Synthesis,Characterization and Anti-Breast Cancer Activity of New 4-Aminoantipyrine-Based Heterocycles

4-Aminoantipyrine was utilized as key intermediate for the synthesis of pyrazolone derivatives bearing biologically active moieties. The newly synthesized compounds were characterized by IR, ¹H- and ¹³C-NMR spectral and microanalytical studies. The compounds were screened as anticancer agents against a human tumor breast cancer cell line MCF7, and the results showed that (Z)-4-((3-amino-5-imino-1-phenyl-1H-pyrazol-4(5H)-ylidene)methylamino)-1,5-dimethyl-2-phenyl-1,2-dihydropyrazol-3-one 5, 3-(4-bromophenyl) -1-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)-4-oxo-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carbonitrile 13, 1-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1-Hpyrazol- 4-yl)-3-(4-iodophenyl)-4-oxo-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carbonitrile 14, 3,3′-(4,4′-sulfonylbis(4,1-phenylene))bis(1-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol- 4-yl)-4-oxo-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carbonitrile) 16, (Z)-1-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)-2-hydrazono-4-oxo-3-phenyl-1,2,3,4-tetrahydropyrimidine-5-carbonitrile 17, (Z)-1-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)-4-oxo-3-phenyl-2-(2-phenylhydrazono)-1,2,3,4-tetrahydro pyrimidine-5-carbonitrile 18, and (Z)-4-(3-amino-6-hydrazono-7-phenyl-6,7-dihydro pyrazolo[3,4-d]pyrimidin-5-yl)-1,5-dimethyl-2-phenyl-1,2-dihydropyrazol-3-one 19 were the most active compounds with IC₅₀ values ranging from 30.68 to 60.72 μM compared with Doxorubicin as positive control with the IC₅₀ value 71.8 μM.     

Inside Cover: Cytotoxicities and Structure–Activity Relationships of Natural and Unnatural Lamellarins toward Cancer Cell Lines (ChemMedChem 3/2009)

The inside cover picture shows the structure of lamellarin N as a representative of cytotoxic marine lamellarin alkaloids, together with a potential molecular target, the topoisomerase I–DNA complex. Systematic SAR studies revealed the importance of the substituents for potent cytotoxicity. For more details, see the Full Paper by P. Ploypradith et al. on p. 457 ff.

     

Cytotoxicities and Structure–Activity Relationships of Natural and Unnatural Lamellarins toward Cancer Cell Lines

Shedding light on the lamellarins : Structural determinants for potent cytotoxic activity toward various cancer cell lines were systematically investigated to establish SARs for the marine alkaloids in the lamellarin family. The C5?C6 double bond ensures not only the planarity of the D‐ring, but also proper alignment of the substituents on the E‐ring with their respective moieties of the target. The importance of the C7 OH group is also revealed for the first time.

     

Synthesis and anticancer activity of the (R,S)-benzofused 1,5-oxathiepine moiety tethered to purines through alkylidenoxy linkers

Herein we report the design, synthesis, and anticancer activity of a series of substituted (R,S)-9-[2- or 3-(3,4-dihydro-2H-1,5-benzoxathiepine-3-yloxy)alkyl]-9H-purines. Derivatives with propylenoxy-linked 2',6'-dichloro- and 6'-bromopurines are more active than their respective ethylenoxy-linked purine conjugates. On the other hand, the compound with a propylenoxy-linked 6'-chloropurine is nearly equipotent to the corresponding ethylenoxy-linked conjugate. Our results show that bromo- and chloropurine-conjugated benzoxathiepines containing a propylenoxy linker are able to inhibit PI3 kinase (PI3K) phosphorylation in MCF-7 breast cancer cells, indicating that the activation of eIF2α, together with inhibition of the PI3K pathway, is the mechanism of action by which these compounds effect their antitumor activity in the MCF-7 cell line; apoptosis was induced in a p53-independent manner.     

Asymmetric Synthesis and Biological Evaluation of Glycosidic Prodrugs for a Selective Cancer Therapy

A severe limitation in cancer therapy is the often insufficient differentiation between malign and benign tissue using known chemotherapeutics. One approach to decrease side effects is antibody‐directed enzyme prodrug therapy (ADEPT). We have developed new glycosidic prodrugs such as (?)‐(1S)‐ 26 b based on the antibiotic (+)‐duocarmycin SA ((+)‐ 1 ) with a QIC₅₀ value of 3500 (QIC₅₀=IC₅₀ of prodrug/IC₅₀ of prodrug+enzyme) and an IC₅₀ value for the corresponding drug (prodrug+enzyme) of 16 pM . The asymmetric synthesis of the precursor (?)‐(1S)‐ 19 was performed by arylation of the enantiomerically pure epoxide (+)‐(S)‐ 29 (≥98 % ee).     

