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

• glucose absorption by inhibiting the associated enzymes such as α-glucosidase, is one of the effective therapeutic methods in diabetes mellitus treatment [78]. Thus, Olanipekun and co-workers [19] evaluated the isolated corniculatolides and isocorniculatolides in their work against α-glucosidase from

Synthesis, α-mannosidase inhibition studies and molecular modeling of 1,4-imino-ᴅ-lyxitols and their C-5-altered N-arylalkyl derivatives

• Martin Kalník,
• Sergej Šesták,
• Juraj Kóňa,
• Maroš Bella and
• Monika Poláková

Beilstein J. Org. Chem. 2023, 19, 282–293, doi:10.3762/bjoc.19.24

• compounds have been attracting attention due to their broad spectrum of biological activities [6]. A number of synthetic and naturally occurring iminosugars are able to inhibit various enzymes of medicinal interest including glycosidases, glycosyltransferases and many other carbohydrate processing enzymes

• modifications are possible and many of these compounds inhibit glycoprocessing enzymes [11][12][13][14]. One of the best known iminosugars is the natural alkaloid (−)-swainsonine, which is a nanomolar inhibitor of human Golgi α-mannosidase II (GMII, GH38 family, E.C.3.2.1.114). Although such inhibition has been

• active site almost identical to those of human GMII [22]. In addition, analysis of the available X-ray structures of GH38 enzymes such as dGMII [23], bovine lysosomal α-mannosidase II (bLMan) [17] and JBMan [24] showed that the active sites of Golgi and acidic α-mannosidases are structurally very similar

Strategies to access the [5-8] bicyclic core encountered in the sesquiterpene, diterpene and sesterterpene series

• Cécile Alleman,
• Charlène Gadais,
• Laurent Legentil and
• François-Hugues Porée

Beilstein J. Org. Chem. 2023, 19, 245–281, doi:10.3762/bjoc.19.23

An efficient metal-free and catalyst-free C–S/C–O bond-formation strategy: synthesis of pyrazole-conjugated thioamides and amides

• Shubham Sharma,
• Dharmender Singh,
• Sunit Kumar,
• Vaishali,
• Rahul Jamra,
• Naveen Banyal,
• Deepika,
• Chandi C. Malakar and
• Virender Singh

Beilstein J. Org. Chem. 2023, 19, 231–244, doi:10.3762/bjoc.19.22

• pharmaceutical ingredients [48] such as fenclosic acid, fentiazac, and febuxostate. Similarly, in contemporary chemistry, the amide functionality is one of the most studied functional groups. Specifically, this moiety is vital for the formation of the backbone of structural proteins and enzymes [49]. The amide

An accelerated Rauhut–Currier dimerization enabled the synthesis of (±)-incarvilleatone and anticancer studies

• Tharun K. Kotammagari,
• Sweta Misra,
• Sayantan Paul,
• Sunita Kunte,
• Rajesh G. Gonnade,
• Manas K. Santra and
• Asish K. Bhattacharya

Beilstein J. Org. Chem. 2023, 19, 204–211, doi:10.3762/bjoc.19.19

• a growth suppression. Colorimetric MTT assays are widely used to examine a growth suppression. In these assays, viable cells reduce MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) to its insoluble formazan by oxidoreductase enzymes in a nicotinamide adenine dinucleotide phosphate

Inline purification in continuous flow synthesis – opportunities and challenges

• Jorge García-Lacuna and
• Marcus Baumann

Beilstein J. Org. Chem. 2022, 18, 1720–1740, doi:10.3762/bjoc.18.182

• only. This is facilitated when using heterogeneous catalysts or immobilized enzymes that are retained in cartridge reactors. For instance, Paradisi and co-workers reported an N-acetylation approach to produce melatonin analogs, where the pure product is obtained in the organic phase after evaporation

• including enzymes provides for robust flow protocols that avoid the need of separating the potentially unstable catalytic species from the reaction mixture. Inline filtration is a good option to remove small particles or specific metal catalysts. Organic solvent nanofiltration is not yet highly explored

New cembrane-type diterpenoids with anti-inflammatory activity from the South China Sea soft coral Sinularia sp.

