共查询到20条相似文献,搜索用时 15 毫秒
1.
Pavla Spáčilová Petr Nauš Dr. Radek Pohl Dr. Ivan Votruba Dr. Jan Snášel Dr. Helena Zábranská Dr. Iva Pichová Dr. Ria Ameral Gabriel Birkuš Dr. Tomáš Cihlář Dr. Michal Hocek Prof. 《ChemMedChem》2010,5(8):1386-1396
A series of cycloSal‐phosphate prodrugs of a recently described new class of nucleoside cytostatics (6‐hetaryl‐7‐deazapurine ribonucleosides) was prepared. The corresponding 2′,3′‐isopropylidene 6‐chloro‐7‐deazapurine nucleosides were converted into 5‐O′‐cycloSal‐phosphates. These underwent a series of Stille or Suzuki cross‐couplings with diverse (het)arylstannanes or ‐boronic acids to yield the protected 6‐(het)aryl‐7‐deazapurine pronucleotides that were subsequently deprotected to give 12 derivatives of free pronucleotides. The in vitro cytostatic effect of the pronucleotides was compared with parent nucleoside analogues. In most cases, the activity of the pronucleotide was similar to or somewhat lower than that of the corresponding parent nucleosides, with the exception of 7‐fluoro pronucleotides 13 a , 13 b , and 13 d , which had exhibited GIC50 values that were improved by one order of magnitude (to the low nanomolar range). The presence of a cycloSal‐phosphate group also influenced selectivity toward various cell lines. Several pronucleotides were found which strongly inhibit human adenosine kinase but only weakly inhibit the MTB adenosine kinase. 相似文献
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Dr. Pavla Perlíková Ludovic Eberlin Petra Ménová Veronika Raindlová Dr. Lenka Slavětínská Eva Tloušťová Dr. Gina Bahador Dr. Yu‐Jen Lee Prof. Dr. Michal Hocek 《ChemMedChem》2013,8(5):832-846
A series of sugar‐modified derivatives of cytostatic 7‐heteroaryl‐7‐deazaadenosines (2′‐deoxy‐2′‐fluororibo‐ and 2′‐deoxy‐2′,2′‐difluororibonucleosides) bearing an aryl or heteroaryl group at position 7 was prepared and screened for biological activity. The difluororibonucleosides were prepared by non‐ stereoselective glycosidation of 6‐chloro‐7‐deazapurine with benzoyl‐protected 2‐deoxy‐2,2‐difluoro‐D ‐erythro‐pentofuranosyl‐1‐mesylate, followed by amination and aqueous Suzuki cross‐couplings with (het)arylboronic acids. The fluororibo derivatives were prepared by aqueous palladium‐catalyzed cross‐coupling reactions of the corresponding 7‐iodo‐7‐deazaadenine 2′‐deoxy‐2′‐fluororibonucleoside 20 with (het)arylboronic acids. The key intermediate 20 was prepared by a six‐step sequence from the corresponding arabinonucleoside by selective protection of 3′‐ and 5′‐hydroxy groups with acid‐labile groups, followed by stereoselective SN2 fluorination and deprotection. Some of the title nucleosides and 7‐iodo‐7‐deazaadenine intermediates showed micromolar cytostatic or anti‐HCV activity. The most active were 7‐iodo and 7‐ethynyl derivatives. The corresponding 2′‐deoxy‐2′,2′‐difluororibonucleoside 5′‐O‐triphosphates were found to be good substrates for bacterial DNA polymerases, but are inhibitors of human polymerase α. 相似文献
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Polymerase Synthesis and Restriction Enzyme Cleavage of DNA Containing 7‐Substituted 7‐Deazaguanine Nucleobases 下载免费PDF全文
Michaela Mačková Soňa Boháčová Dr. Pavla Perlíková Dr. Lenka Poštová Slavětínská Prof. Dr. Michal Hocek 《Chembiochem : a European journal of chemical biology》2015,16(15):2225-2236
Previous studies of polymerase synthesis of base‐modified DNAs and their cleavage by restriction enzymes have mostly related only to 5‐substituted pyrimidine and 7‐substituted 7‐deazaadenine nucleotides. Here we report the synthesis of a series of 7‐substituted 7‐deazaguanine 2′‐deoxyribonucleoside 5′‐O‐triphosphates (dGRTPs), their use as substrates for polymerase synthesis of modified DNA and the influence of the modification on their cleavage by type II restriction endonucleases (REs). The dGRTPs were generally good substrates for polymerases but the PCR products could not be visualised on agarose gels by intercalator staining, due to fluorescence quenching. The presence of 7‐substituted 7‐deazaguanine residues in recognition sequences of REs in most cases completely blocked the cleavage. 相似文献
