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

• substituent (3-quinolinyl nitrogen forming a hydrogen bond with a guanine amino group at the base of the minor groove) and a low pKa tail group. This drug was further selected for the treatment of Gram-positive bacteria Clostridium difficile infections and is currently in the phase II clinical trials

• MGBs is their preference for narrow A·T-rich regions compared to G·C regions because (i) they can form hydrogen bonds to N3 of adenine and O2 of thymine in the A·T region; (ii) less steric hindrance in the A·T region in comparison to the G·C region due to the presence of an extra protruding C2-amino

• group of the guanine base [19]. 2.1. Polypyrroles and polyamides The first two MGBs discovered were distamycin A and netropsin (Figure 3). These naturally occurring molecules are characterized by repeating N-methylpyrrole units with one or more positively charged nitrogen atoms at the end. Their concave

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

• -aminated estrone derivatives are described as inhibitors of estrogen biosynthesis. They are often synthesized via a three-step method including nitration, reduction, and functionalization of the amino group [1][2]. This three-step protocol may be simplified to involve only one or two steps by the

• ]. Thus 13α-estrone is a suitable compound for the development of biologically active steroids lacking estrogenicity. Literature reveals that besides the inversion of C-13, the introduction of an amino group onto C-2 or C-4 of estrone also leads to significant decreases in its binding affinity for nuclear

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

• ]. This type of linkers/spacers offers the capability to release the active drug after simultaneous cascade reactions, as shown in Figure 5. Para-amino benzyl alcohol (PABC; colored in red) is a representative example that can be connected in the amino group via an amide bond to an enzyme-hydrolyzable

• -amino group of the D-Lys side chain of the peptide D-Lys6-LHRH. Notably, both conjugates fully preserved the cytotoxic activity of the parent drugs, DOX or 2-pyrrolino-DOX, respectively, in vitro and also retained the high binding affinity of their peptide carrier to receptors for LHRH on rat pituitary

• on its building block 2-pyrrolino-DOX and tried to construct new PDCs using other peptides. Therefore, they synthesized a new analog, designated AN-238, consisting of the octapeptide RC-121 linked through the α-amino group of its N-terminal D-Phe moiety and a glutaric acid spacer to the 14-OH group

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

• CD13+ HT-1080 human fibrosarcoma and CD13− but integrin positive HT-29 human colon adenocarcinoma cells. However, it seems that the free ε-amino group of Lys in the cycle is not necessary for the biological activity. Therefore, we developed novel cyclic NGR peptide–daunomycin conjugates in which Lys

• homing devices may provide dual targeted delivery of anticancer drugs. According to literature data, one of the most stable and tumor-selective cyclic NGR-peptides is c[KNGRE]-NH2, in which the α-amino group of the N-terminal Lys is coupled to the γ-carboxyl group of the glutamic acid residue (head-to

• the use of orthogonal protecting groups (Figure 1A). Previous studies indicated that the free ε-amino group of Lys does not have an impact on the biological activity [15][17]. To prove our assumption, a set of novel cyclic NGR peptide–Dau conjugates were developed in which the Lys was replaced by

Phosphodiester models for cleavage of nucleic acids

• Satu Mikkola,
• Tuomas Lönnberg and
• Harri Lönnberg

Beilstein J. Org. Chem. 2018, 14, 803–837, doi:10.3762/bjoc.14.68

• transfer from the attacking 2´-OH to non-bridging phosphoryl oxygen. Primary amines are, in turn, used to mimic the action of the ε-amino group of lysine. Both guanidine and primary amino groups are basic functions that at physiological pH are present as guanidinium and ammonium ions. These ions tend to

• reduce electron density in their vicinity, inductively through bonds and electrostatically through space, or they may serve as weak general acids. The guanidine group may additionally participate in proton shuttling through various tautomeric forms [75] and the amino group through bifurcated H-bonds. The

• the lysine ε-amino group in the catalytic center of RNase A has been elucidated by incorporating an amino group covalently in the vicinity of the scissile phosphodiester linkage of the model compound. For this purpose, compound 12a bearing two aminomethyl groups at C4´ was prepared and its reactions

