The preparation and properties of 1,1-difluorocyclopropane derivatives

• Kymbat S. Adekenova,
• Peter B. Wyatt and
• Sergazy M. Adekenov

Beilstein J. Org. Chem. 2021, 17, 245–272, doi:10.3762/bjoc.17.25

Synthesis of pyrrolidinedione-fused hexahydropyrrolo[2,1-a]isoquinolines via three-component [3 + 2] cycloaddition followed by one-pot N-allylation and intramolecular Heck reactions

• Xiaoming Ma,
• Suzhi Meng,
• Xiaofeng Zhang,
• Qiang Zhang,
• Shenghu Yan,
• Yue Zhang and
• Wei Zhang

Beilstein J. Org. Chem. 2020, 16, 1225–1233, doi:10.3762/bjoc.16.106

• crispine A isolated from Carduus crispus L has antitumor activity [3]. Erythrina alkaloids have curare-like neuromuscular blocking activities [4], and also antioxidant activity against DPPH free radicals [5]. Lamellarins isolated from marine invertebrates [6] are inhibitors for HIV-1 integrase and also

Synthesis and anticancer activity of bis(2-arylimidazo[1,2-a]pyridin-3-yl) selenides and diselenides: the copper-catalyzed tandem C–H selenation of 2-arylimidazo[1,2-a]pyridine with selenium

• Mio Matsumura,
• Tsutomu Takahashi,
• Hikari Yamauchi,
• Shunsuke Sakuma,
• Yukako Hayashi,
• Tadashi Hyodo,
• Tohru Obata,
• Kentaro Yamaguchi,
• Yasuyuki Fujiwara and
• Shuji Yasuike

Beilstein J. Org. Chem. 2020, 16, 1075–1083, doi:10.3762/bjoc.16.94

• of UVA-induced stress [17], and bis(2-alkylindol-3-yl) selenides III exhibit antitumor activity toward HT-1080 and MG-22A tumor cell lines [18]. The imidazo[1,2-a]pyridine ring is also an important aromatic heterocycle because its derivatives are biologically active and play an important role in

Combining enyne metathesis with long-established organic transformations: a powerful strategy for the sustainable synthesis of bioactive molecules

• Valerian Dragutan,
• Ileana Dragutan,
• Albert Demonceau and
• Lionel Delaude

Beilstein J. Org. Chem. 2020, 16, 738–755, doi:10.3762/bjoc.16.68

• highly critical parameter for their activity, while certain alterations of the side chain do not affect the cytotoxicity to a notable extent. Anthramycin In an interesting approach to the protected precursor 8 of (+)-anthramycin (8a), a compound with strong antitumor activity having a

Synthesis and biological investigation of (+)-3-hydroxymethylartemisinin

• Toni Smeilus,
• Farnoush Mousavizadeh,
• Johannes Krieger,
• Xingzhao Tu,
• Marcel Kaiser and
• Athanassios Giannis

Beilstein J. Org. Chem. 2019, 15, 567–570, doi:10.3762/bjoc.15.51

• sesquiterpene lactone is still unknown [5]. Whereas artemisinins are almost non-toxic to normal cells, several studies have confirmed their potent antitumor activity [6][7]. In addition, they have been reported to possess immunosuppressive, anti-inflammatory, antiviral, antifungal and antiparasitic activities

Synthesis of a tubugi-1-toxin conjugate by a modulizable disulfide linker system with a neuropeptide Y analogue showing selectivity for hY1R-overexpressing tumor cells

• Rainer Kufka,
• Robert Rennert,
• Goran N. Kaluđerović,
• Lutz Weber,
• Wolfgang Richter and
• Ludger A. Wessjohann

Beilstein J. Org. Chem. 2019, 15, 96–105, doi:10.3762/bjoc.15.11

• cells. Hence, these toxins primarily affect fast dividing cells, for instance all active cancer cells. Tubugis as derivatives of natural tubulysins have an almost identical antitumor activity, but are readily available and, most importantly, are chemically more inert and less degradable than native

• conjugate has a strongly masked antitumor activity against HT-29, PC-3 and Colo320 cells in comparison to the active compound alone, but the activity is restored to a sufficient extent upon linker cleavage (tubugi-1–SS–NPY → tubugi-1-SH). Most importantly, the cytotoxic potential of tubugi-1–SS–NPY

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

• 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

• , cellular uptake and weaker antitumor activity [17][19]. The increased cytostatic activity of Dau–GnRH-III conjugates acylated by a short-chain fatty acid as a “second drug” can be due to the known potential of short-chain fatty acids – especially butyric acid – to induce apoptosis in various tumor cell

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

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

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

• 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

• Table 1. The data indicated, that conjugate 1 in which Dox linked via an ester bond to the homing peptide showed the highest antitumor activity on both cell lines. The conjugates with one Dau linked through oxime linkage showed similar potency on both types of cell. Small improvement of cytostatic

• types through the whole concentration range measured. These trends correlate with the antitumor activity of the conjugates. It was also found that the dimerization of Dau containing conjugates (9–11) did not lead to a significant change in toxicity on any cardiac cell types, except conjugate {[4N-MeSer

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

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

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

• ), 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

• on the phenyl ring where the two benzimidazoles were linked via an oxygen atom. Most of these conjugates showed significant antitumor activity in vitro compared to Hoechst 33258. Amongst them, conjugate 49 (Figure 10) was found to be most potent with IC50 values of 0.56 μM for HL60 (Human

