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European Journal of Medicinal Chemistry (v.51, #)

Graphical contents list (pp. iii-xi).
Editorial board (pp. ifc).

Tuberculosis: The drug development pipeline at a glance by Baptiste Villemagne; Céline Crauste; Marion Flipo; Alain R. Baulard; Benoit Déprez; Nicolas Willand (pp. 1-16).
Tuberculosis is a major disease causing every year 1.8 million deaths worldwide and represents the leading cause of mortality resulting from a bacterial infection. Introduction in the 60's of first-line drug regimen resulted in the control of the disease and TB was perceived as defeating. However, since the progression of HIV leading to co-infection with AIDS and the emergence of drug resistant strains, the need of new anti-tuberculosis drugs was not overstated. However in the past 40 years any new molecule did succeed in reaching the market. Today, the pipeline of potential new treatments has been fulfilled with several compounds in clinical trials or preclinical development with promising activities against sensitive and resistant Mycobacterium tuberculosis strains. Compounds as gatifloxacin, moxifloxacin, metronidazole or linezolid already used against other bacterial infections are currently evaluated in clinical phases 2 or 3 for treating tuberculosis. In addition, analogues of known TB drugs (PA-824, OPC-67683, PNU-100480, AZD5847, SQ609, SQ109, DC-159a) and new chemical entities (TMC207, BTZ043, DNB1,BDM31343) are under development. In this review, we report the chemical synthesis, mode of action when known, in vitro and in vivo activities and clinical data of all current small molecules targeting tuberculosis.Small molecules in clinical trials or preclinical development to treat tuberculosis are reported in this review.Display Omitted► This review presents anti-tuberculosis compounds currently in clinical trials. ► Promising strategies in preclinical development are described. ► The chemical synthesis, target and mechanism of action are highlighted. ► Activities observed in preclinical and clinical studies are reported.

Keywords: Mycobacterium tuberculosis; Drug discovery and drug development; New molecular entitiesAbbreviations; Ac; 2; O; acetic anhydride; AcOEt; ethyl acetate; BINAP; 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl; Boc; tert-butyloxycarbonyl; Cbz; carboxybenzyl; CFU; colony forming unit; DBU; 1,8-diazabicyclo[5.4.0]undec-7-ene; DCM; dichloromethane; Ddn; deazaflavin-dependent nitroreductase; DHP; 2,3-dihydropyran; DIEA; diisopropylethylamine; DMF; dimethylformamide; DOTS; directly observed treatment short-course; EBA; early bactericidal activity; EDCI; N-ethyl-3-(3-dimethylaminopropyl)carbodiimide; EMB; ethambutol; ETH; ethionamide; EtOH; ethanol; HBTU; O-benzotriazole-N,N,N′,N′-tetramethyluronium hexafluorophosphate; HOBt; N-hydroxybenzotriazole; INH; isoniazid; LDA; lithium diisopropylamide; MBD; minimal bactericidal dose; MDR; multidrug resistant; MeCN; acetonitrile; MED; minimal effective dose; MeOH; methanol; Ms; mesyl; MIC; minimal inhibitory concentration; MXF; moxifloxacin; TBS; tert-butyldimethylsilyl; pTsOH; p-toluenesulfonic acid; PZA; pyrazinamide; QR; quinolone resistant; RIF; rifampin; TB; tuberculosis; TEA; triethylamine; THF; tetrahydrofuran; WHO; world health organization; XDR; extensively drug resistant


Recent advances in the synthesis of raloxifene: A selective estrogen receptor modulator by Sureshbabu Dadiboyena (pp. 17-34).
Estrogens are a group of steroids that exert important effects on reproductive and many non-reproductive tissues. Selective estrogen receptor modulators (SERM) are a class of therapeutic agents widely prescribed for the treatment and prevention of breast cancer, osteoporosis, and postmenopausal symptoms. Raloxifene, an example of oral SERM is prescribed primarily for the treatment and prevention of postmenopausal disorders in woman. The current review provides an outline of practical methodologies used to access benzothiophenyl scaffolds of raloxifene and relevant structural analogs. The contents are discussed in five sections: (a) synthesis of raloxifene, (b) organometallic analogs, (c) radiolabelled analogs, (d) constrained raloxifene analogs, and (e) other oxygen, sulfur, and nitrogen based raloxifene analogs. In addition to the synthesis, biological activity of a few synthetic analogs has been discussed.Display Omitted► Selective estrogen receptor modulators (SERM) are widely utilized therapeutic agents. ► Benzothiophene are useful building blocks in raloxifene synthesis. ► Raloxifene, a selective SERM is used in the treatment and prevention of postmenopausal disorders in woman. ► Benzothiophenes with several reactive sites offer the feasibility to construct functionalized molecules. ► Current review provides a discussion on methodologies to synthesize raloxifene and structural analogs.

Keywords: Raloxifene; Evista; ®; Estrogen Receptors; Heterocycles; Benzothiophenes; SERM; Steroids


Design and synthesis of novel magnolol derivatives as potential antimicrobial and antiproliferative compounds by Srinivas Jada; Mahendhar Reddy Doma; Parvinder Pal Singh; Suresh Kumar; Fayaz Malik; Akash Sharma; Inshad Ali Khan; G.N. Qazi; H.M. Sampath Kumar (pp. 35-41).
A series of novel magnolol derivatives were synthesised and evaluated for in vitro antimicrobial and antiproliferative activities. We found that most of the compounds were effective inhibitors of Staphylococcus aureus, MRSA and VRE with MIC in the range of 1–64 μg/mL and MBC in the range of 1–128 μg/mL. Few derivatives also exhibited promising antifungal activity. Some magnolol analogues exhibited promising antiproliferative activity than parent magnolol when tested against three human cancer cell lines.A series of magnolol derivatives were synthesised and evaluated for antimicrobial and antiproliferative activities. Many analogues exhibited promising antibacterial activity against multi-drug resistant bacteria and few derivatives showed significant antiproliferative and antifungal activity.Display Omitted► Present manuscript highlights the synthesis, in vitro antimicrobial and antiproliferative studies of magnolol derivatives. ► Most of the compounds exhibited significant antibacterial activity against Staphylococcus aureus ATCC, MRSA and VRE. ► Few compounds exhibited promising antifungal activity. ► Some halogen substituted derivatives showed improved antiproliferative activity as compared to magnolol. ► DNA laddering and flow cytometric studies established the apoptotic mechanism of cell killing.

Keywords: Magnolol; Antibacterial; MRSA; VRE; Antifungal; Antiproliferative


Enaminones 12. An explanation of anticonvulsant activity and toxicity per Linus Pauling’s clathrate hypothesis by Patrice L. Jackson; Clive D. Hanson; Alanna K. Farrell; Raymond J. Butcher; James P. Stables; Natalie D. Eddington; K.R. Scott (pp. 42-51).
The x-ray crystal structure of 3-((5-methylisoxazol-3-yl)amino)-5-methylcyclohex-2-enone (12b) and 3-((5-methylisoxazolyl-3-yl)amino)-5,5-dimethylcyclohex-2-enone (12c) were determined and correlated to their anticonvulsant activity in mice and rats. A hypothesis for the toxicity of the analogs are advanced. In addition, a series of 5-methyl-N-(3-oxocyclohex-1-enyl)-isoxazole-3-carboxamides were synthesized and evaluated for anticonvulsant activity. These compounds were compared to the activity of the corresponding amino and aminomethyl enaminones. Additional investigation involved the synthesis and evaluation of a trifluoromethyl analog of the active isoxazole tert-butyl 4-(5-methisoxazol-3-yl-amino)-6-methyl-2-oxo-cyclohex-3-ene carboxylate (4f).Clathrate formation of the anticonvulsant active dimethyl enaminone isoxazole analog (12c), assembled as a head-to-tail dimer.Display Omitted► A novel series of carboxamide isoxazole enaminones were synthesized. ► All analogs reported were evaluated for anticonvulsant activity. ► X-ray crystal data proves formation of a clathrate, seen in compound12c. ► The clathrate formation blocks access to the proposed active site.

