2‐Anilino‐3‐Aroylquinolines as Potent Tubulin Polymerization Inhibitors

Several 2‐anilino‐3‐aroylquinolines were designed, synthesized, and screened for their cytotoxic activity against five human cancer cell lines: HeLa, DU‐145, A549, MDA‐MB‐231, and MCF‐7. Their IC₅₀ values ranged from 0.77 to 23.6 μm . Among the series, compounds 7 f [(4‐fluorophenyl)(2‐((4‐fluorophenyl)amino)quinolin‐3‐yl)methanone] and 7 g [(4‐chlorophenyl)(2‐((4‐fluorophenyl)amino)quinolin‐3‐yl)methanone] showed remarkable antiproliferative activity against human lung cancer and prostate cancer cell lines. The IC₅₀ values for inhibiting tubulin polymerization were 2.24 and 2.10 μm for compounds 7 f and 7 g , respectively, and were much lower than that of the reference compound E7010 [N‐(2‐(4‐hydroxyphenylamino)pyridin‐3‐yl)‐4‐methoxybenzenesulfonamide]. Furthermore, flow cytometric analysis revealed that these compounds arrest the cell cycle at the G₂/M phase, leading to apoptosis. Apoptosis was also confirmed by mitochondrial membrane potential, Annexin V–FITC assay, and intracellular ROS generation. Immunohistochemistry, western blot, and tubulin polymerization assays showed that these compounds disrupt tubulin polymerization. Molecular docking studies revealed that these compounds bind efficiently to β‐tubulin at the colchicine binding site.     

Highly Selective Apoptotic Cell Death Induced by Halo‐Salane Titanium Complexes

Metal‐based antitumor agents : Halogen‐substituted titanium salane complexes showed IC₅₀ values comparable to cisplatin. In contrast to their alkyl‐substituted congeners, they almost exclusively induced apoptotic cell death. This unique combination of very low IC₅₀ values and pronounced preference for apoptosis makes them promising therapeutic agents.

     

Synthesis and Biological Evaluation of Indole‐2‐carbohydrazide Derivatives as Anticancer Agents with Anti‐angiogenic and Antiproliferative Activities

A novel series of indole‐2‐carbohydrazide derivatives were synthesized, characterized, and evaluated for their antiproliferative activities against two cancer cell lines, HCT116 and SW480, and a normal human fetal lung fibroblast cell line, MRC‐5. Among this series, compound 24 f displayed potent cytotoxic activities in vitro against HCT116 and SW480 cell lines with GI₅₀ values of 8.1 and 7.9 μm , respectively, and was inactive against MRC‐5 cells. The newly synthesized compounds were also evaluated for anti‐angiogenesis capabilities by chick chorioallantoic membrane, human umbilical vein endothelial cell (HUVEC) migration, and endothelial microtubule formation assays. Moreover, the effects of 24 f on the vascular endothelial growth factor receptor‐2 and the signaling pathway in HUVECs indicated that this compound inhibits VEGFR‐2 and its downstream related proteins. These results indicate that compound 24 f , as well as the other derivatives, are promising inhibitors of angiogenesis.     

α‐Bromoacrylamido N‐Substituted Isatin Derivatives as Potent Inducers of Apoptosis in Human Myeloid Leukemia Cells

A novel series of α‐bromoacryloyl N‐substituted isatin analogues were found to inhibit the growth and viability of human myeloid leukemia HL‐60 and U‐937 cells as well as human lymphoid leukemia MOLT‐3 cells. Cell death induced by these molecules was preceded by a rapid release of cytochrome c from mitochondria into the cytosol and subsequent caspase activation involving caspase‐3, to cleave poly(ADP‐ribose) polymerase (PARP). These findings suggest that these compounds present antiproliferative activity which may be mediated by apoptosis caused by cytochrome c release and caspase activation in human leukemia cells.     

Anticancer Organometallic Osmium(II)‐p‐cymene Complexes

Osmium compounds are attracting increasing attention as potential anticancer drugs. In this context, a series of bifunctional organometallic osmium(II)‐p‐cymene complexes functionalized with alkyl or perfluoroalkyl groups were prepared and screened for their antiproliferative activity. Three compounds from the series display selectivity toward cancer cells, with moderate cytotoxicity observed against human ovarian carcinoma (A2780) cells, whereas no cytotoxicity was observed on non‐cancerous human embryonic kidney (HEK‐293) cells and human endothelial (ECRF24) cells. Two of these three cancer‐cell‐selective compounds induce cell death largely via apoptosis and were also found to disrupt vascularization in the chicken embryo chorioallantoic membrane (CAM) model. Based on these promising properties, these compounds have potential clinical applications.     