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

• preclinical and clinical studies, was zoptarelin-doxorubicin also known as AEZS-108 (previously AN-152) [16]. The anthracycline doxorubicin was conjugated to the ε-amino group of GnRH-I-[6D-Lys] by insertion of a glutaric acid linker. The resulting ester bond can be cleaved by carboxylesterases, leading to

• antiproliferative activity. Furthermore, the absence of the free ε-amino group additionally reduced the endocrine effect [23][24]. Thus, the 8Lys can be utilized as conjugation site for cytotoxic agents like anthracyclines. In the past decade, a variety of different linkage systems has been carried out including

• breast adenocarcinoma cancer cells (MCF-7) and on hormone independent human colon carcinoma cells (HT-29) were analyzed [22][25][27][28]. Thereby, it has been exposed, that an exchange of 4Ser by 4Lys followed by acylation of the ε-amino group with short chain fatty acids (SCFA) improved the cellular

Enzyme-free genetic copying of DNA and RNA sequences

• Marilyne Sosson and
• Clemens Richert

Beilstein J. Org. Chem. 2018, 14, 603–617, doi:10.3762/bjoc.14.47

• arrangement became the most common way of performing the reaction [17][18][19][20]. In this brief account we will focus on primer extension reactions on DNA and RNA templates. The copying of DNA sequences is usually performed with primers terminating in a 3'-amino-2',3'-dideoxynucleoside. The amino group is

Investigations towards the stereoselective organocatalyzed Michael addition of dimethyl malonate to a racemic nitroalkene: possible route to the 4-methylpregabalin core structure

• Denisa Vargová,
• Rastislav Baran and
• Radovan Šebesta

Beilstein J. Org. Chem. 2018, 14, 553–559, doi:10.3762/bjoc.14.42

• amine 9 to compound 11 in two steps. However, under microwave heating conditions, both couplings of the amino group with squarate, as well as methoxymethyl (MOM) deprotection was observed. To the best of our knowledge, there is no report describing methanolysis of MOM-groups under microwave conditions

Stimuli-responsive oligonucleotides in prodrug-based approaches for gene silencing

• Françoise Debart,
• Christelle Dupouy and
• Jean-Jacques Vasseur

Beilstein J. Org. Chem. 2018, 14, 436–469, doi:10.3762/bjoc.14.32

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

• formed by addition from the less sterically hindered amino group. The free amino group was alkylated by reductive amination on reaction with substituted aldehyde or ketones to provide the corresponding pyrazolo[1,5-a]pyrimidine derivatives 139 (Scheme 39). The pyrazolo[1,5-a]pyrimidine derivatives 139

• ) with high regioselectivity without any traces of other possible regioisomeric pyrazolo[1,5-a]pyrimidines 169. The regioselectivity of the reaction was attributed to the higher nucleophilicity of the exocyclic primary amino group over the endocyclic amino group. Synthesis of pyrazolo[1,5-a]pyrimidine

Progress in copper-catalyzed trifluoromethylation

• Guan-bao Li,
• Chao Zhang,
• Chun Song and
• Yu-dao Ma

Beilstein J. Org. Chem. 2018, 14, 155–181, doi:10.3762/bjoc.14.11

• . The amino group can be easily transformed into numerous functional groups including halides or cyano groups, which is known as the Sandmeyer reaction. This transformation contained two steps: Diazotization of aromatic amines led to aryldiazonium salt, followed by conversion of diazonium group into

Aminosugar-based immunomodulator lipid A: synthetic approaches

• Alla Zamyatina

Beilstein J. Org. Chem. 2018, 14, 25–53, doi:10.3762/bjoc.14.3

• DBU to provide a free amino group, the 2’-NH2 and 3-OH groups could be differentiated in the next acylation step by using DCC as activating agent for the N-acylation, and Steglich reaction conditions (DCC and DMAP) for the O-acylation. Following removal of the Alloc protecting group was readily

• group was acylated with myristoyl chloride. Reduction of the 2-azido group by treatment with Zn in acetic acid followed by acylation of the amino group under standard conditions gave hexaacylated intermediate 7. The α-glycosyl phosphate was stereoselectively introduced by first, cleavage of the anomeric