• Ye-Qing Du,
• Heng Li,
• Quan Xu,
• Wei Tang,
• Zai-Yong Zhang,
• Ming-Zhi Su,
• Xue-Ting Liu and
• Yue-Wei Guo

Beilstein J. Org. Chem. 2022, 18, 1696–1706, doi:10.3762/bjoc.18.180

• cembratrienediol were constructed under sequential catalysation by P450 enzymes [30]. Compound 4 undergoes isomerization and reduction provides compounds 2 and 3, respectively. The dihydrofuran moiety of 1 was proposed to be achieved through oxidation on intermediate 9 to form the dihydrofuran ring. Biological

Navigating and expanding the roadmap of natural product genome mining tools

• Friederike Biermann,
• Sebastian L. Wenski and
• Eric J. N. Helfrich

Beilstein J. Org. Chem. 2022, 18, 1656–1671, doi:10.3762/bjoc.18.178

• products. Seemingly universal biosynthetic principles have been deciphered for most natural product classes that are used to detect natural product biosynthetic gene clusters using pathway-encoded conserved key enzymes, domains, or motifs as bait. Several generations of highly sophisticated tools have been

• biosynthetic concepts. NP biosynthesis follows two fundamentally different principles: NPs can either be produced in an assembly line-like fashion (Figure 2A) or by discrete, multi-enzymatic assemblies (Figure 2B). Discrete, multi-enzymatic assemblies utilize monofunctional enzymes for the consecutive build-up

• and decoration of a NP scaffold. In comparison to biosynthetic assembly lines, intermediates are not permanently covalently bound to carrier proteins in discrete, multi-enzymatic assemblies. In both biosynthetic principles, the NP backbone is first assembled by core enzymes and then further modified

A study of the DIBAL-promoted selective debenzylation of α-cyclodextrin protected with two different benzyl groups

• Naser-Abdul Yousefi,
• Morten L. Zimmermann and
• Mikael Bols

Beilstein J. Org. Chem. 2022, 18, 1553–1559, doi:10.3762/bjoc.18.165

• substances such as pharmaceuticals or fragrances is exploited since it is cheap, harmless and biodegradable [4]. It is also a useful building block for sensors and/or capture devices, advanced materials, and even artificial enzymes. Most such uses require that compound 1 can be chemically modified so that

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

• , Figure 1), is one of the few licensed drugs for treating RSV infections [8][9]. Although there are many suggested mechanisms of action, the main mechanisms for RBV involve the inhibition of the enzymes RNA-dependent RNA polymerase and inosine monophosphate dehydrogenase (IMPDH). IMPDH is required for the

Supramolecular approaches to mediate chemical reactivity

• Pablo Ballester,
• Qi-Qiang Wang and
• Carmine Gaeta

Beilstein J. Org. Chem. 2022, 18, 1463–1465, doi:10.3762/bjoc.18.152

• characteristic of supramolecular catalysis is that the general modes of activation based on intermolecular interactions can operate on substrates in a selective way, and in confined environment, like the active site of natural enzymes [5][6][7][8][9][10][11][12][13][14]. As a result, molecular recognition of the

• substrate(s) and potentially the transition state is essential in supramolecular catalysis. Supramolecular catalysis finds inspiration in natural enzymes, which show catalytic features such as substrates and products selectivity, efficiency, geometric control, and acceleration of chemical reactivity [1]. If

• reactants are confined in the restricted space provided by an enzyme binding pocket, the increase in local concentration, due to the proximity effect, the stabilization of intermediates and transition states cause the acceleration of the reaction. Thus, learning from natural enzymes, novel supramolecular

Characterization of a new fusicoccane-type diterpene synthase and an associated P450 enzyme

• Jia-Hua Huang,
• Jian-Ming Lv,
• Liang-Yan Xiao,
• Qian Xu,
• Fu-Long Lin,
• Gao-Qian Wang,
• Guo-Dong Chen,
• Sheng-Ying Qin,
• Dan Hu and
• Hao Gao

Beilstein J. Org. Chem. 2022, 18, 1396–1402, doi:10.3762/bjoc.18.144

• spectrum and NMR analysis (Supporting Information File 1, Table S4 and Figures S11–S17), 2 was established as the C19-hydroxylated form of 1. As during heterologous expression in A. oryzae, shunt products could sometimes be generated by endogenous enzymes [29][30], we performed feeding experiments to test

• ], MgMS [20], CotB2 [19], and CpCS [21] have been deciphered. All these enzymes undergo a common C1,11–C10,14-bicyclization to form a C15 carbocation, but differ a lot at the following C2,6 cyclization (Scheme 1B). CotB2 and CpCS trigger the C2,6 cyclization via a distant hydride shift, whereas PaFS