Keywords: Isoxazole enaminones; Clathrate; MES; scPTZ; GABAInChIKey; RAJYEVUWOYRVOS-UHFFFAOYSA-NAbbreviations; MES; maximal electroshock seizure; TD; 50; toxic dose for 50% of test animals; ED; 50; effective dose for 50% of test animals; ip; intraperitoneal; PI; protective index, TD; 50; /ED; 50; scPTZ; subcutaneous pentylenetetrazol; Tox; neurologic toxicity; ADD; Antiepileptic Drug Development; NINDS; National Institutes of Neurological Disorders and Stroke; ASP; Anticonvulsant Screening Program


Synthesis and in vitro antiplasmodial activities of fluoroquinolone analogs by Sandeep K. Dixit; Nidhi Mishra; Manish Sharma; Shailja Singh; Alka Agarwal; Satish K. Awasthi; V.K. Bhasin (pp. 52-59).
Fluoroquinolone analogs were synthesized by simple alkylation followed by click chemistry and evaluated for their antimalarial in vitro against chloroquine sensitive strain of Plasmodium falciparum while ciprofloxacin was used as standard. Our results showed that the compound12 was found most active with IC50 value of 1.33 μg/mL while ciprofloxacin showed IC50 = 8.81 μg/mL. Therefore, screening of either known or unknown quinolone/fluoroquinolone analogs are worthwhile to find more potent antimalarial drugs which might prove useful in the treatment of mild or severe malaria in human either alone or in combination with existing antimalarial drugs.Fluoroquinolone analogs were synthesized and screened in vitro against Plasmodium falciparum. The compound12 was found most active with IC50 1.33 μg/mL as compared to standard ciprofloxacin with IC50 8.82 μg/mL.Display Omitted► Novel fluoroquinolone analogs were evaluated in vitro against Plasmodium falciparum. ► The compound12 with simple triazole showed highest activity with IC50 1.3 μg/mL. ► The standard drug antibiotic ciprofloxacin showed IC50 8.82 μg/mL. ► The compound8 was crystallized and characterized by X-rays. ► These synthetic fluoroquinolones are more effective than ciprofloxacin.

Keywords: Fluoroquinolones; Antimalarial activity; Plasmodium falciparum; In vitro


Synthesis and biological evaluation of piperidine-substituted triazine derivatives as HIV-1 non-nucleoside reverse transcriptase inhibitors by Xuwang Chen; Peng Zhan; Christophe Pannecouque; Jan Balzarini; Erik De Clercq; Xinyong Liu (pp. 60-66).
A novel series of piperidine-substituted triazine derivatives have been synthesized and evaluated for anti-HIV activities in MT-4 cells. Most compounds displayed extremely promising activity against wild-type HIV-1 with EC50 values in low nanomolar concentration, better than that of Nevirapine, Delavirdine, Zidovudine and Dideoxycitidine, and higher potency towards the resistant mutant strain K103N/Y181C than that of Nevirapine and Delavirdine. Selected compounds were also assayed against reverse transcriptase with lower IC50 values than that of Nevirapine. The structure-activity relationship (SAR) of these novel structural congeners was also discussed.The novel piperidine-substituted triazine derivatives showed extremely promising activity against wild-type HIV-1 and moderate potency towards the K103N/Y181C resistant mutant strain.Display Omitted► Novel piperidine-substituted triazine derivatives were synthesized. ► Promising activity against wild-type HIV-1 (EC50 = 7.0 nM, SI = 3240). ► IC50 values against HIV-1 RT were in low micromolar level.

Keywords: HIV-1; NNRTIs; Piperidine; Triazine; AIDS; SAR


Synthesis and biological activity of 23-ethylidene-26-hydroxy-22-oxocholestane derivatives from spirostanic sapogenins by José Oscar H. Pérez-Díaz; Lucie Rárová; J. Paul Muñoz Ocampo; Nancy E. Magaña-Vergara; Norberto Farfán; Miroslav Strnad; Rosa Santillan (pp. 67-78).
The synthesis and biological evaluation of three new cholestane frameworks of the type: (25 R)-3 β,16 β-Diacetoxy-23-ethylidene-26-hydroxy-22-oxocholestane, starting from spirostanic sapogenins of the 25 R series, is described. The compounds were obtained by the reductive cleavage of the F ring of 22-oxo-231,26-epoxycholestane derivatives using 9-BBN. These modified derivatives exhibit cytotoxic activity against CEM and MCF7 cells and are able to induce apoptosis in them. Its effect on the cell cycle was determined.Display Omitted► Three new ethylidene-oxocholestane derivatives were synthesized from spirostanic sapogenins. ► Reductive cleavage directed by 9-BBN is the pivotal reaction in their synthesis. ► Antiproliferative activity against CEM and MCF7 cancer cells was accounted. ► Cytotoxic selectivity was proved by testing compounds against tumor and normal cells. ► Cell cycle and apoptosis assays were implemented to confirm anti-cancer activity.

Keywords: Spirostanic sapogenins; Reductive cleavage; 9-BBN; CEM; Antiproliferative activity; ApoptosisAbbreviations; Ac-DEVD-AMC; N-acetyl-Asp-Glu-Val-Asp-7-amido-4-methylcoumarin; Ac-DEVD-CHO; N-acetyl-Asp-Glu-Val-Asp-CHO; CHAPS; 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate; DMEM; Dulbecco's modified Eagle's medium; DMF; dimethylformamide; EGTA; ethylene glycol bis(2-aminoethyl ether)-N,N,N′,N′-tetraacetic acid; FBS; fetal bovine serum; IC50; the concentration of 50% cell inhibition; PARP; poly ADP-ribose polymerase-1; PIPES; 1,4-piperazinediethanesulfonic acid; PBS; phosphate buffered saline; PMSF; phenylmethylsulfonyl fluoride


Synthesis of novel spirooxindole derivatives by one pot multicomponent reaction and their antimicrobial activity by Gangaru Bhaskar; Yuvaraj Arun; Chandrasekar Balachandran; Chandrasekara Saikumar; Paramasivan T. Perumal (pp. 79-91).
A series of novel spirooxindoles have been synthesized through 1,3-dipolar cycloaddition of an azomethine ylide generated from isatin and sarcosine orl-proline with the dipolarophile 1,4-naphthoquinone followed by spontaneous dehydrogenation. Synthesised compounds were evaluated for their antimicrobial activities against eight bacteria and three fungi. All the spirooxindole derivatives exhibited significant antibacterial activity against Staphylococcus aureus, S. aureus (MRSA), Enterobacter aerogens, Micrococcus luteus, Proteus vulgaris, Klebsiella pneumonia, Salmonella typhimurium, Salmonella paratyphi-B and anti-fungal activity against Malassesia pachydermatis, Candida albicans and Botyritis cinerea organisms. Among 23 compounds screened, 1′-acetyl-2,5′-dimethyl-2,3-dihydrospiro[benzo[f]isoindole-1,3′-indoline]-2′,4,9-trione was found to be more active against tested bacteria and fungi.A series of novel spirooxindoles have been synthesized through 1,3-dipolar cycloaddition and evaluated for antimicrobial activities against eight bacteria and three fungi. All the compounds have shown significant activity.Display Omitted► Synthesis of novel spirooxindole derivatives by one pot multicomponent reaction. ► Spirooxindoles have versatile biological and pharmacological significance. ► Tandem 1,3-dipolar cycloaddition followed by dehydrogenation reaction. ► Synthesized compounds were tested against eight bacteria and three fungi. ► The synthesized compounds were displayed significant antimicrobial activity.

