Efficient N-arylation of 4-chloroquinazolines en route to novel 4-anilinoquinazolines as potential anticancer agents

• Rodolfo H. V. Nishimura,
• Thiago dos Santos,
• Valter E. Murie,
• Luciana C. Furtado,
• Leticia V. Costa-Lotufo and
• Giuliano C. Clososki

Beilstein J. Org. Chem. 2021, 17, 2968–2975, doi:10.3762/bjoc.17.206

• -anilinoquinazoline; anticancer agents; N-arylation; 4-chloroquinazoline; microwave irradiation; Introduction N-Heterocyclic compounds are commonly present in pharmaceuticals, bioactive natural products, agrochemicals, and synthetic drugs [1][2]. Quinazoline, a benzo-fused N-heterocyclic framework (benzo-1,3-diazine

• of the anticancer agent verubulin. Thus, after regioselective 4-chloroquinazoline metalation by an in situ trapping metalation strategy, reaction quenching with iodine allowed us to isolate 4-chloro-8-iodoquinazoline in 83% yield. Surprisingly, further reaction of 4-chloro-8-iodoquinazoline with 4

• -methylanilines 9a, 9g, and 9l provided the desired 4-anilinoquinazolines 4, 19, and 20 in yields ranging from 90 to 95% (Scheme 5), among which we can highlight the anticancer agent verubulin (4). The methodology reported herein allowed us to prepare numerous novel 4-anilinoquinazolines derivatives in good yield

Selective sulfonylation and isonitrilation of para-quinone methides employing TosMIC as a source of sulfonyl group or isonitrile group

• Chuanhua Qu,
• Run Huang,
• Yong Li,
• Tong Liu,
• Yuan Chen and
• Guiting Song

Beilstein J. Org. Chem. 2021, 17, 2822–2831, doi:10.3762/bjoc.17.193

• , antimicrobial, antimalarial, and anticancer activities [1][2]. Diarylmethane motifs are widely present in natural products and pharmaceuticals that exhibit extraordinary biological activity [3][4] (Figure 1). Among them, their anticancer activity is particularly attractive, demonstrated by drugs such as

• letrozole [5] and entrectinib [6], with especially entrectinib showing a potent anticancer activity against a broad spectrum of human cancer cell lines. In recent decades, the construction of a hybrid system with varied biological and pharmaceutical activities has received extensive attention from medicinal

Highly stereocontrolled total synthesis of racemic codonopsinol B through isoxazolidine-4,5-diol vinylation

• Lukáš Ďurina,
• Anna Ďurinová,
• František Trejtnar,
• Ľuboš Janotka,
• Lucia Messingerová,
• Jana Doháňošová,
• Ján Moncol and
• Róbert Fischer

Beilstein J. Org. Chem. 2021, 17, 2781–2786, doi:10.3762/bjoc.17.188

• , triterpenoids, polysaccharides, and alkaloids are responsible for the majority of the activities found in Codonopsis species. Although the polyhydroxylated pyrrolidine alkaloids from C. pilosula possess glycosidase inhibitory activities and they are considered to be anticancer species, their activity against

• human cancer cell lines has never been described. In view of this, we have developed an efficient and highly diastereoselective approach towards codonopsinol B (1) and its N-nor-methyl analogue 2 from achiral starting materials and evaluated their anticancer activity using four different cancer cell

Synthesis of new pyrazolo[1,2,3]triazines by cyclative cleavage of pyrazolyltriazenes

• Nicolai Wippert,
• Martin Nieger,
• Claudine Herlan,
• Nicole Jung and
• Stefan Bräse

Beilstein J. Org. Chem. 2021, 17, 2773–2780, doi:10.3762/bjoc.17.187

• [3,4-d][1,2,3]triazines and their derivatives, for example, were reported to function as anticancer compounds [28][29][32], herbicides [19][20][21], antimicrobials [18], and pest control agents [35]. Several possibilities have been reported to gain the scaffold of pyrazolo[3,4-d][1,2,3]triazines