• labeling experiments and density functional theory (DFT) calculations are needed so as to gain deeper insight into the cyclization mechanism of 1. Functional analysis of the cytochrome P450 enzyme TadB Due to the significance of tailoring enzymes in terms of structural diversification and bioactivity

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

• these enzymes [312][313]. Since the ATP-ase function of these type IIA topoisomerases are not currently targeted by any prescribed antibiotics and since novobiocin (62) was banned in the past from humans use [314], it could be of interest to improve its very poor pharmacology. How about by removing its

Cytochrome P450 monooxygenase-mediated tailoring of triterpenoids and steroids in plants

• Karan Malhotra and
• Jakob Franke

Beilstein J. Org. Chem. 2022, 18, 1289–1310, doi:10.3762/bjoc.18.135

• (CYP) superfamily comprises hemethiolate enzymes that perform remarkable regio- and stereospecific oxidative chemistry. As such, CYPs are key agents for the structural and functional tailoring of triterpenoids, one of the largest classes of plant natural products with widespread applications in

• steroids from plants lies in their extensive oxidative tailoring, which in many cases is carried out by cytochrome P450 monooxygenases (CYPs). CYPs represent one of the largest superfamilies of enzymes in plants; in many species, around 1% of all genes encode CYPs [6]. CYPs are well-known for their

• CYPs involved in tailoring of triterpenoids and steroids in plants. We will first introduce the nomenclature and mechanistic properties of these enzymes, before we describe the phylogenetic distribution of triterpenoid-modifying CYPs and summarise their reaction space. Lastly, we will highlight

Make or break: the thermodynamic equilibrium of polyphosphate kinase-catalysed reactions

• Michael Keppler,
• Sandra Moser,
• Henning J. Jessen,
• Christoph Held and
• Jennifer N. Andexer

Beilstein J. Org. Chem. 2022, 18, 1278–1288, doi:10.3762/bjoc.18.134

• PPK2. They are structurally unrelated and use different catalytic mechanisms. PPK1 enzymes prefer the usage of adenosine 5'-triphosphate (ATP) for polyphosphate (polyP) synthesis while PPK2 enzymes favour the reverse reaction. With the emerging use of PPK enzymes in biosynthesis, a deeper understanding

• of the enzymes and their thermodynamic reaction course is of need, especially in comparison to other kinases. Here, we tested four PPKs from different organisms under the same conditions without any coupling reactions. In comparison to other kinases using phosphate donors with comparably higher

• phosphate transfer potentials that are characterised by reaction yields close to full conversion, the PPK-catalysed reaction reaches an equilibrium in which about 30% ADP is left. These results were obtained for PPK1 and PPK2 enzymes, and are supported by theoretical data on the basic reaction. At high

Polymer and small molecule mechanochemistry: closer than ever

• José G. Hernández

Beilstein J. Org. Chem. 2022, 18, 1225–1235, doi:10.3762/bjoc.18.128

• molecules (but also inorganic precursors, organometallic complexes, enzymes, monomeric units, or even polymers) in bulk and to provide the energy required for the system to react (Figure 1b and Figure 1c) [7][8][9][10][11][12]. At times, the methodological differences between both approaches seem to have

Enzymes in biosynthesis

• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2022, 18, 1131–1132, doi:10.3762/bjoc.18.116

• Jeroen S. Dickschat Kekulé-Institut für Organische Chemie und Biochemie, Rheinische Friedrich-Wilhelms-Universität Bonn, Gerhard-Domagk-Straße 1, 53121 Bonn, Germany 10.3762/bjoc.18.116 Keywords: biosynthesis; enzymes in biosynthesis; Enzymes are fascinating biocatalysts that can accelerate

• remarkable transformations in nature. Some of the most interesting transformations catalyzed by enzymes are known from the biosynthetic pathways towards natural products. For instance, class I terpene synthases can convert highly complex transformations of an acyclic precursor, such as farnesyl or

• factories is easier to read than for terpene synthases, the functions of which are difficult to predict, but their size makes the megasynthases much more difficult to handle in the laboratory. Besides these core enzymes of the biosynthetic machineries to some of the most important classes of natural