• separation of the anomeric α/β mixture furnished the anomerically pure trisaccharide 15. Next, three acyl residues were introduced at positions 2’, 3’ and 3 by successive deprotection–acylation sequence. The N-Fmoc protecting group was removed using DBU and the resulting free amino group was acylated with (R

The photodecarboxylative addition of carboxylates to phthalimides as a key-step in the synthesis of biologically active 3-arylmethylene-2,3-dihydro-1H-isoindolin-1-ones

• Ommid Anamimoghadam,
• Saira Mumtaz,
• Anke Nietsch,
• Gaetano Saya,
• Cherie A. Motti,
• Jun Wang,
• Peter C. Junk,
• Ashfaq Mahmood Qureshi and
• Michael Oelgemöller

Beilstein J. Org. Chem. 2017, 13, 2833–2841, doi:10.3762/bjoc.13.275

• [41], followed by amination [42] furnishes the desired target compounds. The amino group is introduced in the final step as it would otherwise interfere with the desired photoreaction. In fact, amines are very potent electron donors and are easily oxidized by the excited phthalimide chromophore [43

CF₃SO₂X (X = Na, Cl) as reagents for trifluoromethylation, trifluoromethylsulfenyl-, -sulfinyl- and -sulfonylation. Part 1: Use of CF₃SO₂Na

• Hélène Guyon,
• Hélène Chachignon and
• Dominique Cahard

Beilstein J. Org. Chem. 2017, 13, 2764–2799, doi:10.3762/bjoc.13.272

• authors studied the effect of structural variations in the substrate (R1 = aryl, heteroaryl, alkyl; R2 = H, 6-OMe, 2-Me). Aniline amides gave no conversion nor did quinoline having an ester group at the 8 position instead of the 8-amino group. The chitosan-based copper catalyst was efficiently reused in

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

• synthesis of resonance-stabilized phosphorus ylides 81 (Scheme 51). The obtained ylides underwent further cyclization by the intramolecular acylation of the primary amino group to give the final bicyclic products 82 in 85–90% yields [67]. The synthesis of resonance-stabilized phosphorus ylides via the

Development of a fluorogenic small substrate for dipeptidyl peptidase-4

• Futa Ogawa,
• Masanori Takeda,
• Kanae Miyanaga,
• Keita Tani,
• Ryuji Yamazawa,
• Kiyoshi Ito,
• Atsushi Tarui,
• Kazuyuki Sato and
• Masaaki Omote

Beilstein J. Org. Chem. 2017, 13, 2690–2697, doi:10.3762/bjoc.13.267

• reactions of (E)-trimethyl-(3,3,3-trifluoroprop-1-enyl)silane and iodoanilines. This straightforward method is useful for TFPE introduction and a broad range of iodoanilines can be used without protection of the amino group. We used this approach to synthesize several aniline derivatives containing TFPE

• different, ideally, non-fluorescence and intensive fluorescence, respectively. On the basis of the structural features of 1, we expected that its fluorescence would disappear as a result of peptide derivatization of the amino group, because electron donation by the amino group would be attenuated and the

• -protected glycine was condensed with proline methyl ester under microwave irradiation. Subsequent hydrolysis of the ester gave N-protected Gly-Pro-OH (6). Condensation of dipeptide 6 with 1 was achieved using the corresponding acid chloride. Deprotection of the amino group was achieved by treatment with

Recent progress in the racemic and enantioselective synthesis of monofluoroalkene-based dipeptide isosteres

• Myriam Drouin and
• Jean-François Paquin

Beilstein J. Org. Chem. 2017, 13, 2637–2658, doi:10.3762/bjoc.13.262

• . This was then converted into a protected amino group employing a Mitsunobu reaction. Finally, removal of the nosyl group, followed by hydrolysis using lithium hydroxide, afforded the targeted isostere 24. Sano and co-workers also worked on the Mg(II)-promoted stereoselective synthesis of (Z