Keywords: Spirooxindole; Multicomponent reaction; Azomethine ylide cycloaddition; Antimicrobial activity


Synthesis and evaluation of CS-2100, a potent, orally active and S1P3- sparing S1P1 agonist by Tsuyoshi Nakamura; Masayoshi Asano; Yukiko Sekiguchi; Yumiko Mizuno; Kazuhiko Tamaki; Futoshi Nara; Yumi Kawase; Yoshiyuki Yabe; Daisuke Nakai; Emi Kamiyama; Yoko Urasaki-Kaneno; Takaichi Shimozato; Hiromi Doi-Komuro; Takashi Kagari; Wataru Tomisato; Ryotaku Inoue; Miyuki Nagasaki; Hiroshi Yuita; Keiko Oguchi-Oshima; Reina Kaneko; Takahide Nishi (pp. 92-98).
Modulators of sphingosine phosphate receptor-1 (S1P1) have recently been focused as a suppressant of autoimmunity. We have discovered a 4-ethylthiophene-based S1P1 agonist 1-({4-Ethyl-5-[5-(4-phenoxyphenyl)-1,2,4-oxadiazol-3-yl]-2-thienyl}methyl)azetidine-3-carboxylic acid (CS-2100,8) showing potent S1P1 agonist activity against S1P3 and an excellent in vivo potency. We report herein the synthesis of CS-2100 (8) and pharmacological effects such as S1P1 and S1P3 agonist activity in vitro, peripheral blood lymphocyte lowering effects and the suppressive effects on adjuvant-induced arthritis and experimental autoimmune encephalomyelitis (EAE) in animal models. The pharmacokinetic data were also reported. CS-2100 (8) had >5000-fold greater agonist activity for human S1P1 (EC50; 4.0 nM) relative to S1P3 (EC50; >20000 nM). Following administration of single oral doses of 0.1 and 1 mg/kg of CS-2100 (8) in rats, lymphocyte counts decreased significantly, with a nadir at 8 and/or 12 h post-dose and recovery to vehicle control levels by 24–48 h post-dose. CS-2100 (8) is efficacious in the adjuvant-induced arthritis model in rats (ID50; 0.44 mg/kg). In the EAE model compared to the vehicle-treated group, significant decreases in the cumulative EAE scores were observed for 0.3 and 1 mg/kg CS-2100 (8) groups in mice. While CS-2100 (8) showed potent efficacy in various animal disease models, it was also revealed that the central 1,2,4-oxadiazole ring of CS-2100 (8) was decomposed by enterobacteria in intestine of rats and monkeys, implicating the latent concern about an external susceptibility in its metabolic process in the upcoming clinical studies.We report the synthesis and evaluation of the sphingosine 1-phosphate receptor-1 (S1P1) agonist (CS-2100,8). Compound8 showed potent S1P1 agonist activity against S1P3 and an excellent in vivo potency.Display Omitted► Synthesis of sphingosine 1-phosphate receptor-1 (S1P1) agonist (CS-2100,8). ► Compound8 had >5000-fold greater agonist activity for human S1P1 relative to S1P3. ► The effects of8 on peripheral blood lymphocyte counts were investigated in rats. ► Compound8 showed potent efficacy in several animal disease models.

Keywords: S1P; 1; Agonist; CS-2100; Lymphocyte; Adjuvant-induced arthritis; EAE; Multiple sclerosis


A novel anti-tumor agent, Ln(III) 2-thioacetate benzothiazole induces anti-angiogenic effect and cell death in cancer cell lines by Belal H.M. Hussein; Hassan A. Azab; Mona F. El-Azab; Abdullah I. El-Falouji (pp. 99-109).
New complexes with a potent DNA-binding anti-tumor agent, europium(III)- and terbium(III)-2-thioacetate benzothiazole were synthesized and characterized. These complexes showed strong binding affinity to calf thymus DNA using fluorometric and electronic absorption spectroscopy. The synthesized complexes resulted in inhibition of proliferation of EAC cells and ascites formation. Their anti-tumor effect was found to be through anti-angiogenic activity as was evident by the reduction of microvessel density and down-regulation of VEGF receptor type-2 (Flk-1). It was found that EAC cells had distinct DNA fragmentation patterns analyzed by capillary electrophoresis in the treated animals. Moreover, the synthesized complexes exhibited significant cytotoxic activity against HepG2 and MCF7 cell lines. Furthermore, complexes showed a potent anti-bacterial activity against two pathogenic bacteria Escherichia coli and Salmonella.New complexes with a potent DNA-binding anti-tumor agent, Europium(III) and Terbium(III)-2-thioacetate benzothiazole were synthesized, new complexes showed promising anti-tumor activity and anti-bacterial activity.Display Omitted► New Ln(III)-2-thioacetate benzothiazole complexes were synthesized and characterized. ► Complexes showed promising antitumor activity with IC50 less than 5 μM against MCF7. ► In vivo, complexes down-regulate the expression of VEGF and CD31 in EAC cancer cell. ► The new complexes displayed remarkable in vitro and in vivo anticancer activity. ► Ln(III)-complexes displayed a pronounced activity against the two pathogenic bacteria.

Keywords: Lanthanum complex; 2-Thioacetic acid benzothiazole; Cytotoxicity; Antitumor activity; Antibacterial activity; DNA fragmentation


Studies on gambogic acid (IV): Exploring structure–activity relationship with IκB kinase-beta (IKKβ) by Haopeng Sun; Feihong Chen; Xiaojian Wang; Zongliang Liu; Qian Yang; Xiaojin Zhang; Jia Zhu; Lei Qiang; Qinglong Guo; Qidong You (pp. 110-123).
Previously we have reported a series of gambogic acid's analogs and have identified a compound that possessed comparable in vitro growth inhibitory effect as gambogic acid. However, their target protein as well as the key pharmacophoric motifs on the target have not been identified yet. Herein we report that gambogic acid and its analogs inhibit the activity of IκB Kinase-beta (IKKβ) through suppressing the activation of TNFα/NF-κB pathway, which in turn induces A549 and U251 cell apoptosis. IKKβ can serve as one of gambogic acid's targets. The preparation of the compounds was carefully discussed in the article. Caged 4-oxa-tricyclo[4.3.1.03,7]dec-2-one xanthone, which was identified as the pharmacophoric scaffold, represents a promising therapeutic agent for cancer and useful probe against NF-κB pathway.IKKβ was identified as the molecular target of GA through the research of NF-κB signaling pathway. A series of GA's analogs were synthesized to identify the pharmacophoric motifs against IKKβ.Display Omitted► IKKβ was identified as the key molecular target of gambogic acid (GA). ► Caged 4-oxa-tricyclo[4.3.1.03,7]dec-2-one xanthone was a new scaffold of IKKβ inhibitor. ► Ten simplified GA derivatives were designed and synthesized. ► Compound 20 has equal activity and similar mechanism with GA. ► The binding modes of 4 compounds with IKKβ were studied by molecular modeling.