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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 下载免费PDF全文
Qingfeng Li Prof. Eveline Lescrinier Dr. Elisabetta Groaz Leentje Persoons Prof. Dirk Daelemans Prof. Piet Herdewijn Dr. Steven De Jonghe 《ChemMedChem》2018,13(1):97-104
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. 相似文献
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Potent,Metabolically Stable 2‐Alkyl‐8‐(2H‐1,2,3‐triazol‐2‐yl)‐9H‐adenines as Adenosine A2A Receptor Ligands 下载免费PDF全文
Dr. Silvia Pace Dr. Giandomenico Brogin Dr. Maria Antonietta Stasi Dr. Teresa Riccioni Franco Borsini Dr. Francesca Capocasa Dr. Francesco Manera Carlo Tallarico Dr. Pietro Grossi Dr. Federica Vacondio Dr. Michele Bassi Dr. Francesca Bartoccini Dr. Simone Lucarini Dr. Giovanni Piersanti Prof. Giorgio Tarzia Walter Cabri Dr. Patrizia Minetti 《ChemMedChem》2015,10(7):1149-1152
Inhibition of adenosine A2A receptors has been shown to elicit a therapeutic response in preclinical animal models of Parkinson’s disease (PD). We previously identified the triazolo‐9H‐purine, ST1535, as a potent A2AR antagonist. Studies revealed that ST1535 is extensively hydroxylated at the ω‐1 position of the butyl side chain. Here, we describe the synthesis and evaluation of derivatives in which the ω‐1 position has been substituted (F, Me, OH) in order to block metabolism. The stability of the compounds was evaluated in human liver microsomes (HLM), and the affinity for A2AR was determined. Two compounds, (2‐(3,3‐dimethylbutyl)‐9‐methyl‐8‐(2H‐1,2,3‐triazol‐2‐yl)‐9H‐purin‐6‐amine ( 3 b ) and 4‐(6‐amino‐9‐methyl‐8‐(2H‐1,2,3‐triazol‐2‐yl)‐9H‐purin‐2‐yl)‐2‐methylbutan‐2‐ol ( 3 c ), exhibited good affinity against A2AR (Ki=0.4 nM and 2 nM , respectively) and high in vitro metabolic stability (89.5 % and 95.3 % recovery, respectively, after incubation with HLM for two hours). 相似文献
6.
Dianqing Sun Dr. Hai Xu Dr. Sanath R. Wijerathna Chris Dealwis Dr. Richard E. Lee Dr. 《ChemMedChem》2009,4(10):1649-1656
Analysis of the recently solved X‐ray crystal structures of Saccharomyces cerevisiae ribonucleotide reductase I (ScRnr1) in complex with effectors and substrates led to the discovery of a conserved water molecule located at the active site that interacted with the 2′‐hydroxy group of the nucleoside ribose. In this study 2′‐(2‐hydroxyethyl)‐2′‐deoxyadenosine 1 and the 5′‐diphosphate derivative 2 were designed and synthesized to see if the conserved water molecule could be displaced by a hydroxymethylene group, to generate novel RNR inhibitors as potential antitumor agents. Herein we report the synthesis of analogues 1 and 2 , and the co‐crystal structure of adenosine diphosphate analogue 2 bound to ScRnr1, which shows the conserved water molecule is displaced as hypothesized. 相似文献
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Munmun Maiti Leentje Persoons Prof. Graciela Andrei Prof. Robert Snoeck Prof. Jan Balzarini Prof. Piet Herdewijn 《ChemMedChem》2013,8(6):985-993
