Enolates ambushed – asymmetric tandem conjugate addition and subsequent enolate trapping with conventional and less traditional electrophiles

• Péter Kisszékelyi and
• Radovan Šebesta

Beilstein J. Org. Chem. 2023, 19, 593–634, doi:10.3762/bjoc.19.44

• successfully treated by artemisinin combination therapy (ACT). Artemisinin can be isolated from the Artemisia annua (sweet wormwood) plant. This sesquiterpene lactone bearing a peroxide is a prodrug of the biologically active dihydroartemisinin. In 2012, Zhu and Cook developed a gram-scale asymmetric total

Combretastatins D series and analogues: from isolation, synthetic challenges and biological activities

• Jorge de Lima Neto and
• Paulo Henrique Menezes

Beilstein J. Org. Chem. 2023, 19, 399–427, doi:10.3762/bjoc.19.31

• the obtained phosphoric acid derivative with a series of bases led to the formation of different phosphate salts 184–187 (Scheme 35) [55]. The authors observed that the prodrug salts had substantially improved solubility in water, an important feature for transport to metastatic cancer (Table 3) [75

• to be inactive indicating that the olefin was necessary for cancer cell growth inhibition. For salts 184–187, the authors attributed the decrease in the activity to the lack of phosphatases necessary for the cleavage of the prodrug ester bond and needed to regenerate the drug in the isolated cancer

• -workers [69]. Synthesis of isocorniculatolide B (10) and hydroxyisocorniculatolide B 175 by Kim and co-workers [71]. Synthesis of compound 9, 178, and 11 by Kim and co-workers [71]. Synthesis of combretastatin D-2 prodrug salts [55]. Results from cytotoxicity assays of combretastatin D-3 (3) and D-4 (4

New triazole-substituted triterpene derivatives exhibiting anti-RSV activity: synthesis, biological evaluation, and molecular modeling

• Elenilson F. da Silva,
• Krist Helen Antunes Fernandes,
• Denise Diedrich,
• Jessica Gotardi,
• Marcia Silvana Freire Franco,
• Carlos Henrique Tomich de Paula da Silva,
• Ana Paula Duarte de Souza and
• Simone Cristina Baggio Gnoatto

Beilstein J. Org. Chem. 2022, 18, 1524–1531, doi:10.3762/bjoc.18.161

• with COVID-19 precautions; however, they state that less RSV cases now could reduce immunity and they fear there will be a rebound in infections after the pandemic [4][5][6][7]. As a therapeutic resource, ribavirin, a nucleoside analog prodrug containing a 1,2,4-triazole-3-carboxamide moiety (RBV

On drug discovery against infectious diseases and academic medicinal chemistry contributions

• Yves L. Janin

Beilstein J. Org. Chem. 2022, 18, 1355–1378, doi:10.3762/bjoc.18.141

Synthesis and late stage modifications of Cyl derivatives

• Phil Servatius and
• Uli Kazmaier

Beilstein J. Org. Chem. 2022, 18, 174–181, doi:10.3762/bjoc.18.19

• naturally occurring HDAC inhibitors contain sulfur moieties like, e.g., disulfides or thioesters. They seem to lack a zinc-chelating group at first sight, but the disulfide or thioester acts as a prodrug and are reduced/cleaved in vivo to liberate the free thiol, a strong Zn-binding group [24][25]. Results

• reactions. The chain length in 14 should generally be suitable for effective HDAC inhibition and the thioester moiety might act as a prodrug as described for the natural HDAC inhibitor largazole. Further investigations are currently in progress. Naturally occurring HDAC inhibitors. Naturally occurring HDAC

Synthetic strategies toward 1,3-oxathiolane nucleoside analogues

• Umesh P. Aher,
• Dhananjai Srivastava,
• Girij P. Singh and
• Jayashree B. S

Beilstein J. Org. Chem. 2021, 17, 2680–2715, doi:10.3762/bjoc.17.182

• nucleoside 97 (Scheme 42). Unfortunately, the introduction of a tetrazole ring to the oxathiolane moiety did not result in any anti-HIV activity and higher cytotoxicity. The synthesis of N4-substituted analogue 99 of 2',3'-dideoxy-3'-thiacytosine was discovered by Camplo et al. (Scheme 43) [77]. The prodrug