Keywords: IKKβ; NF-κB signaling pathway; Caged xanthone; Pharmacophoric motif; Inhibitor


Facile synthesis, characterization and pharmacological activities of 3,6-disubstituted 1,2,4-triazolo[3,4- b][1,3,4]thiadiazoles and 5,6-dihydro-3,6-disubstituted-1,2,4-triazolo[3,4- b][1,3,4]thiadiazoles by N. Chidananda; Boja Poojary; V. Sumangala; N. Suchetha Kumari; Prashanth Shetty; T. Arulmoli (pp. 124-136).
Two new series of compounds namely, 3,6-disubstituted-1,2,4-triazolo[3,4- b][1,3,4]thiadizoles (5aj) and 5,6-dihydro-3,6-disubstituted-1,2,4-triazolo[3,4- b][1,3,4]thiadizoles (7aj) were prepared. In continuation of a previously reported study, the first series (5aj) were synthesized by the cyclocondensation of 4-amino-5-(2-bromo-5-methoxyphenyl)-2,4-dihydro-3 H-1,2,4-triazole-3-thione (4) with various substituted aromatic carboxylic acids in phosphorus oxychloride and the second series (7aj) by the reaction of (4) with various substituted aromatic aldehydes in the presence of p-Toluene sulfonic acid. Reaction of (4) with the aldehyde (9) afforded the Schiff's base (10) and not the cyclised product (11) on treatment with p-Toluene sulfonic acid. Synthesized compounds were structurally confirmed by spectral analysis and studied for their anti-inflammatory, analgesic, anti-oxidant and antimicrobial activities. Some of the tested compounds showed significant pharmacological activities.A series of 3,6-disubstituted-1,2,4-triazolo[3,4- b][1,3,4]thiadiazoles (5aj), 5,6-dihydro-3,6-disubstituted-1,2,4-triazolo[3,4- b][1,3,4]thiadiazoles (7aj) and triazolo Schiff's base (10) were prepared and evaluated for their anti-inflammatory, analgesic, anti-oxidant, antibacterial and anti-fungal activities.Display Omitted► New series of 1,2,4-triazolo[1,3,4]thiadiazole derivatives were synthesized. ► All the newly synthesized compounds were characterized by spectral studies. ► Anti-inflammatory and analgesic study was performed. ► Antioxidant activity of the biologically active compounds was also tested. ► Anti-microbial evaluation of synthesized compounds was carried out.

Keywords: Triazoles; Triazolo[3,4-; b; ][1,3,4]thiadiazoles; Anti-inflammatory activity; Analgesic activity; Antioxidant activity; Anti-microbial activities


Synthesis and biological evaluation of novel bifendate derivatives bearing 6,7-dihydro-dibenzo[ c, e]azepine scaffold as potent P-glycoprotein inhibitors by Xiaoke Gu; Zhiguang Ren; Xiaobo Tang; Hui Peng; Qing Zhao; Yisheng Lai; Sixun Peng; Yihua Zhang (pp. 137-144).
Overexpression of P-glycoprotein (P-gp) is one of the major problems in successful treatment of cancers. To find new P-gp inhibitors, a series of bifendate (DDB) derivatives bearing dibenzo[ c, e]azepine scaffold were synthesized and evaluated. Compound4i more potently reversed P-gp-mediated multidrug resistance (MDR) than DDB and verapamil (VRP) by blocking P-gp mediated drug efflux function and increasing drug accumulation in K562/A02 MDR cells, and persisted longer chemo-sensitizing effect (>24 h) than VRP (<6 h). Interestingly, unlike VRP,4i showed no stimulation on the P-gp ATPase activity, suggesting it is not a substrate of P-gp. Given the low intrinsic cytotoxicity of4i in vitro, it may represent a promising lead for developing therapeutics targeting P-gp-mediated MDR in combinational cancer chemotherapy.Compound4i more potently reversed P-gp-mediated multidrug resistance and persisted longer time than verapamil.Display Omitted► Novel DDB derivatives were synthesized and evaluated as P-glycoprotein inhibitors. ► Compound4i more potently reversed P-gp-mediated MDR than DDB and verapamil. ► The chemo-sensitizing effect of4i persisted longer time than that of verapamil. ► Unlike verapamil, compound4i was not a substrate of P-gp.

Keywords: Bifendate; dibenzo[; c; ,; e; ]azepine; P-gp inhibitor; Multidrug resistance


Thieno[2,3- d]pyrimidinedione derivatives as antibacterial agents by Mahender B. Dewal; Amit S. Wani; Celine Vidaillac; David Oupický; Michael J. Rybak; Steven M. Firestine (pp. 145-153).
Several thieno[2,3- d]pyrimidinediones have been synthesized and examined for antibacterial activity against a range of Gram-positive and Gram-negative pathogens. Two compounds displayed potent activity (2–16 mg/L) against multi-drug resistant Gram-positive organisms, including methicillin resistant, vancomycin-intermediate, vancomycin-resistant Staphylococcus aureus (MRSA, VISA, VRSA) and vancomycin-resistant enterococci (VRE). Only one of these agents possessed moderate activity (16–32 mg/L) against Gram-negative strains. An examination of the cytotoxicity of these agents revealed that they displayed low toxicity (40–50 mg/L) against mammalian cells and very low hemolytic activity (2–7%). Taken together, these studies suggest that thieno[2,3- d]pyrimidinediones are interesting scaffolds for the development of novel Gram-positive antibacterial agents.Thieno[2,3- d]pyrimidinedione derivatives have been synthesized and examined for antibacterial activity against Gram-positive and Gram-negative pathogens. Two compounds displayed potent activity (2–16 mg/L) against MRSA, VISA, VRSA and VRE.Display Omitted► Four unique thieno[2,3- d]pyrimidinediones were synthesized by a unique route. ► Two compounds displayed potent activity against antibiotic-resistant Gram-positive bacteria. ► One compound was selectively cytotoxic to bacteria and displayed no hemolytic activity.

Keywords: Thieno[2,3-; d; ]pyrimidinediones; Antibacterial; MRSA; Antibiotic-resistant bacteria; Heterocycle synthesis


Antifungal peptides at membrane interaction by Sara Di Marino; Mario Scrima; Manuela Grimaldi; Gerardino D’Errico; Giuseppe Vitiello; Maurizio Sanguinetti; Margherita De Rosa; Annunziata Soriente; Ettore Novellino; Anna Maria D’Ursi (pp. 154-162).
Many drugs are available for the treatment of systemic or superficial mycoses, but only a limited number of them are effective antifungal drugs, devoid of toxic and undesirable side effects. Furthermore, resistance development and fungistatic rather than fungicidal activities represent limitations of current antifungal therapy. Therefore an urgent need for a new generation of antifungal agents remains.We recently synthesised a set of linear and cyclic peptides characterized by sequences typical of membrane-active antimicrobial peptides (AMP). AMT2, cyclo-AMT2, AMT3 and cyclo-AMT3 () were tested against different yeast species and exhibited general antifungal activity, with a specificity against Cryptococcus neoformans.To evaluate the role of the membrane cell in the mechanism of antifungal activity, we investigated the conformational behaviour of AMT2, cyclo-AMT2, AMT3 and cyclo-AMT3 in different bio-membrane mimicking systems using a combined approach based on spectroscopy and microscopy techniques. Our data highlight the behaviour of the peptides to interact with the bilayer surface, excluding their ability to destabilize or permeabilize the fungal cell wall. Microbial membrane, indeed, may be an important platform for specific interactions of peptides with specific targets involved in the cell wall synthesis.Display Omitted► Antifungal peptides including typical antimicrobial peptide sequence. ► Fluorescence spectroscopy/microscopy depict peptides positioned at membrane interface. ► Arg and Trp residues favour membrane position and interaction with putative target.