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

• 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

• different amino acids (Ala, Leu, Nle, Pro and Ser). The main goal of the present study was to investigate whether the exchange of the lysine in the cycle has any influence on the chemostability, selectivity and antitumor activity of the conjugates. Here we report on the synthesis and characterization 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

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

One-pot preparation of 4-aryl-3-bromocoumarins from 4-aryl-2-propynoic acids with diaryliodonium salts, TBAB, and Na₂S₂O₈

• Teppei Sasaki,
• Katsuhiko Moriyama and
• Hideo Togo

Beilstein J. Org. Chem. 2018, 14, 345–353, doi:10.3762/bjoc.14.22

• , it is known that 4-arylcoumarins have antitumor activity [42]. Therefore, the one-pot preparation of 4-arylcoumarins from 3-aryl-2-alkynoic acids via aryl esters and cyclization is attractive and important. Here, as part of our ongoing investigation of the synthetic use of diaryliodonium salts for

5-Aminopyrazole as precursor in design and synthesis of fused pyrazoloazines

• Ranjana Aggarwal and
• Suresh Kumar

Beilstein J. Org. Chem. 2018, 14, 203–242, doi:10.3762/bjoc.14.15

• -aminopyrazole (R = H, 16) was condensed with 38. It was attributed to cyclocondensation between 1-NH (5-aminopyrazole) and the carbonyl carbon of the enaminone. The compounds were found to have cytotoxicity against the normal fibroblast (BHK) cell line and antitumor activity against the colon cancer cell line

Vinylphosphonium and 2-aminovinylphosphonium salts – preparation and applications in organic synthesis

• Anna Kuźnik,
• Roman Mazurkiewicz and
• Beata Fryczkowska

Beilstein J. Org. Chem. 2017, 13, 2710–2738, doi:10.3762/bjoc.13.269

• -Aminobutyric acid is a major neurotransmitter used to treat epilepsy [52]. Analogs of this acid displaying antitumor activity, such as hapalosin, dolastatins, and caliculins were found in natural marine products [53][54][55]. Palacios et al. also described the Wittig reactions of 2-aminovinylphosphonium salts

Pd- and Cu-catalyzed approaches in the syntheses of new cholane aminoanthraquinone pincer-like ligands

• Nikolay V. Lukashev,
• Gennadii A. Grabovyi,
• Dmitry A. Erzunov,
• Alexey V. Kazantsev,
• Gennadij V. Latyshev,
• Alexei D. Averin and
• Irina P. Beletskaya.

Beilstein J. Org. Chem. 2017, 13, 564–570, doi:10.3762/bjoc.13.55

• ability, chromophoric properties, and antitumor activity as well [40]. We compared several CuI-based catalytic systems in the arylation of amine 3b with 4-iodotoluene as a model substrate. We found out that the CuI/L-proline combination with K2CO3 led to the target aniline 4 in excellent yield (Scheme 3

Synthesis of spiro[isoindole-1,5’-isoxazolidin]-3(2H)-ones as potential inhibitors of the MDM2-p53 interaction

• Salvatore V. Giofrè,
• Santa Cirmi,
• Raffaella Mancuso,
• Francesco Nicolò,
• Giuseppe Lanza,
• Laura Legnani,
• Agata Campisi,
• Maria A. Chiacchio,
• Michele Navarra,
• Bartolo Gabriele and
• Roberto Romeo

Beilstein J. Org. Chem. 2016, 12, 2793–2807, doi:10.3762/bjoc.12.278

• -benzylnitrone with isoindolin-3-methylene-1-ones. The regio- and stereoselectivity of the process have been rationalized by computational methods. The obtained compounds show cytotoxic properties and antiproliferative activity in the range of 9–22 μM. Biological tests suggest that the antitumor activity could

• example MI-63 and MI-219, [15][16][17][18] have demonstrated cellular activity consistent with inhibition of MDM2-p53 binding and have shown in vivo antitumor activity [15][19] (Figure 1). Isoindolinones, belonging to the alkaloids family, are found in many natural products such as vitedoamine A

• have resulted in the identification of a number of potential MDM2-p53 interaction inhibitors. Biological tests confirm our initial hypothesis indicating for compounds 3 an antiproliferative activity in the range of 9–22 μM: the antitumor activity appears to be linked to the inhibition of the protein

Biomimetic synthesis and HPLC–ECD analysis of the isomers of dracocephins A and B

• Viktor Ilkei,
• András Spaits,
• Anita Prechl,
• Áron Szigetvári,
• Zoltán Béni,
• Miklós Dékány,
• Csaba Szántay Jr,
• Judit Müller,
• Árpád Könczöl,
• Ádám Szappanos,
• Attila Mándi,
• Sándor Antus,
• Ana Martins,
• Attila Hunyadi,
• György Tibor Balogh,
• György Kalaus (†),
• Hedvig Bölcskei,
• László Hazai and
• Tibor Kurtán

Beilstein J. Org. Chem. 2016, 12, 2523–2534, doi:10.3762/bjoc.12.247

• towards CNS cytotoxic activity on undifferentiated SH-SY5Y neuroblastoma cells. None of the two isomeric compounds exerted cytotoxicity on this cell line (IC50 > 150 μM for both compounds), which rules out their potential CNS antitumor activity and it also suggests them as non-neurotoxic substances. On