Mn-mediated sequential three-component domino Knoevenagel/cyclization/Michael addition/oxidative cyclization reaction towards annulated imidazo[1,2-a]pyridines

• Olga A. Storozhenko,
• Alexey A. Festa,
• Delphine R. Bella Ndoutoume,
• Alexander V. Aksenov,
• Alexey V. Varlamov and
• Leonid G. Voskressensky

Beilstein J. Org. Chem. 2018, 14, 3078–3087, doi:10.3762/bjoc.14.287

• may be found in crolibulin, an antitumor agent, undergoing phase II clinical trials [31], chromenotacrine CT-6, a potential anti-Alzheimer agent [32], and pranoprofen, a marketed anti-inflammatory drug [33]. Combination of chromene and imidazopyridine rings led to the discovery of compound A with

Repurposing the anticancer drug cisplatin with the aim of developing novel Pseudomonas aeruginosa infection control agents

• Mingjun Yuan,
• Song Lin Chua,
• Yang Liu,
• Daniela I. Drautz-Moses,
• Joey Kuok Hoong Yam,
• Thet Tun Aung,
• Roger W. Beuerman,
• May Margarette Santillan Salido,
• Stephan C. Schuster,
• Choon-Hong Tan,
• Michael Givskov,
• Liang Yang and
• Thomas E. Nielsen

Beilstein J. Org. Chem. 2018, 14, 3059–3069, doi:10.3762/bjoc.14.284

• compounds in both academia and the pharmaceutical industry. Here, we report how the widely used antitumor drug cisplatin may be repurposed as an effective antimicrobial against the nosocomial pathogen Pseudomonas aeruginosa. Cisplatin was found to effectively kill strains of P. aeruginosa. In such

Synthesis of dihydroquinazolines from 2-aminobenzylamine: N³-aryl derivatives with electron-withdrawing groups

• Nadia Gruber,
• Jimena E. Díaz and
• Liliana R. Orelli

Beilstein J. Org. Chem. 2018, 14, 2510–2519, doi:10.3762/bjoc.14.227

• pharmacological interest. For example, vasicine is a 3,4-dihydroquinazoline alkaloid isolated from natural sources with antitumor activity [1]. Vasicine and deoxyvasicine are also potent butyrylcholinesterase (BChE) inhibitors [2]. Some synthetic derivatives containing the dihydroquinazoline scaffold have shown

Comparative cell biological study of in vitro antitumor and antimetastatic activity on melanoma cells of GnRH-III-containing conjugates modified with short-chain fatty acids

• Eszter Lajkó,
• Sarah Spring,
• Rózsa Hegedüs,
• Beáta Biri-Kovács,
• Sven Ingebrandt,
• Gábor Mező and
• László Kőhidai

Beilstein J. Org. Chem. 2018, 14, 2495–2509, doi:10.3762/bjoc.14.226

• melanoma cells was increased by [4Lys(Ac)]-GnRH-III(Dau=Aoa), while the GnRH-III(Dau=Aoa) and [4Lys(Bu)]-GnRH-III(Dau=Aoa) decreased this activity. Conclusion: Internalization and cytotoxicity of the conjugates showed that GnRH-III peptides could guard Dau to melanoma cells and promote antitumor activity

• doxorubicin (formerly known as AEZS-108 or AN-152), in which the superagonist [D-6Lys]-GnRH-I allows the tumor targeting of the traditional chemotherapeutical drug doxorubicin covalently linked via an ester bond [3][10]. However, while in the phase II trial, zoptarelin doxorubicin showed promising antitumor

• most potent one in all different assays (enzymatic stability, cellular uptake, and in vitro antitumor activity) on HT-29 colon carcinoma cell lines [19]. The different hydrophobicity of conjugates having a short, fatty acid side chain (2–6 carbon atoms) could be excluded as an explanation for their

Synergistic approach to polycycles through Suzuki–Miyaura cross coupling and metathesis as key steps

• Sambasivarao Kotha,
• Milind Meshram and
• Chandravathi Chakkapalli

Beilstein J. Org. Chem. 2018, 14, 2468–2481, doi:10.3762/bjoc.14.223

• CM by using Mo complex 6. In this regard, they assembled stilbene derivative 85 as an antitumor agent by a two-step strategy that involve catalytic CM and SM coupling. To this end, the Z-selective CM of a styrene derivative (e.g., 81) with vinyl-B(pin) 82 was realized in the presence of Mo complex 6