Keywords: Antimicrobial peptides; Fluorescence spectroscopy; NMR spectroscopy; Conformational analysisAbbreviations; AMP; membrane-active antimicrobial peptides; AIDS; acquired immunodeficiency syndrome; SPPS; solid phase peptide synthesis; Dap; l; -diamino propionic acid; FMOC; fluorenylmethyloxycarbonyl; NBD; 7-nitrobenzo-2-oxa-1,3-diazole; NMR; nuclear magnetic resonance; SDS; sodium dodecyl sulphate; DOPC; 1,2-dioleoyl-; sn; -glycero-3-phosphocholine; DOPG; 1,2-dioleoyl-; sn; -glycero-3-[phospho-; rac; -(1-glycerol)]; LUV; large unilamellar vesicle; NOESY; nuclear Overhauser effectspectroscopy; DQF-COSY; double quantum filter correlated spectroscopy; TOCSY; total correlation spectroscopy


Novel isoxazole polycyclic aromatic hydrocarbons as DNA-intercalating agents by Antonio Rescifina; Maria Giulia Varrica; Caterina Carnovale; Giovanni Romeo; Ugo Chiacchio (pp. 163-173).
The third generation of isoxazole polycyclic aromatic hydrocarbons, acting as DNA-intercalator agents and possessing the binding constants in the range 104–105 M−1, in order to easily diffuse targeting remotely implanted tumors, has been synthesized in good yields according to the 1,3-dipolar cycloaddition methodology. The structure of the obtained cycloadducts has been determined by NOE experiments and supported by computational studies at PM3 level. All the obtained compounds have been tested for their in vitro cytotoxic activity and the most potent of them, (3 RS,5 SR)-2-benzyl- N, N-dimethyl-3-(pyren-1-yl)isoxazolidine-5-carboxamide (7d), showed an IC50 of 4 μM upon the human lung cancer (A-549) cells. Moreover, compound7d showed binding constant for the intercalation with calf thymus DNA, poly-d(AT)2 and poly-d(GC)2 of 1.7 × 105 M−1, 1.6 × 105 M−1 and 0.3 × 105 M−1, respectively. Biological and docking studies showed that, in vitro, these compounds complex by intercalation between base pairs, approaching the DNA from its minor groove with a preference for the AT nucleobases pairs.Display Omitted► The most potent of them showed an IC50 of 4 μM upon the human lung cancer cell. ► The binding constant for intercalation with calf thymus DNA is of 1.7 × 105 M−1. ► Docking studies showed a clear selectivity to AT nucleobases.

Keywords: DNA intercalation; Antitumor agent; Docking; Polycyclic aromatic hydrocarbons; Isoxazole; 1,3-Dipolar cycloaddition


Novel glycolipid TLR2 ligands of the type Pam2Cys-α-Gal: Synthesis and biological properties by Jean-Sébastien Thomann; Fanny Monneaux; Gaëlle Creusat; Maria Vittoria Spanedda; Béatrice Heurtault; Chloé Habermacher; Francis Schuber; Line Bourel-Bonnet; Benoît Frisch (pp. 174-183).
A more complete understanding of the mechanism of action of TLR agonists has fueled the investigation of new synthetic immunoadjuvants. In this context, we designed and synthesized glycolipids of the type Pam2Cys-α-Galactose as novel immunoadjuvants. Their synthesis required modifying a hydrophobic tBoc-[2,3-bispalmitoyloxy-(2 R)-propyl]- R-cysteinyl moiety, i.e. the minimal structure required for TLR2 agonist activity, by addition of a hydrophilic head, either an α-Galactosylpyranose or an α-Galactosylfuranose to gain respectively Pam2CGal p and Pam2CGal f. While preparing a carbohydrate building block, an unexpected stereoselectivity was observed during a halide ion-catalytic process on a protected galactofuranose: the alpha anomer was obtained with surprisingly high selectivity ( α/ β ratio>9) and with good isolated yield (51%). The TLR2 binding properties of Pam2CGal p and Pam2CGal f were then fully evaluated. Their efficiency in triggering the proliferation of BALB/c mouse splenocytes was also compared to that of Pam2CAG and Pam3CAG, two well-established ligands of TLRs. Moreover, the maturation state of murine dendritic cells previously incubated with either Pam2CGal p or Pam2CGal f was monitored by flow cytometry and compared to that induced by lipopolysaccharide. Pam2CGal p and Pam2CGal f were found to be equivalent TLR2 agonists, and induced splenocyte proliferation and DC maturation. With very similar activity, Pam2CGal p and Pam2CGal f were also 10-fold to 100-fold better than Pam2CAG and Pam3CAG at inducing B cell proliferation. This represents the first time a glucidic head has been added to the tBoc-[2,3-bispalmitoyloxy-(2 R)-propyl]- R-cysteinyl moiety whilst maintaining the immunomodulating activity. This should greatly enrich the data available on Pam2C structure/activity relationships.Display Omitted► Glycolipid TLR2 ligands were synthesized and characterized for the first time. ► The available data on Pam2C structure/activity relationships are thus enriched. ► An unexpected stereoselectivity was observed when preparing a galactofuranose ring. ► Toll-Like Receptor 2 (TLR2) agonist properties were fully demonstrated. ► Comprehensive binding and functional tests highlighted their interest as immunoadjuvants.

Keywords: Pam; 2; CAG; TLR2 agonist; Glycolipid; Immunoadjuvant; DC maturationAbbreviations; α-Gal; f; alpha-; d; -galactofuranose; α-Gal; p; alpha-; d; -galactopyranose; APC; antigen presenting cell; BOP; benzotriazol-1-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate; CD; cluster of differenciation; DC; dendritic cell; DIEA; diisopropylethylamine; DMAP; dimethylaminopyridine; DMSO; dimethylsulfoxyde; EDTA; ethylene diamine tetraacetic acid; ELISA; enzyme linked immunosorbent assay; FACS; fluorescence-activated cell sorting; FITC; fluorescein isothiocyanate; HEK; human embryonic cells; HRMS; high-resolution mass spectrometry; IFN; interferon; IL; interleukin; LPS; lipopolysaccharide; MALP; macrophage-activating lipopeptide; NF-κB; nuclear factor-κB; NKT; natural killer T; Pam; 2; CAG; t; Boc-[2,3-bispalmitoyloxy-(2; R; )-propyl]-; R; -cysteinyl-alanyl-glycine; Pam; 3; CAG; N; -Palmitoyl-[2,3-bispalmitoyloxy-(2; R; )-propyl]-; R; -cysteinyl-alanyl-glycine; PBS; phosphate buffer saline; PC; phosphatidylcholine; PE; phycoerythrin; PG; phosphatidylglycerol; rmGM-CSF; recombinant mouse granulocyte/macrophase colony-stimulating factor; SEAPted; secreted embryonic alkaline phosphatase; SUV; small unilamellar vesicle; TFA; trifluoroacetic acid; THP; human monocytic leukemia; THP-1; cells; TLR; toll-like receptor; TNF; tumor necrosis factor