A novel synthetic approach to hydroimidazo[1,5-b]pyridazines by the recyclization of itaconimides and HPLC–HRMS monitoring of the reaction pathway

• Dmitry Yu. Vandyshev,
• Khidmet S. Shikhaliev,
• Andrey Yu. Potapov,
• Michael Yu. Krysin,
• Fedor I. Zubkov and
• Lyudmila V. Sapronova

Beilstein J. Org. Chem. 2017, 13, 2561–2568, doi:10.3762/bjoc.13.252

• -addition by the activated C=C double bond and subsequent intramolecular recyclization of the intermediate with the amino group involved. Keywords: cascade reaction; diaminoimidazoles; HPLC–HRESIMS; imidazo[1,5-b]pyridazines; itaconimides; Introduction Among the numerous bicyclic fused imidazole

• -b][1,2]diazepines 10, respectively, can be obtained. As a result of the initial addition of diaminoimidazole 4 as a 1,4-N,N-dinucleophile, intermediates 6 and 7 could be formed, whose heterocyclization with a second amino group could lead to imidazotriazepines 11 and 13 or imidazotriazocines 12 and

• aminoazole systems containing an amino group at the second position of the cycle [43]. The heterocyclization of intermediate 6 involving the C5 atom of the imidazole is improbable (not shown in the Scheme 5). The key criterion for the choice of the structure of the compounds obtained is the presence of the

Sulfation and amidinohydrolysis in the biosynthesis of giant linear polyenes

• Hui Hong,
• Markiyan Samborskyy,
• Katsiaryna Usachova,
• Katharina Schnatz and
• Peter F. Leadlay

Beilstein J. Org. Chem. 2017, 13, 2408–2415, doi:10.3762/bjoc.13.238

• difference expected between the cle and the med clusters was the presence of an essential amidinohydrolase gene, encoding an enzyme that would act at a late stage in the pathway to unmask the primary amino group of the mediomycins, as we have previously described for the biosynthesis of aminomarginolactone

Synthesis, effect of substituents on the regiochemistry and equilibrium studies of tetrazolo[1,5-a]pyrimidine/2-azidopyrimidines

• Elisandra Scapin,
• Paulo R. S. Salbego,
• Caroline R. Bender,
• Alexandre R. Meyer,
• Anderson B. Pagliari,
• Tainára Orlando,
• Geórgia C. Zimmer,
• Clarissa P. Frizzo,
• Helio G. Bonacorso,
• Nilo Zanatta and
• Marcos A. P. Martins

Beilstein J. Org. Chem. 2017, 13, 2396–2407, doi:10.3762/bjoc.13.237

• efficient and regioselective synthesis of pyrazolo[1,5-a]pyrimidines and aryl[heteroaryl]pyrazolo[1,5-a]pyrimidines in acetic acid under reflux. The regioselectivity was attributed to the high nucleophilicity of the amino group in 3-amino-5-methyl-1H-pyrazole and the high electrophilicity of the β-carbon

• CF3 can be found at the β-carbon C3 (Figure 2a). Under acidic conditions, in which the reactions were performed, C1 is the carbon with the highest LUMO coefficient (0.235) when R = phenyl (Figure 2b). Consequently, the first nucleophilic attack from the amino group of 5-aminotetrazole occurs at C1

• 5h. The first nucleophilic attack from the amino group of 5-aminotetrazole was evidenced by HOMO coefficient calculations (Table S3 in Supporting Information File 1). The highest HOMO coefficient for the NH2 group indicates the superior nucleophilicity of the NH2 group in the aminotetrazole molecule

Homologated amino acids with three vicinal fluorines positioned along the backbone: development of a stereoselective synthesis

• Raju Cheerlavancha,
• Ahmed Ahmed,
• Yun Cheuk Leung,
• Aggie Lawer,
• Qing-Quan Liu,
• Marina Cagnes,
• Hee-Chan Jang,
• Xiang-Guo Hu and
• Luke Hunter

