticancer activity of these compounds was evaluated by CCK-8 method against carcinoma VX2, lung cancer A549, stomach cancer cell lines MKN45 and MGC in vitro. The results showed that all compounds showed good antiproliferative activity. In particular, compound 2.1 showed the most prominent inhibition of VX2 cell lines with IC₅₀ of 3.80 ± 0.75 μM. Compound 2.2 exhibited highly potent anticancer activity of stomach MGC cell lines with IC₅₀ of 3.72 ± 0.11 μM. A549 and MKN45 cell lines were sensitive to compound 2.5 with IC₅₀ of 5.47 ± 1.11 and 3.04 ± 0.02 μM, respectively.     

Synthesis and antiproliferative activities of thioxoflavonoids on three human cancer cells

Two series of fifteen novel thioxoflavonoids 2a-2h and 4a-4g were synthesized from corresponding flavonoids 1a-1h and 3a-3g by reacting with Lawesson’s reagent, respectively. Their in vitro antiproliferative activities were evaluated on a panel of three human cancer cell lines (Hela, HCC1954 and SK-OV-3) using cell counting kit-8 (CCK-8) assay. The results showed that most of the target compounds exhibited moderate to good antiproliferative activities against the three human cancer cell lines. In particular, thioxoflavonoids 2f and 2g showed the strongest antiproliferative activity on all three human cancer cell lines with IC₅₀ values ranging from 3.34 to 4.67 μM, 4f showed the best antiproliferative activity on Hela cells (IC₅₀ 2.30 μM), 2e showed the best antiproliferative activity on HCC1954 cells (IC₅₀ 2.13 μM) and SK-OV-3 cells (IC₅₀ 2.33 μM). The antiproliferative activities may be involved in their antioxidant activity, which can be speculated by their ability to scavenge free radicals and by their capacity of affecting key redox enzymes.     

Green synthesis of some tetrahydroquinoline derivatives and evaluation as anticancer agents

This study demonstrates the design and synthesis of heterocyclic compounds with diverse biological effects. Using an ionic liquid catalyst, a sonosynthetic approach for the assembly of bis-arylidene cycloalkanone derivatives (bis-chalcones) has been reported. Three cancer cell lines Hepatocellular carcinoma cells (HepG-2), Breast carcinoma cells (MCF-7), and Lung carcinoma cells (A-549) were utilized to investigate the antiproliferative effects of some selected samples. Many evaluated drugs exhibited good to moderate cytotoxicity against the examined cell lines. Notably, the IC₅₀ values for the S-alkyl derivatives ranged from 2.86 to 13.14 µg/mL.     

Synthesis and Biological Evaluation of Harmirins,Novel Harmine–Coumarin Hybrids as Potential Anticancer Agents

As cancer remains one of the major health burdens worldwide, novel agents, due to the development of resistance, are needed. In this work, we designed and synthesized harmirins, which are hybrid compounds comprising harmine and coumarin scaffolds, evaluated their antiproliferative activity, and conducted cell localization and cell cycle analysis experiments. Harmirins were prepared from the corresponding alkynes and azides under mild reaction conditions using Cu(I) catalyzed azide–alkyne cycloaddition, leading to the formation of the 1H-1,2,3-triazole ring. Antiproliferative activity of harmirins was evaluated in vitro against four human cancer cell lines (MCF-7, HCT116, SW620, and HepG2) and one human non-cancer cell line (HEK293T). The most pronounced activities were exerted against MCF-7 and HCT116 cell lines (IC₅₀ in the single-digit micromolar range), while the most selective harmirins were 5b and 12b, substituted at C-3 and O-7 of the β-carboline core and bearing methyl substituent at position 6 of the coumarin ring (SIs > 7.2). Further experiments demonstrated that harmirin 12b is localized exclusively in the cytoplasm. In addition, it induced a strong G1 arrest and reduced the percentage of cells in the S phase, suggesting that it might exert its antiproliferative activity through inhibition of DNA synthesis, rather than DNA damage. In conclusion, harmirin 12b is a novel harmine and coumarin hybrid with significant antiproliferative activity and warrants further evaluation as a potential anticancer agent.     

Design,synthesis, and biological evaluation of sorafenib derivatives containing indole (ketone) semicarbazide analogs as antitumor agents

A series of new sorafenib derivatives was designed and synthesized. The antiproliferative activity of the synthesized compounds against human lung cancer cell (A549), human pancreatic cancer cell (PC-3), human leukemia cell (K562), and human hepatoma cell (SMMC-7721) was evaluated by MTT assay. The results revealed that several compounds displayed more significant antitumor activities than commercial anticancer agent sorafenib against SMMC-7721. In addition, compounds 7a , 7g , 7l , 7m , and 7p represented obvious growth inhibition with IC₅₀ values of 1-9 μM against four cancer cell lines, demonstrating more predominant activities against cancer cells as compared to sorafenib. Furthermore, some structure-activity relationships have also been established. Compounds containing indole and benzene ring substituted by halogen showed better activity than sorafenib. Wound healing assay suggested that cells would be targeted on their migratory capacity by 7g , potentially affecting the migration activity of these tumors. The effects of A549 and PC-3 cell apoptosis induced by compound 7g were significantly increased compared with sorafenib. Importantly, the result of western blot assay showed that 7g inhibited cell growth by suppressing the activity of EGFR, especially the expression of p-EGFR (Tyr1068).     

Synthesis,cytotoxicity and apoptosis-inducing activity of novel 1H-benzo[d]imidazole derivatives of dehydroabietic acid

With the expectation of finding new and effective antitumor drugs, a series of novel N-(1H-benzo[d]imidazole-2-yl)-benzamide/benzenesulfonamide derivatives of dehydroabietic acid were synthesized and evaluated for cytotoxic activity against three human cancer cell lines (MCF-7, HeLa, and HepG2 cells) and one human normal hepatocyte cell line (LO2). As a result, a number of derivatives showed moderate to good antitumor activities. Among them, compound 8h exhibited the most potent activities against three cancer cell lines with IC₅₀ values of 0.87 ± 0.18, 9.39 ± 0.72, and 8.31 ± 0.64 μM, respectively, and was less active to normal hepatocyte LO2 cells. Further mechanism studies revealed that compound 8h could arrest the cell cycle of MCF-7 cells at S phase and induce the apoptosis of MCF-7 cells in ROS-mediated mitochondrial pathway.