A recent overview on the synthesis of 1,4,5-trisubstituted 1,2,3-triazoles

• Pezhman Shiri,
• Ali Mohammad Amani and
• Thomas Mayer-Gall

Beilstein J. Org. Chem. 2021, 17, 1600–1628, doi:10.3762/bjoc.17.114

• fully decorated triazoles 53 (Scheme 18a). A research group reported a novel polymer 56 functionalized by doxorubicin (DOX). To produce this prodrug, cyclooctyne-derivatized doxorubicin 55 was grafted on an azide-functionalized polymer 54. In the final step of the construction of this prodrug, the

• after the support of DOX molecules on the polymer prodrug, which resulted in reduced side effects (Scheme 18b) [48][49]. Cu-catalyzed synthesis of fully decorated triazoles The Cu-catalyzed regioselective cyclization of alkynes 57 and azides 58, followed by coupling with propargylic carbonates 59

β-Lactamase inhibition profile of new amidine-substituted diazabicyclooctanes

• Zafar Iqbal,
• Lijuan Zhai,
• Yuanyu Gao,
• Dong Tang,
• Xueqin Ma,
• Jinbo Ji,
• Jian Sun,
• Jingwen Ji,
• Yuanbai Liu,
• Rui Jiang,
• Yangxiu Mu,
• Lili He,
• Haikang Yang and
• Zhixiang Yang

Beilstein J. Org. Chem. 2021, 17, 711–718, doi:10.3762/bjoc.17.60

• ][21]. Of note, these combinations are not effective against class B metallo-lactamases and most of class D (OXA) β-lactamases. Therefore, several other DBO-based BLIs [17], such as durlobactam, nacubactam [22], zidebactam, ETX0282, ARX-1796 (a prodrug of avibactam) [23], and WCK 4234 [18][24] are

Synthesis of 4-amino-5-fluoropyrimidines and 5-amino-4-fluoropyrazoles from a β-fluoroenolate salt

• Tobias Lucas,
• Jule-Philipp Dietz and
• Till Opatz

Beilstein J. Org. Chem. 2020, 16, 445–450, doi:10.3762/bjoc.16.41

• nucleoside analogues which can either act as antimetabolites or as nucleoside reverse transcriptase inhibitors (NRTIs). Two of the most common 5-fluoropyrimidines are the cytostatic 5-fluorouracil (1) [27] and the antimycotic prodrug 5-fluorocytosine (2) [28][29], which is also part of the anti-HIV agents

Reversible photoswitching of the DNA-binding properties of styrylquinolizinium derivatives through photochromic [2 + 2] cycloaddition and cycloreversion

• Sarah Kölsch,
• Heiko Ihmels,
• Jochen Mattay,
• Norbert Sewald and
• Brian O. Patrick

Beilstein J. Org. Chem. 2020, 16, 111–124, doi:10.3762/bjoc.16.13

• an otherwise inactive substrate (prodrug) because light is noninvasive, traceless, and easy to apply, and it enables local and temporal control [14]. To this end, photochromic systems appear to be highly attractive as a basis for photocontrollable substrates because they allow to switch the

Archangelolide: A sesquiterpene lactone with immunobiological potential from Laserpitium archangelica

• Silvie Rimpelová,
• Michal Jurášek,
• Lucie Peterková,
• Jiří Bejček,
• Vojtěch Spiwok,
• Miloš Majdl,
• Michal Jirásko,
• Miloš Buděšínský,
• Juraj Harmatha,
• Eva Kmoníčková,
• Pavel Drašar and
• Tomáš Ruml

Beilstein J. Org. Chem. 2019, 15, 1933–1944, doi:10.3762/bjoc.15.189

• trigger programmed cell death prompted the development of mipsagargin/G202 [5], a thapsigargin-derived prodrug that completed phase-I and phase-II clinical trials [6] for several types of solid tumors. The structurally similar compound 2 was found to act by the same mechanism in cells as thapsigargin [7

An improved synthesis of adefovir and related analogues

• David J. Jones,
• Eileen M. O’Leary and
• Timothy P. O’Sullivan

Beilstein J. Org. Chem. 2019, 15, 801–810, doi:10.3762/bjoc.15.77

• the versatility of our approach. Keywords: acyclic nucleoside phosphonate; adefovir; alkylation; antiviral; N-alkylation; purine; Introduction The acyclic nucleoside phosphonate adefovir (1) [1], administered as its dipivoxil prodrug form (2) [2], is used clinically for the treatment of infections