Strong binding and fluorescence sensing of bisphosphonates by guanidinium-modified calix[5]arene

• Jie Gao,
• Zhe Zheng,
• Lin Shi,
• Si-Qi Wu,
• Hongwei Sun and
• Dong-Sheng Guo

Beilstein J. Org. Chem. 2018, 14, 1840–1845, doi:10.3762/bjoc.14.157

• , hypercalcaemia and bone pain caused by bone metastases of malignant tumors [2][3]. In addition, BPs are increasingly considered due to their potential role in preventing and treating cancer-induced bone loss and antitumor effects [4][5]. With this regard, assays for BPs are significant for identifying the

Synthesis of spirocyclic scaffolds using hypervalent iodine reagents

• Fateh V. Singh,
• Priyanka B. Kole,
• Saeesh R. Mangaonkar and
• Samata E. Shetgaonkar

Beilstein J. Org. Chem. 2018, 14, 1778–1805, doi:10.3762/bjoc.14.152

• starting from catechol derivative 142. Marine sesquiterpenoids are mainly known for their biological importance such as antitumor, antiviral and antibiotic properties [132]. In this report, the catechol-derived starting substrate 142 was cyclized to spirocyclic product 143 in 67% yield using PIFA (31) as

Natural and redesigned wasp venom peptides with selective antitumoral activity

• Marcelo D. T. Torres,
• Gislaine P. Andrade,
• Roseli H. Sato,
• Cibele N. Pedron,
• Tania M. Manieri,
• Giselle Cerchiaro,
• Anderson O. Ribeiro,
• Cesar de la Fuente-Nunez and
• Vani X. Oliveira Jr.

Beilstein J. Org. Chem. 2018, 14, 1693–1703, doi:10.3762/bjoc.14.144

• ., Dec-NH2, [Pro]4-Dec-NH2, [Arg]1-Dec-NH2, [Phe]2-Dec-NH2 and [Phe]6-Des[Thr]11-Dec-NH2. The analogs presented similar antitumor activity in growth inhibition assays with MCF-7 breast cancer cells. Dec-NH2, Trp- and Phe-substituted analogs were described as the most hemolytic peptides of their family

β-Hydroxy sulfides and their syntheses

• Mokgethwa B. Marakalala,
• Edwin M. Mmutlane and
• Henok H. Kinfe

Beilstein J. Org. Chem. 2018, 14, 1668–1692, doi:10.3762/bjoc.14.143

• architectural extreme are: the ecteinascidins, antitumor tetrahydroisoquinoline alkaloids from the colonial Ascidian Ecteinascidia turbinata as exemplified by ecteinascidin 729 (4) [6]; ulbactins F (5a) and G (5b), two polycyclic thiazoline congeners isolated from a culture extract of a sponge derived

Anomeric modification of carbohydrates using the Mitsunobu reaction

• Julia Hain,
• Patrick Rollin,
• Werner Klaffke and
• Thisbe K. Lindhorst

Beilstein J. Org. Chem. 2018, 14, 1619–1636, doi:10.3762/bjoc.14.138

• synthesis of phyllanthostatin antitumor agents, A. B. Smith and colleagues soundly investigated the suitability of the Mitsunobu reaction [29]. They concluded already back in 1986 that “the anomeric hydroxyl group of various pyranose hemiacetals can be esterified with inversion of configuration

Glycosylation reactions mediated by hypervalent iodine: application to the synthesis of nucleosides and carbohydrates

• Yuichi Yoshimura,
• Hideaki Wakamatsu,
• Yoshihiro Natori,
• Yukako Saito and
• Noriaki Minakawa

Beilstein J. Org. Chem. 2018, 14, 1595–1618, doi:10.3762/bjoc.14.137

• , we have steadily pursued the identification of novel antitumor and antiviral nucleoside derivatives [17][20][21][22]. Matsuda and co-workers reported a 2’-substituted cytidine derivative, DMDC (1), with potent antitumor activity [23][24]. In other reports, Walker [25] and Secrist [26] independently