Synthesis, modeling and functional activity of substituted styrene-amides as small-molecule CXCR7 agonists by Maikel Wijtmans; David Maussang; Francesco Sirci; Danny J. Scholten; Meritxell Canals; Azra Mujić-Delić; Milagros Chong; Kristell L.S. Chatalic; Hans Custers; Elwin Janssen; Chris de Graaf; Martine J. Smit; Iwan J.P. de Esch; Rob Leurs (pp. 184-192).
The chemokine receptor CXCR7 is an atypical G protein-coupled receptor as it preferentially signals through the β-arrestin pathway rather than through G proteins. CXCR7 is thought to be of importance in cancer and the development of CXCR7-targeting ligands is of huge importance to further elucidate the pharmacology and the therapeutic potential of CXCR7. In the present study, we synthesized 24 derivatives based on a compound scaffold patented by Chemocentryx and obtained CXCR7 ligands with p Ki values ranging from 5.3 to 8.1. SAR studies were supported by computational 3D Fingerprint studies, revealing several important affinity descriptors. Two key compounds (29 and30, VUF11207 and VUF11403) were found to be high-potency ligands that induce recruitment of β-arrestin2 and subsequent internalization of CXCR7, making them important tool compounds in future CXCR7 research.Display Omitted► Substituted styrene-amides are excellent CXCR7 binders. ► Computational model suggests important molecular descriptors. ► Key compounds induce recruitment of β-arrestin2 to CXCR7. ► Key compounds induce CXCR7 internalization.

Keywords: CXCR7; Ligand; Agonist; 3D fingerprint; β-arrestin2; InternalizationAbbrevations; BRET; bioluminescence resonance energy transfer; Cm; coelenteramide; CzH; coelenterazine H; EDCI; 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide; ELISA; enzyme-linked immunosorbent assay; ERK; extracellular signal-regulated kinase; FLAP; fingerprints for ligands and proteins; GPCR; G protein-coupled receptor; HBSS; Hank’s balanced salt solution; HOBT; hydroxybenzotriazole; LDA; linear discriminant analysis; MIF; molecular interaction field; NOESY; nuclear overhauser effect spectroscopy; RLuc; Renilla Luciferase; RT; room temperature; YFP; yellow fluorescent protein


Dimeric 3,5-bis(benzylidene)-4-piperidones: A novel cluster of tumour-selective cytotoxins possessing multidrug-resistant properties by Swagatika Das; Umashankar Das; Hiroshi Sakagami; Naoki Umemura; Shoko Iwamoto; Tomohiko Matsuta; Masami Kawase; Joseph Molnár; Julianna Serly; Dennis K.J. Gorecki; Jonathan R. Dimmock (pp. 193-199).
A series of bis[3,5-bis(benzylidene)-4-oxo-1-piperidinyl]amides1 display potent cytotoxic properties towards a wide range of tumours. A number of the CC50 and IC50 values are in the range of 10−8 M. Specifically, these compounds have the following important properties. First, greater toxicity was demonstrated towards certain tumours than various non-malignant cells. Second, various compounds in series1 are toxic to a number of human colon cancer and leukaemic cells. Third, these compounds reverse P-gp mediated multidrug resistance. Various prototypic molecules such as1a,b and1i were identified as lead molecules for further studies. A representative lead molecule1b induces apoptosis via internucleosomal DNA fragmentation and PARP cleavage in HSC-2 and HL-60 cells while flow cytometry revealed that this compound blocked the G2/M and S-phases in the cell cycle of human colon cancer HCT-116 cells.Display Omitted► Dimeric 3,5-bis(benzylidene)-4-piperidones1 are a novel class of potent cytotoxic agents. ► Demonstrate noteworthy tumour-selective toxicities compared to a number of normal cells. ► Mode of action includes apoptosis, PARP cleavage and G2/M phase blockage of the cell cycle. ► Potent multidrug-resistant reversal agents.

Keywords: Cytotoxicity; Tumour-selectivity; MDR-revertants; Structure–activity relationships; α,β-Unsaturated ketones


Synthesis and antitumor activity of 5,6-dihydro-17-hydroxy icogenin analogs by Yu-yao Guan; Dan Zheng; Zheng Yan; Nan Wang; Ping-sheng Lei (pp. 200-205).
Four 5,6-dihydro-17-hydroxy icogenin analogs were designed and synthesized. Their in vitro antitumor activities were tested by the standard MTT assay. Compound22 (IC50 = 3.38–8.30 μM) and compound23 (IC50 = 1.90–9.69 μM) showed potential antitumor activities against the entire tested seven cancer cell lines. The SAR (structure activity relationship) research showed that the introduction of 17-hydroxy lowered the antitumor activity to an extent.Four 5,6-dihydro-17-hydroxy icogenin analogs were synthesized and tested for antitumor activity.Display Omitted► We designed and synthesized four 5,6-dihydro-17-hydroxy icogenin analogs. ►22 (IC50 = 3.38–8.30 μM) and23 (IC50 = 1.90–9.69 μM) showed potential antitumor activity. ► The introduction of 17-hydroxy lowered the antitumor activity to an extent.

Keywords: Icogenin analog; Saponin; Antitumor activity; Synthesis


Synthesis of new troglitazone derivatives: Anti-proliferative activity in breast cancer cell lines and preliminary toxicological study by Stéphane Salamone; Christelle Colin; Isabelle Grillier-Vuissoz; Sandra Kuntz; Sabine Mazerbourg; Stéphane Flament; Hélène Martin; Lysiane Richert; Yves Chapleur; Michel Boisbrun (pp. 206-215).
Breast cancer is the most prevalent cancer in women. The development of resistances to therapeutic agents and the absence of targeted therapy for triple negative breast cancer motivate the search for alternative treatments. With this aim in mind, we synthesised new derivatives of troglitazone, a compound which was formerly used as an anti-diabetic agent and which exhibits anti-proliferative activity on various cancer cell lines. Among the compounds prepared, some displayed micromolar activity against hormone-dependent and hormone-independent breast cancer cells. Furthermore, the influence of the compounds on the viability of primary cultures of human hepatocytes was evaluated. This enabled us to obtain for the first time interesting structure–toxicity relationships in this family of compounds, resulting in6b and8b, which show good anti-proliferative activities and poor toxicity towards hepatocytes, compared to troglitazone.Display Omitted► Synthesis of new troglitazone derivatives is reported. ► Anti-proliferative activity against breast cancer cell lines showed micromolar potency. ► Clear structure–toxicity relationships were assessed in this series of compounds.

Keywords: Troglitazone; Chromane; Breast cancer; Hepatotoxicity


Progresses in the pursuit of aldose reductase inhibitors: The structure-based lead optimization step by Anna Ramunno; Sandro Cosconati; Stefania Sartini; Vita Maglio; Sara Angiuoli; Valeria La Pietra; Salvatore Di Maro; Mariateresa Giustiniano; Concettina La Motta; Federico Da Settimo; Luciana Marinelli; Ettore Novellino (pp. 216-226).
Aldose reductase (ALR2) is a crucial enzyme in the development of the major complications of diabetes mellitus. Very recently it has been demonstrated that the ARL2 inhibitor, fidarestat, significantly prevents inflammatory signals (TNF-α, LPS) that cause cancer (colon, breast, prostate and lung), metastasis, asthma, and other inflammatory diseases. Currently, fidarestat is in phase III clinical trial for diabetic neuropathy and was found to be safe. Thus the finding of novel, potent ARL2 inhibitors is today more than in the past in great demand as they can pave the way for a novel therapeutic approach for a number of diseases besides the diabetes. Herein, starting from the virtual screening-derived ALR2 inhibitor S12728 (1), a rational receptor-based lead optimization has been undertaken. The design and synthetic efforts here reported led to the discovery of several new compounds endowed with low micromolar/submicromolar activities.Display Omitted► Aldose reductase is crucial for diabetes complications, inflammation and tumors. ► From a VS-derived ARI a lead optimization was made. ► New inhibitors endowed with low micromolar/submicromolar activities were discovered.