Molecular Mechanism of Action of 2‐Ferrocenyl‐1,1‐diphenylbut‐1‐ene on HL‐60 Leukemia Cells

The aim of this work was to investigate the mechanism of action of 2‐ferrocenyl‐1,1‐diphenylbut‐1‐ene ( 1 ) on HL‐60 human leukemia cells. While inactive against noncancerous cells, 1 provoked a concentration‐dependent decrease in viable tumor cells, primarily via apoptosis, as evidenced by analysis of cell morphology, activation of caspases 3 and 7, increased DNA fragmentation, and externalization of phosphatidylserine. Necrosis was observed only at the highest tested concentration (4 μM ). Compound 1 interfered with the cell cycle, causing an accumulation of cells in the G₁/G₀ phase. Interaction of 1 with dsDNA and ssDNA was observed by differential pulse voltammetry and confirmed by hyperchromicity in the UV/Vis spectra of dsDNA, with an interaction constant of 2×10⁴ M ^?1. Both the organic analogue 1,1,2‐triphenylbut‐1‐ene ( 2 ) and ferrocene were inactive against cancer and noncancer cell lines and did not react with DNA. These results reinforce the idea that the hybrid strategy of conjugating ferrocene to the structure of tamoxifen derivatives is advantageous in finding new substances with antineoplastic activity.     

Synthesis and Biological Evaluation of Pyrrolo[2,1‐f][1,2,4]triazine C‐Nucleosides with a Ribose, 2′‐Deoxyribose,and 2′,3′‐Dideoxyribose Sugar Moiety

The synthesis of hitherto unknown pyrrolo[2,1‐f][1,2,4]triazine C‐nucleosides is described. Structural variations (chlorine, bromine, iodine, and cyano groups) were introduced at position 7 of 4‐aza‐7,9‐dideazaadenine. In addition, pyrrolo[2,1‐f][1,2,4]triazine C‐nucleosides bearing a 2′‐deoxy‐, 2′,3′‐dideoxy‐, and 2′,3′‐dehydrodideoxyribose moiety were also prepared. Among these analogues, the pyrrolo[2,1‐f][1,2,4]triazine C‐ribonucleosides with either a hydrogen atom or cyano group at position 7 of the nucleobase displayed potent cytotoxic activity in a panel of various cancer cell lines.     

Development of 3‐Phenyl‐N‐(2‐(3‐phenylureido)ethyl)‐thiophene‐2‐sulfonamide Compounds as Inhibitors of Antiapoptotic Bcl‐2 Family Proteins

Antiapoptotic Bcl‐2 family proteins, such as Bcl‐x_L, Bcl‐2, and Mcl‐1, are often overexpressed in tumor cells, which contributes to tumor cell resistance to chemotherapies and radiotherapies. Inhibitors of these proteins thus have potential applications in cancer treatment. We discovered, through structure‐based virtual screening, a lead compound with micromolar binding affinity to Mcl‐1 (inhibition constant (K_i)=3 μM ). It contains a phenyltetrazole and a hydrazinecarbothioamide moiety, and it represents a structural scaffold not observed among known Bcl‐2 inhibitors. This work presents the structural optimization of this lead compound. By following the scaffold‐hopping strategy, we have designed and synthesized a total of 82 compounds in three sets. All of the compounds were evaluated in a fluorescence‐polarization binding assay to measure their binding affinities to Bcl‐x_L, Bcl‐2, and Mcl‐1. Some of the compounds with a 3‐phenylthiophene‐2‐sulfonamide core moiety showed sub‐micromolar binding affinities to Mcl‐1 (K_i=0.3–0.4 μM ) or Bcl‐2 (K_i≈1 μM ). They also showed obvious cytotoxicity on tumor cells (IC₅₀<10 μM ). Two‐dimensional heteronuclear single quantum coherence NMR spectra of three selected compounds, that is, YCW‐E5, YCW‐E10, and YCW‐E11, indicated that they bind to the BH3‐binding groove on Bcl‐x_L in a similar mode to ABT‐737. Several apoptotic assays conducted on HL‐60 cells demonstrated that these compounds are able to induce cell apoptosis through the mitochondrial pathway. We propose that the compounds with the 3‐phenylthiophene‐2‐sulfonamide core moiety are worth further optimization as effective apoptosis inducers with an interesting selectivity towards Mcl‐1 and Bcl‐2.     