• promising candidates for novel antitumor agents. Thus, we designed a novel 2’-substituted 4’-thiocytidine, 4’-thioDMDC (3), as our target molecule for potential antitumor agents [27][28] (Figure 1). At the time we started our project, there had been no reports regarding the synthesis of even 2-substituted 4

Drug targeting to decrease cardiotoxicity – determination of the cytotoxic effect of GnRH-based conjugates containing doxorubicin, daunorubicin and methotrexate on human cardiomyocytes and endothelial cells

• Livia Polgár,
• Eszter Lajkó,
• Pál Soós,
• Orsolya Láng,
• Marilena Manea,
• Béla Merkely,
• Gábor Mező and
• László Kőhidai

Beilstein J. Org. Chem. 2018, 14, 1583–1594, doi:10.3762/bjoc.14.136

• cytotoxic effect on cardiomyocytes were identified. In the future, these compounds could provide a more targeted antitumor therapy with no cardiotoxic adverse effects. Moreover, impedimetric cytotoxicity analysis could be a valuable technique to determine the effect of drugs on cardiomyocytes. Keywords

• the pituitary [4]. GnRH-III (Glp-His-Trp-Ser-His-Trp-Lys-Pro-Gly-NH2, where Glp is pyroglutamic acid) is a naturally occurring isoform of GnRH, which was first isolated from sea lamprey [5]. GnRH-III has been shown to exert an effective antitumor activity against a number of tumor types [6][7][8

• technique of high interest, by which cytotoxic drugs are attached to specific molecules (homing devices) with the aim of increasing the accumulation of the drug in the specific target cells. Consequently, this leads to a more efficient antitumor effect and to the reduction of potential adverse side effects

Lanyamycin, a macrolide antibiotic from Sorangium cellulosum, strain Soce 481 (Myxobacteria)

• Lucky S. Mulwa,
• Rolf Jansen,
• Dimas F. Praditya,
• Kathrin I. Mohr,
• Patrick W. Okanya,
• Joachim Wink,
• Eike Steinmann and
• Marc Stadler

Beilstein J. Org. Chem. 2018, 14, 1554–1562, doi:10.3762/bjoc.14.132

• of which were found to exert anti-HIV activity while sorazolones, argyrins and tubulysins showed antitumor activity or cytotoxicity [4][5][6][7][8]. In our studies on the secondary metabolites of Sorangium cellulosum (strain Soce 481), we observed strong antifungal activity in the raw extract. On RP

• , nematodes, insects, immunosuppressant or with antitumor activities [12][13][14][15]. Therefore, lanyamycin (1/2) was tested in our screening panel against bacteria, fungi, mammalian cell cultures and for antiviral activity against HCV in human liver cells. Lanyamycin (1/2) was analyzed for antimicrobial

Metal-free formal synthesis of phenoxazine

• Gabriella Kervefors,
• Antonia Becker,
• Chandan Dey and
• Berit Olofsson

Beilstein J. Org. Chem. 2018, 14, 1491–1497, doi:10.3762/bjoc.14.126

• fused between two benzene rings. A range of compounds with interesting biological or photophysical properties contain the phenoxazine core, where the amine moiety is either functionalized or oxidized to the corresponding imine [1][2][3][4]. Phenoxazine derivatives can display antitumor activity [5][6][7

[3 + 2]-Cycloaddition reaction of sydnones with alkynes

• Veronika Hladíková,
• Jiří Váňa and
• Jiří Hanusek

Beilstein J. Org. Chem. 2018, 14, 1317–1348, doi:10.3762/bjoc.14.113

• -oxohexanoic acid with 4-fluoro-3-(4-methylphenyl)sydnone (Scheme 12). Unfortunately the regioselectivity of the reaction was not specified. An aryne generation (Scheme 13) was also used for the synthesis of a key intermediate of the potent antitumor PARP inhibitor – niraparib – containing an indazole core

One hundred years of benzotropone chemistry

• Arif Dastan,
• Haydar Kilic and
• Nurullah Saracoglu

Beilstein J. Org. Chem. 2018, 14, 1120–1180, doi:10.3762/bjoc.14.98

• and in a number of other natural compounds that have shown a highly diverse range of biological activity [1][2][3][4][5][6][7][8][9], like the inhibitory activity of inositol monophosphatase [10][11], antitumor [12], antibiotic [12][13], and antibacterial activity [14] and lipoxygenase inhibitor