Synthesis of enantiopure oxoindolo‐quinolizines

Methyl (1S,3S and 1R,3S)‐1‐(2, 2‐dimethoxyethyl)‐1,2,3,4‐tetrahydrocarboline‐3‐carboxylate ( 3 ) was hydrolyzed in the presence of sodium hydroxide to give (1S,3S and 1R,3S)‐1‐(2,2‐dimethoxyethyl)‐1,2,3,4‐tetrahydrocarboline‐3‐carboxylic acid ( 4 ), which was reduced with LiAlH₄ to provide (1S,3S)‐ and (1R,3S)‐1‐(2,2‐dimethoxyethyl)‐3‐hydroxymethyl‐1,2,3,4‐tetrahydrocarbolines ( 10 ), and then amidated in ammonia containing methanol to obtain (1S,3S)‐ and (1R,3S)‐1‐(2,2‐dimethoxyethyl)‐1,2,3,4‐tetrahydrocarboline‐3‐carboxamide ( 14 ). Acylation of (1S,3S and 1R,3S)‐ 3 , (1S,3S and 1R,3S)‐ 4 , (1S,3S)‐ 10 , (1R, 3S)‐ 10 , (1S, 3S)‐ 14 and (1R,3S)‐ 14 afforded the corresponding methyl (1S,3S and 1R,3S)‐1‐(2,2‐dimethoxyethyl)‐ 2‐(1,3‐dioxobutyl)‐1,2,3,4‐tetrahydrocarbolines‐3‐carboxylate ( 6 ), (1S,3S and 1R,3S)‐1‐(2,2‐dimethoxyethyl)‐2‐(1,3‐dioxobutyl)‐1,2,3,4‐tetrahydrocarboline‐3‐carboxylic acid ( 5 ), (1S,3S)‐ and (1R,3S)‐1‐(2,2‐dimethoxyethyl)‐2‐(1,3‐dioxobutyl)‐3‐(1,3‐dioxobutyl)oxymethyl‐1,2,3,4‐tetrahydrocarboline ( 11 ), (1S,3S)‐ and (1R,3S)‐1‐(2,2‐dimethoxyethyl)‐2‐(1,3‐dioxobutyl)‐1,2,3,4‐tetrahydrocarboline‐3‐carboxamide ( 15 ), respectively. After Aldol reaction, dehydration and dehydrogenation the desired (6S)‐6‐substituted 4,6,7,12‐tetrahydro‐4‐oxoindolo[2,3‐a]quinolizines 8 , 9 , 12 , 13 , and 16 were obtained. Their anticancer activities in vitro were investigated.     

Synthesis and Biological Evaluation of N‐Substituted Noscapine Analogues

Noscapine is a phthalideisoquinoline alkaloid isolated from the opium poppy Papaver somniferum. It has long been used as an antitussive agent, but has more recently been found to possess microtubule‐modulating properties and anticancer activity. Herein we report the synthesis and pharmacological evaluation of a series of 6′‐substituted noscapine derivatives. To underpin this structure–activity study, an efficient synthesis of N‐nornoscapine and its subsequent reduction to the cyclic ether derivative of N‐nornoscapine was developed. Reaction of the latter with a range of alkyl halides, acid chlorides, isocyanates, thioisocyanates, and chloroformate reagents resulted in the formation of the corresponding N‐alkyl, N‐acyl, N‐carbamoyl, N‐thiocarbamoyl, and N‐carbamate derivatives, respectively. The ability of these compounds to inhibit cell proliferation was assessed in cell‐cycle cytotoxicity assays using prostate cancer (PC3), breast cancer (MCF‐7), and colon cancer (Caco‐2) cell lines. Compounds that showed activity in the cell‐cycle assay were further evaluated in cell viability assays using PC3 and MCF‐7 cells.     

Synthesis and Biological Activity of 10‐Aza‐narciclasine

The first active aza analogue of narciclasine was synthesized from a pentasubstituted derivative of nicotinic acid. The key features of the synthesis include a halogen dance of bromopyridine and an intramolecular Heck reaction with a conduramine derived chemoenzymatically from bromobenzene. 10‐Aza‐narciclasine was found to have reasonable activity against several cancer cell lines.