• investigational prodrug strategies is typically measured by derivatising proven therapeutics such as adefovir and comparing the properties of the resulting compounds to the parent substrate [15][19][20][21][22][23][24][25][26][27][28][29][30]. Additionally, the solid state and spectroscopic properties of adefovir

• incorporation of an amidine moiety allows for regioselective alkylations with 14 and facilitates the synthesis of novel N7-substituted adefovir analogues. Adefovir (1) and its prodrug 2. Retrosynthetic analysis of 6 to synthons 9 and 10. Retrosynthesis of 6 to synthons 14 and 3. HMBC spectrum confirms N7

Homo- and hetero-difunctionalized β-cyclodextrins: Short direct synthesis in gram scale and analysis of regiochemistry

• Gábor Benkovics,
• Mihály Bálint,
• Éva Fenyvesi,
• Erzsébet Varga,
• Szabolcs Béni,
• Konstantina Yannakopoulou and
• Milo Malanga

Beilstein J. Org. Chem. 2019, 15, 710–720, doi:10.3762/bjoc.15.66

• drug carriers, incorporating two different groups, for example a targeting unit and a prodrug, pseudoenantiomeric purity is not required, but the side-selective substitution has to be ensured. This has led us to develop a versatile and simple synthetic route towards difunctionalized β-CD, carrying non

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

• Dau) had a synergistic effect with histone deacetylase inhibitors (e.g., prodrug of butyric acid) in several malignant cell lines [38]. This finding could also be a possible explanation for the increased cytotoxic effect of the conjugates containing acylated Lys compared to the parent one. Involvement

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

Mechanochemistry of nucleosides, nucleotides and related materials

• Olga Eguaogie,
• Joseph S. Vyle,
• Patrick F. Conlon,
• Manuela A. Gîlea and
• Yipei Liang

Beilstein J. Org. Chem. 2018, 14, 955–970, doi:10.3762/bjoc.14.81

• both solvent and energy input are particularly relevant in fine chemical manufacturing processes which typically have very high E-factors and low energy efficiency [37]. Although mechanochemistry was not involved in redesigning the synthesis of the antiviral prodrug ganciclovir (Figure 2), the high

• crystal polymorphs of the antiviral nucleoside prodrug clevudine were characterised and a large scale preparation of the most stable form from commercial material was performed using LAG in a mortar [91]. Geckeler and co-workers described the efficient preparation of both multi-walled and single-walled

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

• prodrug with enhanced plasma stability and/or cell permeability [27] and in the same time diminished toxicity for normal cells; c) covalent attachment of a drug on a tumor-targeting element (small molecule, peptide or antibody) able to selectively target and permeate cancer cells. The conjugation is being

Recent advances in synthetic approaches for medicinal chemistry of C-nucleosides

• Kartik Temburnikar and
• Katherine L. Seley-Radtke

Beilstein J. Org. Chem. 2018, 14, 772–785, doi:10.3762/bjoc.14.65

• it to the masked monophosphates (10 and 11, Figure 7C), which serves to facilitate transport into the infected cells, and conversion to the active triphosphate form, thereby leading to high and persistent levels [63][64][65]. The 2-ethylbutyl L-alanine phosphoramidate prodrug (Sp isomer, GS-5734, 11

• ) increases the loading of macrophages derived from human monocytes over its unmasked analogue [64]. It was also observed that intravenous administration of the prodrug leads to increased liver loading (as the triphosphate) in hamsters compared to oral dosing [63]. Draffan et al. synthesized a series of 2'-β

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

• and some of them have been successful. Moreover, in the search for an alternative way to make efficient ON-based drugs, the general concept of prodrugs was applied to the oligonucleotide field. A prodrug is defined as a compound that undergoes transformations in vivo to yield the parent active drug

• under different stimuli. The interest in stimuli-responsive ONs for gene silencing functions has been notable in recent years. The ON prodrug strategies usually help to overcome limitations of natural ONs due to their low metabolic stability and poor delivery. Nevertheless, compared to permanent ON