An overview of recent advances in duplex DNA recognition by small molecules

• Sayantan Bhaduri,
• Nihar Ranjan and
• Dev P. Arya

Beilstein J. Org. Chem. 2018, 14, 1051–1086, doi:10.3762/bjoc.14.93

• a broad spectrum of in vitro and in vivo antitumor activities. Tallimustine retains the preference for A·T-rich regions in the minor groove that alkylates N3 of adenine in a highly sequence specific manner, thereby inhibiting the binding of transcription factors such as OTF-1 and NFE1 on specific AT

• reported other conjugates with two thiazoles directly linked via an amide bond, which retained activity to a lesser extent. Baraldi et al. designed and synthesized a novel conjugate 7 by combining naturally occurring antitumor agent distamycin A with the pyrrolo[2,1-c][1,4]benzodiazepine moiety (PBD

• ), related to the naturally occurring anthramycin for investigating its antitumor activity [56]. Conjugate 7 demonstrated much better activity compared to distamycin in vitro by inhibiting cell growth of neoplastic cell lines and preferentially binding to G·C-rich sequences in the minor groove. In similar

The first Pd-catalyzed Buchwald–Hartwig aminations at C-2 or C-4 in the estrone series

• Ildikó Bacsa,
• Dávid Szemerédi,
• János Wölfling,
• Gyula Schneider,
• Lilla Fekete and
• Erzsébet Mernyák

Beilstein J. Org. Chem. 2018, 14, 998–1003, doi:10.3762/bjoc.14.85

• , which may enhance the proliferation of tumor cells [31]. Effective inhibition of 17β-HSD1 may result in an antitumor effect in hormone-dependent cancers [32]. It is known that several 2- or 4-substituted estrone derivatives possess substantial 17β-HSD1 inhibitory action [19][20][33]. The presence of a

On the design principles of peptide–drug conjugates for targeted drug delivery to the malignant tumor site

• Eirinaios I. Vrettos,
• Gábor Mező and
• Andreas G. Tzakos

Beilstein J. Org. Chem. 2018, 14, 930–954, doi:10.3762/bjoc.14.80

• . evaluated the antitumor effects of AN-152 in vivo in human LHRH-R-positive HEC-1B endometrial and NIH:OVCAR-3 ovarian cancers, and in the LHRH-R-negative SK-OV-3 ovarian cancer cell line via intravenous injections [128]. The tumor volumes of HEC-1B and NIH:OVCAR-3 cancers were reduced significantly even

• antitumor activity but less toxicity with respect to the parent drugs DOX and 2-pyrrolino-DOX and can be used versus a wide variety of ovarian, prostate, endometrial and breast tumors. Notably, after the extensive evaluation of analog AN-152 in preclinical models, starting from 2006 it has been tested in

Development of novel cyclic NGR peptide–daunomycin conjugates with dual targeting property

• Andrea Angelo Pierluigi Tripodi,
• Szilárd Tóth,
• Kata Nóra Enyedi,
• Gitta Schlosser,
• Gergely Szakács and
• Gábor Mező

Beilstein J. Org. Chem. 2018, 14, 911–918, doi:10.3762/bjoc.14.78

• Vienna, Austria 10.3762/bjoc.14.78 Abstract Cyclic NGR peptides as homing devices are good candidates for the development of drug conjugates for targeted tumor therapy. In our previous study we reported that the Dau=Aoa-GFLGK(c[KNGRE]-GG-)-NH2 conjugate has a significant antitumor activity against both

• selectivity to CD13+ cells. However, the cellular uptake and cytotoxic effect of Dau=Aoa-GFLGK(c[NleNGRE]-GG-)-NH2 was higher in comparison to the control especially on HT-29 cells. Therefore, this conjugate is more suitable for drug targeting with dual targeting property. Keywords: antitumor activity; drug

• conjugates revealed substantial in vitro cytostatic/cytotoxic effects. Our results indicated that the conjugates had an antitumor effect against both CD13+ HT-1080 cells and CD13− (but integrin receptor positive) HT-29 human colon cancer cells. Moreover, we showed that the toxicity and the selectivity of the

An efficient and facile access to highly functionalized pyrrole derivatives

• Meng Gao,
• Wenting Zhao,
• Hongyi Zhao,
• Ziyun Lin,
• Dongfeng Zhang and
• Haihong Huang