Keywords: Aldose reductase; Inflammation; Diabetes; Docking; Enzyme


Novel NSAID 1-acyl-4-cycloalkyl/arylsemicarbazides and 1-acyl-5-benzyloxy/hydroxy carbamoylcarbazides as potential anticancer agents and antioxidants by I. Perković; I. Butula; M. Kralj; I. Martin-Kleiner; J. Balzarini; D. Hadjipavlou-Litina; A.-M. Katsori; B. Zorc (pp. 227-238).
The novel 1-acyl-4-cycloalkyl/arylsemicarbazides (5ay) and 1-acyl-5-benzyloxy/hydroxycarbamoylcarbazides (8af) derived from the nonsteroidal anti-inflammatory drugs ibuprofen, fenoprofen and reduced ketoprofen were prepared, fully chemically characterized and evaluated for their cytostatic, antiviral and antioxidant activities. Compounds5 and8 consist of a region rich in electronegative atoms (five to nine nitrogen and oxygen atoms) framed by aryl or cycloalkyl residues on one or both terminal ends. The synthetic pathways applied for the preparation of the title compounds involved a benzotriazole as a synthetic auxiliary in several steps. Three of the tested compounds, namely 4-benzhydryl-1-[2-(3-phenoxyphenyl)propanoyl]semicarbazide (5l), 4-benzhydryl-1-[2-(3-benzylphenyl)propanoyl]semicarbazide (5s), and 4-benzhydryl-1-[2-(4-isobutylphenyl)propanoyl]semicarbazide (5f) showed pronounced antiproliferative activity in vitro against six cancer cell lines (IC50=3–23μM). The same compounds highly inhibited soybean lipoxygenase (IC50=60 and 51.5μM) and lipid peroxidation as well (99, 88 and 74%, respectively). 4-Benzyloxy-1-[2-(4-isobutylphenyl)propanoyl]semicarbazide (5t) and 5-benzyloxycarbamoyl-1-[2-(3-benzylphenyl)propanoyl]carbazide (8c) exerted complete lipid peroxidation inhibition. Semicarbazides5wy and carbazides8df bearing a hydroxamic acid/hydroxyurea moiety showed a modest antiradical activity in DPPH test, while the best radical scavenger was 1-(1-benzotriazolecarbonyl)-4-benzyloxysemicarbazide (7). None of the compounds were inhibitory to a broad panel of DNA and RNA viruses in the cell culture at subtoxic concentrations.Display Omitted► NSAID semicarbazides, carbazides, ureas and hydroxamic acids are prepared. ► Benzhydryl semicarbazides showed excellent antiproliferative activity. ► Three compounds exerted high inhibition of lipid peroxidation and LOX inhibition.

Keywords: NSAID; Semicarbazide; Carbazide; Cytostatic activity; Lipoxygenase; Lipid peroxidation


Inhibitory effect of novel S, N-bisphosphonates on some carcinoma cell lines, osteoarthritis, and chronic inflammation by Azza A. Kamel; Athina Geronikaki; Wafaa M. Abdou (pp. 239-249).
A new series of S, N-bisphosphonate derivatives was synthesized and evaluated as antitumor agents against breast-, cervix-, liver, and colon cancer diseases. Antiarthritic and antichronic inflammatory properties of the new bisphosphonates (BPs) were also investigated. The studies demonstrated an efficient site selective method for making condensation products of BP-derivatives in high yields from thiazinethiones and tetraethyl methylenebisphosphonate reagent. The bioscreening evaluation showed that one of the tested BPs exhibited remarkable antitumor activity against the four tested carcinoma cell lines; nevertheless, all tested S, N-BP-derivatives (11 compounds) showed significant to moderate anti-inflammatory activity and capable of inhibiting polyarthritis.A new series of S, N-bisphosphonate derivatives was synthesized and evaluated as antitumor agents against breast cancer, cervix, liver, and colon. Antiarthritic and antichronic inflammatory properties of the new bisphosphonates were investigated.Display Omitted► Condensation reactions of thiazinethiones with methylenebisphosphonate reagent. ► Synthesis of a new series of S, and N-bisphosphonates and relevant acids. ► The new bisphosphonates showed potency against four carcinoma cell lines. ► Four out of eleven tested bisphosphonates capable of inhibiting polyarthritis. ► All tested S, N-bisphosphonates showed significant to moderate anti-inflammatory activity.

Keywords: S; ,; N; -bisphosphonates; Thiazinethiones; Antitumor activity; Antiarthritic- and anti- inflammatory activity


Synthesis and SAR studies of phenanthroindolizidine and phenanthroquinolizidine alkaloids as potent anti-tumor agents by Ziwen Wang; Meng Wu; Yi Wang; Zheng Li; Lei Wang; Guifang Han; Fazhong Chen; Yuxiu Liu; Kailiang Wang; Ao Zhang; Linghua Meng; Qingmin Wang (pp. 250-258).
A series of phenanthroindolizidine and phenanthroquinolizidine alkaloids and their 14-amino-derivatives (144) were prepared and systematically evaluated for their anti-tumor activities against A549 and HL60 cell lines. The bioassay results showed that most of these alkaloids possess good anti-tumor activities. Especially, compounds15,22,28,3336,40 and42 displayed low nanomolar or subnanomolar levels of anti-tumor activity. The configuration of (13a S,14 S)-14-hydroxyphenanthroindolizidines and (14a R,15 R)-15-hydroxyphenanthroquinolizidines was confirmed to be optimal. 14-Amino-phenanthroindolizidines with increased polarity possess good anti-tumor activity, especially for compounds26 and28. Most of the phenanthroquinolizidine alkaloids exhibited higher anti-tumor activity than that of phenanthroindolizidine alkaloids. Our present study provides fundamental support for development and optimization of phenanthroindolizidine and phenanthroquinolizidine alkaloids as potential anti-tumor drugs.A series of phenanthroindolizidine and phenanthroquinolizidine alkaloids and their 14-amino-derivatives (144) were prepared and systematically evaluated for their anti-tumor activities against A549 and HL60 cell lines.Display Omitted► A series of phenanthroindolizidine and phenanthroquinolizidine alkaloids and their 14-amino-derivatives were prepared. ► We systematically evaluated their anti-tumor activities against A549 and HL60 cell lines. ► Most of these alkaloids possess good anti-tumor activities. ► Compounds15,22,28,3336,40 and42 display low nanomolar or subnanomolar levels of anti-tumor activity.

Keywords: Phenanthroindolizidine; Phenanthroquinolizidine; 14-Amino-derivative; A549; HL60; Anti-tumor activity


Design of [(2-pyrimidinylthio)acetyl]benzenesulfonamides as inhibitors of human carbonic anhydrases by Edita Čapkauskaitė; Asta Zubrienė; Lina Baranauskienė; Giedrė Tamulaitienė; Elena Manakova; Visvaldas Kairys; Saulius Gražulis; Sigitas Tumkevičius; Daumantas Matulis (pp. 259-270).
A series of [(2-pyrimidinylthio)acetyl]benzenesulfonamides were designed and synthesized. Their binding affinities as inhibitors of several recombinant human carbonic anhydrase (CA) isozymes were determined by isothermal titration calorimetry (ITC) and thermal shift assay (TSA). A group of compounds containing a chlorine atom in the benzenesulfonamide ring were found to exhibit higher selectivity but lower binding affinity toward tested CAs. The crystal structures of selected compounds in complex with CA II were determined to atomic resolution. Docking studies were performed to compare the binding modes of experimentally determined crystallographic structures with computational prediction of the pyrimidine derivative binding to CA II. Several compounds bound to select CAs with single-digit nanomolar affinities and could be used as leads for inhibitor development toward a select CA isozyme.Display Omitted► [(2-pyrimidinylthio)acetyl]benzenesulfonamides are efficient CA binders. ► Compound affinities were ranked by titration calorimetry and thermal shift assay. ► Crystal structures and docking provide insight for novel inhibitor design. ► Affinities of up to 10–20 nM were reached by selected compounds. ► Selectivities of up to 50 times toward selected CA isozymes were achieved.