Among the many prodrug approaches aimed at delivering nucleoside monophosphates into cells, the phosphoramidate ProTide approach is one that has shown success, which has made it possible for some of the phosphoramidates to enter into clinical trials. Herein, we report the synthesis and antiviral activity of a series of phosphoramidate ProTides designed to bypass the thymidine kinase (TK) dependence of the parent nucleoside analogues. Phosphoramidate derivatives of (E)‐5‐(2‐bromovinyl)‐2′‐deoxyuridine (BVDU) that contain L ‐alanine or pivaloyloxymethyl iminodiacetate (IDA‐POM) exhibit anti‐HSV‐1 and anti‐VZV activity in cell cultures, but they largely lost antiviral potency against TK‐deficient virus strains. Among deazapurine nucleosides and their phosphoramidate derivatives, the 7‐deazaadenine containing nucleosides and their phosphoramidate triester derivatives showed weak antiviral activity against VZV. Apparently, intracellular nucleotide delivery with these phosphoramidates is partly successful. However, none of the compound prodrugs showed superior activity to their parent drugs. 相似文献
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Dr. Silvia Meneghesso Dr. Andrea Brancale Prof. Jan Balzarini Prof. Lieve Naesens Prof. Christopher McGuigan 《ChemMedChem》2013,8(3):415-425
2′‐Fluoro‐2′‐deoxyguanosine has been reported to have potent anti‐influenza virus activity in vitro and in vivo. Herein we describe the synthesis and biological evaluation of 6‐modified 2′‐fluoro‐2′‐deoxyguanosine analogues and their corresponding phosphoramidate ProTides as potential anti‐influenza virus agents. Whereas the parent nucleosides were devoid of antiviral activity in two different cellular assays, the 5′‐O‐naphthyl(methoxy‐L ‐alaninyl) ProTide derivatives of 6‐O‐methyl‐2′‐fluoro‐2′‐deoxyguanosine, 6‐O‐ethyl‐2′‐fluoro‐2′‐deoxyguanosine, and 2′‐deoxy‐2′‐fluoro‐6‐chloroguanosine, and the 5′‐O‐naphthyl(ethoxy‐L ‐alaninyl) ProTide of 6‐O‐ethyl‐2′‐fluoro‐2′‐deoxyguanosine displayed antiviral EC99 values of ~12 μM . The antiviral results are supported by metabolism studies. Rapid conversion into the L ‐alaninyl metabolite and then 6‐modified 2′‐fluoro‐2′‐deoxyguanosine 5′‐monophosphate was observed in enzymatic assays with yeast carboxypeptidase Y or crude cell lysate. Evidence for efficient removal of the 6‐substituent on the guanine part was provided by enzymatic studies with adenosine deaminase, and by molecular modeling of the nucleoside 5′‐monophosphates in the catalytic site of a model of ADAL1, thus indicating the utility of the double prodrug concept. 相似文献
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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 下载免费PDF全文
Dr. Raffaella Amici Dr. Chiara Bigogno Dr. Roberto Boggio Dr. Andrea Colombo Dr. Stephen M. Courtney Dr. Roberto Dal Zuffo Dr. Giulio Dondio Dr. Fulvia Fusar Dr. Stefania Gagliardi Prof. Dr. Saverio Minucci Dr. Marco Molteni Dr. Christian A. G. N. Montalbetti Dr. Annalisa Mortoni Dr. Mario Varasi Dr. Stefania Vultaggio Dr. Ciro Mercurio 《ChemMedChem》2014,9(7):1574-1585
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. 相似文献
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Development of 3‐Phenyl‐N‐(2‐(3‐phenylureido)ethyl)‐thiophene‐2‐sulfonamide Compounds as Inhibitors of Antiapoptotic Bcl‐2 Family Proteins 下载免费PDF全文
Dr. Chengwen Yang Sha Chen Mi Zhou Dr. Yan Li Yangfeng Li Zhengxi Zhang Dr. Zhen Liu Dr. Qian Ba Dr. Jingquan Li Prof. Hui Wang Prof. Xiaomei Yan Prof. Dawei Ma Prof. Renxiao Wang 《ChemMedChem》2014,9(7):1436-1452
Antiapoptotic Bcl‐2 family proteins, such as Bcl‐xL, 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 (Ki)=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‐xL, 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 (Ki=0.3–0.4 μM ) or Bcl‐2 (Ki≈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‐xL 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. 相似文献