• modifications, transient modifications in prodrugs offer the opportunity to regulate ON activity as a function of stimuli acting as switches. Generally, the ON prodrug is not active until it is triggered to release an unmodified ON. However, as it will be described in some examples, the opposite effect can be

Strategies toward protecting group-free glycosylation through selective activation of the anomeric center

• A. Michael Downey and
• Michal Hocek

Beilstein J. Org. Chem. 2017, 13, 1239–1279, doi:10.3762/bjoc.13.123

Kinetic analysis of mechanoradical formation during the mechanolysis of dextran and glycogen

• Naoki Doi,
• Yasushi Sasai,
• Yukinori Yamauchi,
• Tetsuo Adachi,
• Masayuki Kuzuya and
• Shin-ichi Kondo

Beilstein J. Org. Chem. 2017, 13, 1174–1183, doi:10.3762/bjoc.13.116

• prodrugs produced as a prototype [19]. However, HEC is not metabolized by humans. Therefore if one could use a polymer metabolized by humans, such as Dx or glycogen (Gly), a promising graft polymeric prodrug could be obtained through a mechanochemical reaction in a totally dry process. It is necessary to

• elucidate the structure and stability of mechanoradicals of Dx and Gly as a pre-screening test for the development of such a graft polymeric prodrug. However, to our knowledge, there are no reports describing the formation of Dx or Gly mechanoradicals at room temperature. In this paper we discuss the

Novel β-cyclodextrin–eosin conjugates

• Gábor Benkovics,
• Damien Afonso,
• András Darcsi,
• Szabolcs Béni,
• Sabrina Conoci,
• Éva Fenyvesi,
• Lajos Szente,
• Milo Malanga and
• Salvatore Sortino

Beilstein J. Org. Chem. 2017, 13, 543–551, doi:10.3762/bjoc.13.52

• diffuses in the cellular environment over short distances (few tens of nm) resulting in negligible systemic side effects. For PDT applications CDs have been conjugated with porphyrin [7] and protoporphyrin (5-aminolevulinic acid) [8] in order to enhance the membrane penetration of the PS (or its prodrug

Synthesis of a deuterated probe for the confocal Raman microscopy imaging of squalenoyl nanomedicines

• Eric Buchy,
• Branko Vukosavljevic,
• Maike Windbergs,
• Dunja Sobot,
• Camille Dejean,
• Simona Mura,
• Patrick Couvreur and
• Didier Desmaële

Beilstein J. Org. Chem. 2016, 12, 1127–1135, doi:10.3762/bjoc.12.109

• triterpene, to a drug led to the formation of a prodrug that spontaneously self-assembled as nanoparticles in water. The advantage of this approach is a very high drug loading into the nanoparticles and the absence of burst release [5]. The proof of concept of this method has been done using gemcitabine (2

Effective in silico prediction of new oxazolidinone antibiotics: force field simulations of the antibiotic–ribosome complex supervised by experiment and electronic structure methods

• Jörg Grunenberg and
• Giuseppe Licari

Beilstein J. Org. Chem. 2016, 12, 415–428, doi:10.3762/bjoc.12.45

• potency both in vitro and in vivo antibacterial activities [46]. Candidate 7 represents the active form of the prodrug torezolid, the phosphate disodium salt, which was synthetized in order to improve the solubility of its parent drug. Highly active against MRSA, MSSA (methicillin-sensitive Staphylococcus

• characterized linezolid analogues that were used as test cases for our simulation protocol. Compound 7 is the active form of the prodrug torezolid. For references, see the text. Predicted new linezolid-like candidates. Computed relative binding energies in comparison with MIC values for the experimental

Enabling technologies and green processes in cyclodextrin chemistry

• Giancarlo Cravotto,
• Marina Caporaso,
• Laszlo Jicsinszky and
• Katia Martina

Beilstein J. Org. Chem. 2016, 12, 278–294, doi:10.3762/bjoc.12.30

• , Italy), a similar approach was used for the preparation of an ester prodrug of diclofenac and β-CD, but in a monomode MW oven (CEM Discover S-class MW reactor). The reaction was heated at 140 °C for 40 min and the diclofenac β-CD derivative was obtained with a yield of 20% [45]. Analogously, a general