Keywords: Carbonic anhydrase isozymes; Isothermal titration calorimetry; Thermal shift assay; ThermoFluor; ®; Sulfonamides as CA inhibitorsAbbreviations; c; cyclic form; CA; carbonic anhydrase; ITC; isothermal titration calorimetry; o; open chain form; TSA; thermal shift assay


Metal–ligand interactions: An analysis of zinc binding groups using the Protein Data Bank by Kentaro Kawai; Naoya Nagata (pp. 271-276).
In the present study, we investigated zinc binding groups (ZBGs) using the coordinates of protein–ligand complex structures obtained from the Protein Data Bank. The distance from the zinc to the nearest ligand atom was measured to determine whether the atom was part of the ZBG. The most frequently found ZBG was carboxylate, followed by sulfonamide, hydroxamate, and phosphonate/phosphate. Because it was found that few heteroatoms, such as nitrogen, oxygen, and sulfur atoms, interacted with zinc, ideal distances between the zinc and these heteroatoms were identified. Whereas carboxylates bound to the zinc via both monodentate and bidentate interactions, the hydroxamates bound dominantly in a bidentate manner. These results will aid in the design of new inhibitors with the potential to interact with zinc in the target protein.A database of zinc binding groups (ZBGs) was developed using coordinates obtained from the Protein Data Bank. In addition, Zn-ZBG interactions were analyzed to help the design of new ZBGs.Display Omitted► Zinc metalloproteins contain many drug targets. ► ZBGs are important for the inhibition of the enzymes. ► Many ZBGs were identified and classified. ► Details of the coordination of ZBGs were described. ► A Method to design new inhibitors by the replacement of the ZBG moiety was proposed.

Keywords: Metal–ligand interaction; Zinc metalloproteins; Protein Data Bank; Zinc binding group


Growth inhibition of Mycobacterium smegmatis by prodrugs of deoxyxylulose phosphate reducto-isomerase inhibitors, promising anti-mycobacterial agents by Sarah Ponaire; Catherine Zinglé; Denis Tritsch; Catherine Grosdemange-Billiard; Michel Rohmer (pp. 277-285).
Since Mycobacterium tuberculosis sets up several multiple anti-tuberculosis drug resistance mechanisms, development of new drugs with innovative target is urgent. The methylerythritol phosphate pathway (MEP) involved in the biosynthesis of essential metabolites for the survival of mycobacteria, represents such a target. Fosmidomycin1a and FR9000981b, two inhibitors of DXR, do not affect the viability of M. tuberculosis cells, due to a lack of uptake. To overcome the absence of the mycobacterial cell wall crossing of these compounds, we synthesized and tested the inhibition potency of acyloxymethyl phosphonate esters as prodrugs of fosmidomycin1a, FR9000981b and their analogs2a and2b on Mycobacterium smegmatis. Only the prodrugs4b6b inhibit the bacterial growth and could be effective anti-mycobacterial agents.Display Omitted► Fosmidomycin and analogs do not inhibit mycobacterial growth. ► Resistance to these compounds is due to absence of cell wall crossing. ► Phosphonate groups were masked as acyloxymethyl phosphonate esters. ► Prodrugs4b6b inhibit mycobacterial growth, prodrug4b was the most active. ► Fosmidomycin and FR900098 prodrugs3a and3b were inefficient.

Keywords: Isoprenoid biosynthesis; Prodrug synthesis; Deoxyxylulose 5-phosphate reducto-isomerase; Mycobacterium


Structure–activity relationship of selected polyphenol derivatives as inhibitors of Bax/Bcl-xL interaction by Duc Duy Vo; Fabien Gautier; Philippe Juin; René Grée (pp. 286-293).
This paper describes the synthesis of nine selected diaryl/heteroaryl-containing phenol and polyphenol derivatives which have been evaluated against Bax/Bcl-xL interaction in comparison with ABT-737. Using a BRET assay, six of these derivatives exhibit activity comparable to ABT-737 to disrupt Bax/Bcl-xL interaction. These preliminary results demonstrate that such polyphenol-derived molecules are attractive compounds regarding anticancer activity and that the phenol at position 3 is important regarding disruption of Bax/Bcl-xL interaction.Display Omitted► synthesis of selected polyphenol derivatives which have been evaluated against Bax/Bcl-xL interaction. ► six of these derivatives exhibit activity comparable to ABT-737 to disrupt Bax/Bcl-xL interaction. ► the phenol at position 3 is important regarding Bax/Bcl-xL interaction.

Keywords: Phenol; Bax; Bcl-xL; Apoptosis; BRET; Cancer


Design and synthesis of novel 5-phenyl- N-piperidine ethanone containing 4,5-dihydropyrazole derivatives as potential antitumor agents by Xin-Hua Liu; Jun Li; Jing Bo Shi; Bao-An Song; Xing-Bao Qi (pp. 294-299).
A series of novel 5-phenyl- N-piperidine ethanone-4,5-dihydropyrazole derivatives as potential telomerase inhibitors were synthesized. The bioassays demonstrated that compounds4d,4f,7a and7b occupied high antiproliferative activities against SGC-7901, MGC-803 and Bcap-37 cell lines. By a modified TRAP assay, some titled compounds were tested against telomerase, and compound7b showed the most potent inhibitory activity with IC50 value at 2.00 ± 0.40 μM. The active compound4d was also docked into the telomerase TERT active site to determine the probable binding model. The results indicated that conserved residues Lys189, Asp254 and Gln308 were important for ligand binding via hydrogen bond interactions.Novel dihydropyrazole-piperidine ethanone derivatives as potential telomerase inhibitors were synthesized. Titled compound7b showed the most potent inhibitory activity. Docking results indicated that conserved residues Lys189, Asp254 and Gln308 were important for ligand binding.Display Omitted► Novel dihydropyrazole-piperidines were designed and two of them were determined by X-ray. ► Their antiproliferative activities against MGC-803, Bcap-37 and SGC-7901 were evaluated. ► Compound7b showed the most potent inhibitory activity. ► Docking result indicated that residues Lys189, Asp254, Gln308 were important for ligand binding.

Keywords: Synthesis; Piperidine; 4,5-Dihydropyrazole; Antitumor agents

Corrigendum to “Activity of novel quinoxaline-derived chalcones on in vitro glioma cell proliferation” [European Journal of Medicinal Chemistry, 48 (2012) 255–264] by Tânia R. Mielcke; Alessandra Mascarello; Eduardo Filippi-Chiela; Rafael F. Zanin; Guido Lenz; Paulo César Leal; Louise Domeneghini Chiaradia; Rosendo A. Yunes; Ricardo J. Nunes; Ana M.O. Battastini; Fernanda B. Morrone; Maria M. Camposa (pp. 300-300).
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