Beilstein J. Org. Chem. 2018, 14, 884–890, doi:10.3762/bjoc.14.75

• in medicinal chemistry (Figure 1), such as analgesic agent 1 [1], BET bromodomain inhibitor 2 [2], selective PARP-1 inhibitor 3 [3], histone deacetylase inhibitor with antitumor activity 4 [4], Flavivirus inhibitor 5 [5], and for treating cardiovascular diseases (atorvastatin, 6) [6]. A number of

Synthesis and in vitro biochemical evaluation of oxime bond-linked daunorubicin–GnRH-III conjugates developed for targeted drug delivery

• Sabine Schuster,
• Beáta Biri-Kovács,
• Bálint Szeder,
• Viktor Farkas,
• László Buday,
• Zsuzsanna Szabó,
• Gábor Halmos and
• Gábor Mező

Beilstein J. Org. Chem. 2018, 14, 756–771, doi:10.3762/bjoc.14.64

• reported on the identification of a novel daunorubicin–GnRH-III conjugate (GnRH-III–[4Lys(Bu), 8Lys(Dau=Aoa)] with efficient in vitro and in vivo antitumor activity. To get a deeper insight into the mechanism of action of our lead compound, the cellular uptake was followed by confocal laser scanning

• cellular uptake of the bioconjugates were strongly affected by the amino acid exchange which in turn had an impact on the antitumor activity of the bioconjugates. Keywords: cytostatic effect; daunorubicin; drug-targeting; GnRH derivatives; oxime linkage; Introduction Cancer is one of the most serious

• uptake and the antitumor activity [29]. Moreover, these GnRH-III bioconjugates displayed an enhanced stability in the presence of gastrointestinal enzymes. The most potent and efficient bioconjugate which has been evaluated in in vitro cytostatic effect measurements on human breast cancer cells (MCF7

Synthesis of a sucrose-based macrocycle with unsymmetrical monosaccharides "arms"

• Karolina Tiara,
• Mykhaylo A. Potopnyk and
• Sławomir Jarosz

Beilstein J. Org. Chem. 2018, 14, 634–641, doi:10.3762/bjoc.14.50

• demonstrate antimicrobial and antitumor activities [26][27]. Results and Discussion Recently, we have prepared sucrose-based macrocyclic derivative 4 in which the terminal positions of this disaccharide (C6 and C6’) are connected via a long polyhydroxylated bridge [28]. In this model study, both terminal

Sequential Ugi reaction/base-induced ring closing/IAAC protocol toward triazolobenzodiazepine-fused diketopiperazines and hydantoins

• Robby Vroemans,
• Fante Bamba,
• Jonas Winters,
• Joice Thomas,
• Jeroen Jacobs,
• Luc Van Meervelt,
• Jubi John and
• Wim Dehaen

Beilstein J. Org. Chem. 2018, 14, 626–633, doi:10.3762/bjoc.14.49

• withdrawal, etc. [26][27][28][29][30][31][32][33][34]. In addition, these azaheterocycles also exhibit anti-inflammatory, antitumor, antiparasitic and anxiolytic activities [35][36][37][38][39][40][41][42]. In particular, 1,4-benzodiazepine derivatives are proposed to serve as a structural mimic of peptide β

Mannich base-connected syntheses mediated by ortho-quinone methides

• Petra Barta,
• Ferenc Fülöp and
• István Szatmári

Beilstein J. Org. Chem. 2018, 14, 560–575, doi:10.3762/bjoc.14.43

• are also known to undergo oligomerization in the absence of dienophiles and nucleophiles via an oxo-Diels–Alder protocol (Table 4). During the syntheses of 1,4,9,10-anthradiquinones with potential antitumor activity, Kucklaender et al. isolated new spiro derivatives 38 [77]. These latter spirocyclic

• mostly examined from the point of view of their application as DNA alkylating agents. One of the first examples was reported by Kearney et al. in 1996 about preformulation studies of the antitumor agent topotecan [91]. The antitumor activity of the compound could be explained by its degradation to highly

• phenolic Mannich bases bearing functional groups that are suitable for cross-linking DNA; therefore, their antitumor effects could also be confirmed [96]. The formation of o-QMs and their biological properties were also illustrated by kinetic studies. Rokita et al. using laser flash photolysis showed that