Beilstein J. Org. Chem. 2017, 13, 2316–2325, doi:10.3762/bjoc.13.228

• trifluoroalkane 40b (Scheme 4) [17]. Trifluoroalkanes 40a and 40b (Scheme 4) were advanced intermediates along the route towards the target trifluorinated amino acids (6). To complete the synthesis, the final requirements were to oxidise the aryl moiety into a carboxylic acid, and to deprotect the amino group

Diosgenyl 2-amino-2-deoxy-β-D-galactopyranoside: synthesis, derivatives and antimicrobial activity

• Henryk Myszka,
• Patrycja Sokołowska,
• Agnieszka Cieślińska,
• Andrzej Nowacki,
• Maciej Jaśkiewicz,
• Wojciech Kamysz and
• Beata Liberek

Beilstein J. Org. Chem. 2017, 13, 2310–2315, doi:10.3762/bjoc.13.227

• ]. Modifications of the amino group in this synthetic saponin led to analogs with promising antitumor, antifungal and antibacterial activities [24][25][26][27][28][29][30][31]. In this paper, for the first time, syntheses of diosgenyl 2-amino-2-deoxy-β-D-galactopyranoside, its hydrochloride as well as N-acyl, 2

• . This procedure removes the TCP and acetyl protecting groups in a one-pot reaction and yields diosgenyl 2-amino-2-deoxy-β-D-galactopyranoside (4). Saponin 4 treated with the HCl in MeOH was converted into hydrochloride 5. To explore the influence of different modifications of the amino group in 4 on its

• isocyanate (10) with the amino group of 4. Isocyanate was added to the 1:1 (v/v) chloroform–methanol solution of 4 and Et3N each time. The yields of these reactions were very good (90% for 8) or good (60% for 9). However, phenylurea derivative 10 was isolated with only 34% yield, and the formation of various

A mechanochemical approach to access the proline–proline diketopiperazine framework

• Nicolas Pétry,
• Hafid Benakki,
• Eric Clot,
• Pascal Retailleau,
• Farhate Guenoun,
• Fatima Asserar,
• Chakib Sekkat,
• Thomas-Xavier Métro,
• Jean Martinez and
• Frédéric Lamaty

Beilstein J. Org. Chem. 2017, 13, 2169–2178, doi:10.3762/bjoc.13.217

• ). Pyrrolidine cis-11 is an N-protected amino ester, which can be used in the synthesis of diketopiperazines by deprotecting either the amino group or the ester function. Hydrogenolysis of the benzyl group of cis-11 provided the nitrogen-free pyrrolidine derivative 12 in excellent yield and purity after

High-speed vibration-milling-promoted synthesis of symmetrical frameworks containing two or three pyrrole units

• Marco Leonardi,
• Mercedes Villacampa and
• J. Carlos Menéndez

Beilstein J. Org. Chem. 2017, 13, 1957–1962, doi:10.3762/bjoc.13.190

• hydrogen bonding, which would be disrupted in the alternative conditions involving the use of methanol as solvent. The scope of the method is summarized in Figure 1. In some cases (compounds 1a–g) the spacer was simply a polymethylene chain, but the inclusion of spacer chains containing an amino group (1h

• ), piperazine (1i,j) or tetramethyldisiloxane (1k–o) fragments, was also feasible. Interestingly, the use of N1-(2-aminoethyl)ethane-1,2-diamine as the starting material was also possible, without interference from the secondary amino group in spite of its nucleophilicity, to give compound 1h. This kind of

Mechanochemical synthesis of thioureas, ureas and guanidines

• Vjekoslav Štrukil

Beilstein J. Org. Chem. 2017, 13, 1828–1849, doi:10.3762/bjoc.13.178

• patterns observed experimentally. The FMO analysis of 19b showed more electron density on the sulfur atom compared to the nitrogen of the amino group in the highest occupied molecular orbital (HOMO−1). In contrast, the coefficient was larger on the NH2 nitrogen atom in HOMO−1 of mono-urea 36 thus making it

• hydantoins. The in situ basic conditions, necessary for the deprotonation of the amino acid methyl ester hydrochloride salts in order to make the amino group nucleophilic, were generated by the hydrolysis of KOCN. Following the addition reaction with KOCN starting from hydrochloride salts of L-phenylalanine