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A new soluble fluorescent polymer, poly[2‐decyloxy‐5‐(2′‐(6′‐dodecyl‐oxy)naphthyl)‐1,4‐phenylenevinylene] (DDN‐PPV), with no tolane‐bisbenzyl (TBB) structure defects is prepared by the dehydrohalogenation of 1,4‐bis(bromomethyl)‐2‐decyloxy‐5‐(2′‐(6′‐dodecyloxy)naphthyl)benzene (as monomer) in this study. The aforementioned monomer is synthesized via such chemical reactions as alkylation, bromination, and Suzuki coupling reactions. The structure and properties of the DDN‐PPV are examined by 1H NMR, FTIR, UV/vis, TGA, photoluminescence (PL), and electroluminescence (EL) analyses. The two asymmetric decyloxy and 6′‐dodecyloxynaphthyl substituents on the phenylene ring make the DDN‐PPV soluble in organic solvents and eliminate the TBB structure defects. With the DDN‐PPV acting as a light‐emitting polymer, a device is fabricated with a sequential lamination of ITO/PEDOT/DDN‐PPV/Ca/Ag. The EL spectrum of the device shows a maximum emission at 538 nm. The turn on voltage of the device is about 16.6 V. Its maximum brightness is 14 cd/m2 at a voltage of 18.2 V. © 2006 Wiley Periodicals, Inc. J Appl Polym Sci 103: 2734–2741, 2007 相似文献
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Dr. Ulrich Lücking Dr. Rolf Jautelat Dr. Martin Krüger Dr. Thomas Brumby Dr. Philip Lienau Dr. Martina Schäfer Dr. Hans Briem Dr. Julia Schulze Prof. Dr. Alexander Hillisch Dr. Andreas Reichel Dr. Antje Margret Wengner Dr. Gerhard Siemeister 《ChemMedChem》2013,8(7):1067-1085
Lead optimization of a high‐throughput screening hit led to the rapid identification of aminopyrimidine ZK 304709, a multitargeted CDK and VEGF‐R inhibitor that displayed a promising preclinical profile. Nevertheless, ZK 304709 failed in phase I studies due to dose‐limited absorption and high inter‐patient variability, which was attributed to limited aqueous solubility and off‐target activity against carbonic anhydrases. Further lead optimization efforts to address the off‐target activity profile finally resulted in the introduction of a sulfoximine group, which is still a rather unusual approach in medicinal chemistry. However, the sulfoximine series of compounds quickly revealed very interesting properties, culminating in the identification of the nanomolar pan‐CDK inhibitor BAY 1000394, which is currently being investigated in phase I clinical trials. 相似文献
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In recent years, clinical symptoms resulting from West Nile virus (WNV) infection have worsened in severity, with an increased frequency in neuroinvasive diseases among the elderly. As there are presently no successful therapies against WNV for use in humans, continual efforts to develop new chemotherapeutics against this virus are highly desired. The viral NS2B‐NS3 protease is a promising target for viral inhibition due to its importance in viral replication and its unique substrate preference. In this study, a WNV NS2B‐NS3 protease inhibitor with a 2‐{6‐[2‐(5‐phenyl‐4H‐[1,2,4]triazol‐3‐ylsulfanyl)acetylamino]benzothiazol‐2‐ylsulfanyl}acetamide scaffold was identified during screening. Optimization of this initial hit by synthesis and screening of a focused compound library with this scaffold led to the identification of a novel uncompetitive inhibitor ( 1 a24 , IC50=3.4±0.2 μM ) of the WNV NS2B‐NS3 protease. Molecular docking of 1 a24 into the WNV protease showed that the compound interferes with productive interactions of the NS2B cofactor with the NS3 protease and is an allosteric inhibitor of the WNV NS3 protease. 相似文献
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BODIPY‐Appended 2‐(2‐Pyridyl)benzimidazole Platinum(II) Catecholates for Mitochondria‐Targeted Photocytotoxicity 下载免费PDF全文
Dr. Koushambi Mitra Srishti Gautam Prof. Paturu Kondaiah Prof. Akhil R. Chakravarty 《ChemMedChem》2016,11(17):1956-1967