Chiral Resolution and Pharmacological Characterization of the Enantiomers of the Hsp90 Inhibitor 2‐Amino‐7‐[4‐fluoro‐2‐(3‐pyridyl)phenyl]‐4‐methyl‐7,8‐dihydro‐6H‐quinazolin‐5‐one Oxime

Heat‐shock protein 90 (Hsp90) is a molecular chaperone involved in the stabilization of key oncogenic signaling proteins, and therefore, inhibition of Hsp90 represents a new strategy in cancer therapy. 2‐Amino‐7‐[4‐fluoro‐2‐(3‐pyridyl)phenyl]‐4‐methyl‐7,8‐dihydro‐6H‐quinazolin‐5‐one oxime is a racemic Hsp90 inhibitor that targets the N‐terminal adenosine triphosphatase site. We developed a method to resolve the enantiomers and evaluated their inhibitory activity on Hsp90 and the consequent antitumor effects. The (S) stereoisomer emerged as a potent Hsp90 inhibitor in biochemical and cellular assays. In addition, this enantiomer exhibited high oral bioavailability in mice and excellent antitumor activity in two different human cancer xenograft models.     

Design and Synthesis of DNA‐Interactive β‐Carboline–Oxindole Hybrids as Cytotoxic and Apoptosis‐Inducing Agents

A new series of (E)‐3‐[(1‐aryl‐9H‐pyrido[3,4‐b]indol‐3‐yl)methylene]indolin‐2‐one hybrids were synthesized and evaluated for their in vitro cytotoxic activity against a panel of selected human cancer cell lines, namely, HCT‐15, HCT‐116, A549, NCI‐H460, and MCF‐7, including HFL. Among the tested compounds, (E)‐1‐benzyl‐5‐bromo‐3‐{[1‐(2,5‐dimethoxyphenyl)‐9H‐pyrido[3,4‐b]indol‐3‐yl]methylene}indolin‐2‐one ( 10 s ) showed potent cytotoxicity against HCT‐15 cancer cells with an IC₅₀ value of 1.43±0.26 μm and a GI₅₀ value of 0.89±0.06 μm . Notably, induction of apoptosis by 10 s on the HCT‐15 cell line was characterized by using different staining techniques, such as acridine orange/ethidium bromide (AO/EB) and DAPI. Further, to understand the mechanism of anticancer effects, various assays such as annexin V‐FITC/PI, DCFDA, and JC‐1were performed. The flow cytometric analysis revealed that compound 10 s arrests the HCT‐15 cancer cells at the G0/G1 phase of the cell cycle. Additionally, western blot analysis indicated that treatment of 10 s on HCT‐15 cancer cells led to decreased expression of anti‐apoptotic Bcl‐2 and increased protein expression of both pro‐apoptotic Bax and caspase‐3, ‐8, and ‐9, and cleaved PARP with reference to actin. Next, a clonogenic assay revealed the inhibition of colony formation in HCT‐15 cancer cells by 10 s in a dose‐dependent manner. Moreover, upon testing on normal human lung cells (HFL), the compounds were observed to be safer with a low toxicity profile. In addition, viscosity and molecular‐docking studies showed that compound 10 s has typical intercalation with DNA.     

Derivation of a Retinoid X Receptor Scaffold from Peroxisome Proliferator‐Activated Receptor γ Ligand 1‐Di(1H‐indol‐3‐yl)methyl‐4‐trifluoromethylbenzene

PPARγ agonist DIM‐Ph‐4‐CF ₃ , a template for RXRα agonist (E)‐3‐[5‐di(1‐methyl‐1H‐indol‐3‐yl)methyl‐2‐thienyl] acrylic acid: DIM‐Ph‐CF₃ is reported to inhibit cancer growth independent of PPARγ and to interact with NR4A1. As both receptors dimerize with RXR, and natural PPARγ ligands activate RXR, DIM‐Ph‐4‐CF₃ was investigated as an RXR ligand. It displaces 9‐cis‐retinoic acid from RXRα but does not activate RXRα. Structure‐based direct design led to an RXRα agonist.