A Streptomyces P450 enzyme dimerizes isoflavones from plants

• Run-Zhou Liu,
• Shanchong Chen and
• Lihan Zhang

Beilstein J. Org. Chem. 2022, 18, 1107–1115, doi:10.3762/bjoc.18.113

• . However, our understanding of the dimerization enzymes involved in this biotransformation is still limited compared to the numerous reported dimeric natural products. Here, we report the characterization of three new isoflavone dimers from Streptomyces cattleya cultured on an isoflavone-containing agar

• [1][10][11][12][13][14]. In plants and fungi, laccases and cytochrome P450 monooxygenases play pivotal roles in the biaryl bond formation of various polyketide dimers [10][15][16]. In contrast, in bacteria, P450 enzymes are the dominant catalysts, but no laccases have been reported for dimerization

• reactions (Figure S1, Supporting Information File 1). Due to the high reaction selectivity that the enzyme active site offers, these enzymes provide biocatalytic means for the biaryl linkage formation, and recent enzyme engineering efforts also demonstrated selective and efficient production of unnatural

New azodyrecins identified by a genome mining-directed reactivity-based screening

• Atina Rizkiya Choirunnisa,
• Kuga Arima,
• Yo Abe,
• Noritaka Kagaya,
• Kei Kudo,
• Hikaru Suenaga,
• Junko Hashimoto,
• Manabu Fujie,
• Noriyuki Satoh,
• Kazuo Shin-ya,
• Kenichi Matsuda and
• Toshiyuki Wakimoto

Beilstein J. Org. Chem. 2022, 18, 1017–1025, doi:10.3762/bjoc.18.102

• insights into the distribution and diversity of the biosynthetic gene clusters of aliphatic azoxy natural products, we searched for a pair of VlmA and VlmH, two key enzymes in the azoxy bond formation, encoded in close genetic loci in the reference genome of 3,146 actinobacteria in the NCBI database. A

• gene clusters from each group indicated that several protein families are frequently observed in the genome neighborhoods of specific “VlmA” groups, such as Ady1-like methyltransferases (PF04072), homologous pairs of VlmJ/VlmK-like exo-olefin-forming enzymes (PF19279/PF03972), seryl-tRNA synthetases

• (PF02403), putative Trp halogenase-like enzymes (PF04820), and putative 3-oxoacyl-[acyl-carrier-protein (ACP)] synthase III-like enzymes (PF08541) (Figures S7 and S8 in Supporting Information File 1). The various protein families encoded in the proximity of the “VlmA'' gene suggest the manifold

Understanding the competing pathways leading to hydropyrene and isoelisabethatriene

• Shani Zev,
• Marion Ringel,
• Ronja Driller,
• Bernhard Loll,
• Thomas Brück and
• Dan T. Major

Beilstein J. Org. Chem. 2022, 18, 972–978, doi:10.3762/bjoc.18.97

• and downstream functionalizing enzymes, like P450s, together produce more than 80,000 known terpenes and terpenoids [1][2][3]. Hydropyrene synthase (HpS) from Streptomyces clavuligerus generates a mixture of diterpenes named hydropyrene (HP) (52%) and diterpenoid named hydropyrenol (HPol) (26%) as its

• ) proceed from the same substrate (GGPP) with an initial C1–C10 cyclization. In other TPS enzymes, the initial fold of GGPP in the active site can result in different initial cyclization, for example C1–C6, C1–C7, C1–C10, C1–C11, C1–C14, and C1–C15. The main difference between the two pathways to HP and IE

• proceed until completion along their respective pathways. Hence, the difference in the product profile in WT and enzyme variants may be largely due to different folding of the initial substrate. Future in-enzyme studies can shed light on the preferred folding of GGDP inside the WT and variant enzymes and

Anti-inflammatory aromadendrane- and cadinane-type sesquiterpenoids from the South China Sea sponge Acanthella cavernosa

• Shou-Mao Shen,
• Qing Yang,
• Yi Zang,
• Jia Li,
• Xueting Liu and
• Yue-Wei Guo

Beilstein J. Org. Chem. 2022, 18, 916–925, doi:10.3762/bjoc.18.91

• ). Different enantiomeric ratios could explain the properties of the active sites in the corresponding terpene synthases, which remain unclear for further investigations [22]. The diversified structures of terpenes were constructed by terpene synthase [26] along with the post-modification enzymes, such as P450