     

Synthesis and in Vitro Evaluation of Novel 5-Nitroindole Derivatives as c-Myc G-Quadruplex Binders with Anticancer Activity

Lead-optimization strategies for compounds targeting c-Myc G-quadruplex (G4) DNA are being pursued to develop anticancer drugs. Here, we investigate the structure-activity- relationship (SAR) of a newly synthesized series of molecules based on the pyrrolidine-substituted 5-nitro indole scaffold to target G4 DNA. Our synthesized series allows modulation of flexible elements with a structurally preserved scaffold. Biological and biophysical analyses illustrate that substituted 5-nitroindole scaffolds bind to the c-Myc promoter G-quadruplex. These compounds downregulate c-Myc expression and induce cell-cycle arrest in the sub-G1/G1 phase in cancer cells. They further increase the concentration of intracellular reactive oxygen species. NMR spectra show that three of the newly synthesized compounds interact with the terminal G-quartets (5′- and 3′-ends) in a 2 : 1 stoichiometry.     

The Synthesis and Biological Evaluation of Multifunctionalised Derivatives of Noscapine as Cytotoxic Agents

Noscapine, a phthalideisoquinoline alkaloid derived from Papaver somniferum, is a well‐known antitussive drug that has a relatively safe in vitro toxicity profile. Noscapine is also known to possess weak anticancer efficacy, and since its discovery, efforts have been made to design derivatives with improved potency. Herein, the synthesis of a series of noscapine analogues, which have been modified in the 6′, 9′, 1 and 7‐positions, is described. In a previous study, replacement of the naturally occurring N‐methyl group in the 6′‐position with an N‐ethylaminocarbonyl was shown to promote cell‐cycle arrest and cytotoxicity against three cancer cell lines. Here, this modification has been combined with other structural changes that have previously been shown to improve anticancer activity, namely halo substitution in the 9′‐position, regioselective O‐demethylation to reveal a free phenol in the 7‐position, and reduction of the lactone to the corresponding cyclic ether in the 1‐position. The incorporation of new aryl substituents in the 9′‐position was also investigated. The study identified interesting new compounds able to induce G2/M cell‐cycle arrest and that possess cytotoxic activity against the human prostate carcinoma cell line PC3, the human breast adenocarcinoma cell line MCF‐7, and the human pancreatic epithelioid carcinoma cell line PANC‐1. In particular, the ethyl urea cyclic ether noscapinoids and a compound containing a 6′‐ethylaminocarbonyl along with 9′‐chloro, 7‐hydroxy and lactone moieties exhibited the most promising biological activities, with EC₅₀ values in the low micromolar range against all three cancer cell lines, and these derivatives warrant further investigation.     

Synthesis,Biological Evaluation of 1,1‐Diarylethylenes as a Novel Class of Antimitotic Agents

The cytotoxic activities of 23 new isocombretastatin A derivatives with modifications on the B‐ring were investigated. Several compounds exhibited excellent antiproliferative activity at nanomolar concentrations against a panel of human cancer cell lines. Compounds isoFCA‐4 ( 2 e ), isoCA‐4 ( 2 k ) and isoNH₂CA‐4 ( 2 s ) were the most cytotoxic, and strongly inhibited tubulin polymerization with IC₅₀ values of 4, 2 and 1.5 μM , respectively. These derivatives were found to be 10‐fold more active than phenstatin and colchicine with respect to growth inhibition but displayed similar activities as tubulin polymerization inhibitors. In addition, cell cycle arrest in the G₂/M phase and subsequent apoptosis was observed in three cancer cell lines when treated with these compounds. The disruptive effect of 2 e , 2 k and 2 s on the vessel‐like structures formed by human umbilical vein endothelial cells (HUVEC) suggest that these compounds may act as vascular disrupting agents. Both compounds 2 k and 2 s have the potential for further prodrug modification and development as vascular disrupting agents for treatment of solid tumors.     