     

Structural Investigation of the Binding of 5‐Substituted Swainsonine Analogues to Golgi α‐Mannosidase II

Golgi α‐mannosidase II (GMII) is a key enzyme in the N‐glycosylation pathway and is a potential target for cancer chemotherapy. The natural product swainsonine is a potent inhibitor of GMII. In this paper we characterize the binding of 5α‐substituted swainsonine analogues to the soluble catalytic domain of Drosophila GMII by X‐ray crystallography. These inhibitors enjoy an advantage over previously reported GMII inhibitors in that they did not significantly decrease the inhibitory potential of the swainsonine head‐group. The phenyl groups of these analogues occupy a portion of the binding site not previously seen to be populated with either substrate analogues or other inhibitors and they form novel hydrophobic interactions. They displace a well‐organized water cluster, but the presence of a C(10) carbonyl allows the reestablishment of important hydrogen bonds. Already approximately tenfold more active against the Golgi enzyme than the lysosomal enzyme, these inhibitors offer the potential of being extended into the N‐acetylglucosamine binding site of GMII for the creation of even more potent and selective GMII inhibitors.     

Evaluation of Palladacycles as a Non‐Rhodium Based Alternative for the Asymmetric Conjugate 1,4‐Addition of Arylboronic Acids to α,β‐Unsaturated Enones

The asymmetric conjugate 1,4‐addition of arylboronic acids to α,β‐unsaturated carbonyl compounds is an extremely versatile and widely used organic transformation. While the rhodium(I)‐catalysed reaction has been thoroughly explored, the asymmetric palladium‐catalysed protocol is far less developed and understood, particularly with acyclic enones as substrates. Herein, we report the systematic evaluation of a series of metallacycles for this reaction and the conjugate addition of arylboronic acids to a wide range of α,β‐unsaturated enones, catalysed by an easily accessible and robust chiral phosphapalladacycle in high yields and enantioselectivities.

     

6,7‐Dimethoxy‐2‐{2‐[4‐(1H‐1,2,3‐triazol‐1‐yl)phenyl]ethyl}‐1,2,3,4‐tetrahydroisoquinolines as Superior Reversal Agents for P‐Glycoprotein‐Mediated Multidrug Resistance

P‐glycoprotein (P‐gp)‐mediated multidrug resistance (MDR) is a major obstacle for successful cancer chemotherapy. Based on our previous study, 17 novel compounds with the 6,7‐dimethoxy‐2‐{2‐[4‐(1H‐1,2,3‐triazol‐1‐yl)phenyl]ethyl}‐1,2,3,4‐tetrahydroisoquinoline scaffold were designed and synthesized. Among them, 2‐[(1‐{4‐[2‐(6,7‐dimethoxy‐3,4‐dihydroisoquinolin‐2(1H)‐yl)ethyl]phenyl}‐1H‐1,2,3‐triazol‐4‐yl)methoxy]‐N‐(p‐tolyl)benzamide (compound 7 h ) was identified as a potent modulator of P‐gp‐mediated MDR, with high potency (EC₅₀=127.5±9.1 nM ), low cytotoxicity (TI>784.3), and long duration (>24 h) in reversing doxorubicin (DOX) resistance in K562/A02 cells. Compound 7 h also enhanced the effects of other MDR‐related cytotoxic agents (paclitaxel, vinblastine, and daunorubicin), increased the accumulation of DOX and blocked P‐gp‐mediated rhodamine 123 efflux function in K562/A02 MDR cells. Moreover, 7 h did not have any effect on cytochrome (CYP3A4) activity. These results indicate that 7 h is a relatively safe modulator of P‐gp‐mediated MDR that has good potential for further development.     

Structural characterization of α‐ and β‐nucleated isotactic polypropylene

Modification of isotactic polypropylene (iPP) with two nucleation agents, namely 1,3:24‐bis(3,4‐dimethylobenzylideno) sorbitol (DMDBS) (α‐nucleator) and N, N′‐dicyclohexylo‐2,6‐naphthaleno dicarboxy amide (NJ) (β‐nucleator), leads to significant changes of the structure, morphology and properties. Both nucleating agents cause an increase in the crystallization temperature. The efficiency determined in a self‐nucleation test is 73.4 % for DMDBS and 55.9 % for NJ. The modification with NJ induces the creation of the hexagonal β‐form of iPP. The addition of DMDBS lowers the haze of iPP while the presence of NJ increases the haze. Copyright © 2004 Society of Chemical Industry