Platinum(II) complexes of the type [Pt(L)(cat)] ( 1 and 2 ), in which H2cat is catechol and L represents two 2‐(2‐pyridyl)benzimidazole ligands with 4,4‐difluoro‐4‐bora‐3a,4a‐diaza‐s‐indacene (BODIPY) pendants, were synthesized to achieve mitochondria‐targeted photocytotoxicity. The complexes showed strong absorptions in the range λ=510–540 nm. Complex 1 exhibited intense emission at λ=525 nm in 1 % DMSO/water solution (fluorescence quantum yield of 0.06). Nanosecond transient absorption spectral features indicated an enhanced population of the triplet excited state in di‐iodinated complex 2 . The generation of singlet oxygen by complex 2 upon exposure to visible light, as evidenced from experiments with 1,3‐diphenylisobenzofuran, is suitable for photodynamic therapy because of the remarkable photosensitizing ability. The complexes resulted in excellent photocytotoxicity in HaCaT cells (half maximal inhibitory concentration IC50≈3 μm , λ=400–700 nm, light dose=10 J cm?2), but they remained non‐toxic in the dark (IC50>100 μm ). Confocal microscopy images of 1 and Pt estimation from isolated mitochondria showed colocalization of the complexes in the mitochondria. Complex 2 displayed generation of reactive oxygen species induced by visible light, disruption of the mitochondrial membrane potential, and apoptosis. 相似文献
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Prashant S. Kharkar Dr. Angela M. Batman Juan Zhen Dr. Patrick M. Beardsley Prof. Maarten E. A. Reith Prof. Aloke K. Dutta Prof. 《ChemMedChem》2009,4(7):1075-1085
A novel series of optically active molecules based on a 4‐(2‐(benzhydryloxy)ethyl)‐1‐((R)‐2‐hydroxy‐2‐phenylethyl)‐piperidin‐3‐ol template were developed. Depending on stereochemistry, the compounds exhibit various degrees of affinity for three dopamine, serotonin, and norepinephrine transporters. These molecules have the potential for treating several neurological disorders such as drug abuse, depression, and attention deficit hyperactivity disorder.
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3‐(2‐Oxoethylidene)indolin‐2‐one Derivatives Activate Nrf2 and Inhibit NF‐κB: Potential Candidates for Chemoprevention 下载免费PDF全文
Dr. Amrita A. Nagle Dr. Shridhivya A. Reddy Dr. Helene Bertrand Dr. Hisashi Tajima Dr. Truong‐Minh Dang Dr. Siew‐Cheng Wong Prof. John D. Hayes Dr. Geoffrey Wells Dr. Eng‐Hui Chew 《ChemMedChem》2014,9(8):1763-1774
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Structure–Activity Relationship of Tumor‐Selective 5‐Substituted 2‐Amino‐3‐carboxymethylthiophene Derivatives 下载免费PDF全文
Dr. Joice Thomas Dr. Alenka Jejcic Peter Vervaeke Prof. Romeo Romagnoli Prof. Sandra Liekens Prof. Jan Balzarini Prof. Wim Dehaen 《ChemMedChem》2014,9(12):2744-2753
Methyl‐2‐amino‐5‐[2‐(4‐methoxyphenethyl)]thiophene‐3‐carboxylate ( 8 c ) is the prototype of a well‐defined class of tumor‐selective agents. Compound 8 c preferentially inhibited the proliferation of a number of tumor cell lines including many human T‐lymphoma/leukemia cells, but also several prostate, renal, central nervous system and liver tumor cell types. Instead, a broad variety of other tumor cell lines including B‐lymphomas and HeLa cells were not affected. The tumor selectivity (TS; selectivity index or preferential suppression of CEM lymphoma (IC50=0.90 μM ) versus HeLa tumor cell carcinoma (IC50=39 μM )) amounted up to ~43 for 8 c . At higher concentrations, the compound proved cytotoxic rather than cytostatic. The antiproliferative potency and selectivity of 8 c could be preserved by replacing the ethyl linker between the 2‐amino‐3‐carboxymethylthiophene and the substituted aryl by a thioalkyl but not by an oxyalkyl nor an aminoalkyl. Among >50 novel 8 c derivatives, the 5‐(4‐ethyl‐ and 4‐isopropylarylmethylthio)thiophene analogues, methyl‐2‐amino‐5‐((4‐ethylphenylthio)methyl)thiophene‐3‐carboxylate ( 13 m ) and methyl‐2‐amino‐5‐((4‐isopropylphenylthio)methyl)thiophene‐3‐carboxylate ( 13 n ), were more potent (IC50: 0.3–0.4 μM ) and selective (TS: 100–144) anti‐T‐lymphoma/leukemia agents than the prototype compound. 相似文献