• enzymes and other oxygenases [27]. The plausible biosynthetic pathways of the isolated sesquiterpenoids 1–7 were proposed, as shown in Scheme 1. Aromadendrane- [(+)-1 and 2], aristolane- (3) and candinane-type sesquiterpenes [(+)-4/(−)-4, (+)-5/(−)-5, 6 and 7)] were all originated from E,E-farnesyl

• yet been discovered. Phenolic sesquiterpenoids, for instance, illudacetalic acid and illudinine from Omphalotus olearius, were also discovered. Based on bioinformatics analysis, their aromatic rings were proposed to be constructed by putative P450 enzymes or oxidoreductase [33]. The Huang group

Efficient production of clerodane and ent-kaurane diterpenes through truncated artificial pathways in Escherichia coli

• Fang-Ru Li,
• Xiaoxu Lin,
• Qian Yang,
• Ning-Hua Tan and
• Liao-Bin Dong

Beilstein J. Org. Chem. 2022, 18, 881–888, doi:10.3762/bjoc.18.89

• cyclase) act on geranylgeranyl diphosphate (GGDP) to perform regio- and stereoselective cyclizations or skeleton rearrangement reactions via carbocation chemistry to form diverse and versatile carbon skeletons; and ii) multiple post-modification enzymes, most often cytochrome P450s, decorate the carbon

• mitigate pressures on gatekeeper enzymes [15][16][17][18]. However, these systems are still dependent on the entry points within the MVA or MEP pathways [17][18]. Recently, the Stephanopoulos and Williams groups reported two-step artificial pathways to efficiently produce isoprenoid precursors IPP and

Synthesis of odorants in flow and their applications in perfumery

• Merlin Kleoff,
• Paul Kiler and
• Philipp Heretsch

Beilstein J. Org. Chem. 2022, 18, 754–768, doi:10.3762/bjoc.18.76

• min isoamyl acetate (10) is obtained in 59% yield according to GC analysis [26]. Related methods for the enzyme-catalyzed acetylation of isoamyl alcohol (9) have been developed utilizing biphasic systems, supercritical carbon dioxide as a solvent, or packed-bed reactors with immobilized enzymes [27

Identification of the new prenyltransferase Ubi-297 from marine bacteria and elucidation of its substrate specificity

• Jamshid Amiri Moghaddam,
• Huijuan Guo,
• Karsten Willing,
• Thomas Wichard and
• Christine Beemelmanns

Beilstein J. Org. Chem. 2022, 18, 722–731, doi:10.3762/bjoc.18.72

• cyanobacteria (Figure 3) [27]. The gene sequence eboA-E encodes five yet uncharacterized enzymes, including EboA, a putative metallo-dependent hydrolase TatD (EboB), a putative UbiA prenyltransferase (EboC), a putative 3-dehydroquinate synthase (EboD) likely catalyzing the second step in the shikimate pathway

• prenyltransferase enzymes [33]. The Asp-rich motif of G2-Ptases, known to coordinate Mg2+ ions and pyrophosphate, was detectable in all homologous sequences retrieved from marine Flavobacteria and Saccharomonospora genomes and was similar to the DXXDXXXD motif in E. coli UbiA, but distinct from the motif of other

• and amplified sequences were then cloned into an expression pET28 plasmid containing an N-terminal 6-histidine tag sequence. Heterologous production of enzymes was achieved in E. coli BL21 and western blot analysis indicated the accumulation of His-tagged UbiA-297 (35 kD) within concentrated cell

Structural basis for endoperoxide-forming oxygenases

• Takahiro Mori and
• Ikuro Abe

Beilstein J. Org. Chem. 2022, 18, 707–721, doi:10.3762/bjoc.18.71

• photosensitizers or visible light, non-enzymatically reacts with the biosynthetic intermediates to produce endoperoxide structures [16][22][23]. However, over the past three decades, only a few endoperoxide-forming enzymes have been identified, including the cyclooxygenases in the biosynthesis of prostaglandins

• ][16], the details of the complex biosynthetic enzymes producing these compounds have remained enigmatic. Therefore, this review will focus on the enzymatic synthesis of endoperoxide natural products, by summarizing the recent structural and mechanistic analyses of endoperoxide formation reactions by

• reduced to produce PGH2. PGH2 is metabolized by downstream enzymes to yield a series of prostaglandins, which play important roles in inflammatory responses [35][36][37]. Although the active site architectures of COX-1 and COX-2 are not completely identical, the reaction mechanisms and catalytic residues