The Quest for Orally Available Selective Estrogen Receptor Degraders (SERDs)

Estrogen receptor-alpha (ERα) is the target of endocrine therapies for the treatment of more than 70 % of ERα-positive breast cancers. Selective estrogen receptor degraders (SERDs) antagonize estrogen binding and target the receptor for degradation, representing the last line of treatment for resistant metastatic breast cancer patients. However, the clinical efficacy of the lone clinically approved SERD (Fulvestrant) is limited by its poor oral bioavailability. Recently, several analogues of GW5638, an acrylic acid-based ERα ligand developed by Glaxo Research Institute in 1994, have been reported as promising orally bioavailable SERDs. Some of these compounds are currently in clinical trials, while various other structurally novel SERDs have also been reported by pharma as well as academic research groups. This review provides a critical analysis of the recent developments in orally available SERDs, with a focus on the structure–activity relationships, binding interactions and pharmacokinetic properties of these compounds     

Cationic and Neutral N‐Heterocyclic Carbene Gold(I) Complexes: Cytotoxicity,NCI‐60 Screening,Cellular Uptake,Inhibition of Mammalian Thioredoxin Reductase,and Reactive Oxygen Species Formation

A structurally diverse library of 14 gold(I) cationic bis(NHC) and neutral mono(NHC) complexes (NHC: N‐heterocyclic carbene) was synthesized and characterized in this work. Four of them were new cationic gold(I) complexes containing functionalized NHCs, and their X‐ray crystal structures are presented herein. All of the complexes were investigated for their anticancer activities in four cancer cell lines, including a cisplatin‐resistant variant, and a noncancerous cell line. Seven of the cationic gold(I) complexes were found to display high and specific cytotoxic activities toward cancer cells. Two of them were even able to overcome cisplatin resistance. Two highly potent cationic complexes ( 11 and 15 ) were also submitted to the NCI‐60 cancer panel for further cytotoxicity evaluation. Complex 15 showed a surprisingly high potency toward leukemia among the nine examined cancer subtypes, particularly toward the CCRF‐CEM leukemia cell line with a concentration for 50 % inhibition of growth down to 79.4 nm . In addition, cationic complex 13 , which demonstrated a remarkable cytotoxicity against hepatocellular carcinoma, was selected to obtain insight into the mechanistic aspects in HepG2 cells. Cellular uptake measurements were indicative of good bioavailability. By various biochemical assays, this complex was found to effectively inhibit thioredoxin reductase and its cytotoxicity toward HepG2 cells was found to be reactive oxygen species dependent.     

Synthesis and anticancer activity of (R,S)-9-(2,3-dihydro-1,4-benzoxathiin-3-ylmethyl)-9H-purines

A series of eleven 2- and 6-substituted (R,S)-9-(2,3-dihydro-1,4-benzoxathiin-3-ylmethyl)-9H-purine derivatives was obtained by applying a standard Mitsunobu protocol that led to a six-membered ring contraction from (R,S)-3,4-dihydro-2H-1,5-benzoxathiepin-3-ol via an episulfonium intermediate. The signal approximately delta=151 ppm, which corresponds to the C4' carbon atom, is unequivocal proof of the N9' regioisomer. The potential of the target molecules as anticancer agents is reflected in their activity against the MCF-7 cancer cell line. The most active compounds have IC(50) values of (6.18+/-1.70) and (8.97+/-0.83) microM. The results indicate that the anticancer activity for the most active compounds is correlated with their capacity to induce apoptosis.     

Design,Synthesis, and Biological Evaluation of Pyrazoline‐Based Hydroxamic Acid Derivatives as Aminopeptidase N (APN) Inhibitors

Aminopeptidase N (APN) has been recognized as a target for anticancer treatment due to its overexpression on diverse malignant tumor cells and association with cancer invasion, metastasis and angiogenesis. Herein we describe the synthesis, biological evaluation, and structure–activity relationship study of two new series of pyrazoline analogues as APN inhibitors. Among these compounds, 5‐(2‐(2‐(hydroxyamino)‐2‐oxoethoxy)phenyl)‐3‐phenyl‐4,5‐dihydro‐1H‐pyrazole‐1‐carboxamide (compound 13 e ) showed the best APN inhibition with an IC₅₀ value of 0.16±0.02 μm , which is more than one order of magnitude lower than that of bestatin (IC₅₀=9.4±0.5 μm ). Moreover, compound 13 e was found to inhibit the proliferation of diverse carcinoma cells and to show potent anti‐angiogenesis activity. At the same concentration, compound 13 e presents significantly higher anti‐angiogenesis activity than bestatin in human umbilical vein endothelial cells (HUVECs) capillary tube formation assays. The putative binding mode of 13 e in the active site of APN is also discussed.     

Development and Biological Evaluation of a Novel Aurora A Kinase Inhibitor

Stop dividing : In the quest for antitumorigenic compounds, aurora A kinase has recently emerged as a potential drug target. In this paper three novel aurora inhibitors (shown in the illustration) have been tested for their biological activity in cultured cells. One of them (TC‐28) appears to be a promising specific aurora A inhibitor in vivo.