Recent advances in the asymmetric phosphoric acid-catalyzed synthesis of axially chiral compounds

• Alemayehu Gashaw Woldegiorgis and
• Xufeng Lin

Beilstein J. Org. Chem. 2021, 17, 2729–2764, doi:10.3762/bjoc.17.185

• moderate yield with >90% enantioselectivity (Scheme 20c) and tolerable diastereoselectivity (4:1) [73]. The optically enriched benzimidazoles are N-heterocycles which are of great interest as drug-like molecules [75], and exhibit biological activities such as anticancer, antiviral, antifungal, and

The ethoxycarbonyl group as both activating and protective group in N-acyl-Pictet–Spengler reactions using methoxystyrenes. A short approach to racemic 1-benzyltetrahydroisoquinoline alkaloids

• Marco Keller,
• Karl Sauvageot-Witzku,
• Franz Geisslinger,
• Nicole Urban,
• Michael Schaefer,
• Karin Bartel and
• Franz Bracher

Beilstein J. Org. Chem. 2021, 17, 2716–2725, doi:10.3762/bjoc.17.183

• second benzylisoquinoline moiety of the bisbenzylisoquinolines [15]. Antiproliferative activity Several anticancer effects have been reported for benzylisoquinoline alkaloids, for instance antiproliferative and antimigratory as well as chemoresistance-reversing activities [6][15][46][47]. Yet, detailed

• effects of benzyltetrahydroisoquinolines, including modulation of TPC2 and anticancer effects, as natural benzyltetrahydroisoquinolines bearing only hydroxy, methoxy and/or methylenedioxy substituents show no significant activity in this regard. Conclusion In the present investigation we demonstrated the

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

• incorporated into the growing DNA strand. However, the absence of a 3'-hydroxy group prevents further strand elongation. The anticancer and antiviral activity of 2’,3’-dideoxynucleosides is mainly based on inhibition of DNA synthesis, either through the chain termination process or by competitive inhibition [3

Synthesis of new bile acid-fused tetrazoles using the Schmidt reaction

• Dušan Đ. Škorić,
• Olivera R. Klisurić,
• Dimitar S. Jakimov,
• Marija N. Sakač and
• János J. Csanádi

Beilstein J. Org. Chem. 2021, 17, 2611–2620, doi:10.3762/bjoc.17.174

• and metabolic stability of the molecule [16]. Steroid molecules with nitrogen-containing heterocyclic rings are promising candidates for the treatment of many types of cancer or hormonal disorders [17]. There are several examples of steroidal tetrazoles showing anticancer potential (Figure 1) [18][19

• were washed with water. After drying and evaporation of the solvent in vacuo, the obtained crude products were crystallized from the appropriate solvent. Structures of the steroidal tetrazoles that showed anticancer potential in vitro. Mechanism of the Schmidt reaction. Mercury [51] drawing of the

α-Ketol and α-iminol rearrangements in synthetic organic and biosynthetic reactions

• Scott Benz and
• Andrew S. Murkin

Beilstein J. Org. Chem. 2021, 17, 2570–2584, doi:10.3762/bjoc.17.172

• episilvestrol (35), natural products with potent anticancer properties. The step prior to the rearrangement involved a photoinduced [3 + 2] cycloaddition between hydroxyflavone 36 and methyl cinnamate (37), resulting in the bicyclic α-ketol 38 as a mixture of diastereomers (Ph and CO2Me groups trans) (Figure 9

Silica gel and microwave-promoted synthesis of dihydropyrrolizines and tetrahydroindolizines from enaminones

• Robin Klintworth,
• Garreth L. Morgans,
• Stefania M. Scalzullo,
• Charles B. de Koning,
• Willem A. L. van Otterlo and
• Joseph P. Michael

Beilstein J. Org. Chem. 2021, 17, 2543–2552, doi:10.3762/bjoc.17.170

• pomegranate alkaloid punicagranine (5) (Figure 1) [5]. The 2,3-dihydro-1H-pyrrolizine motif is also a structural component of potential drugs with a variety of pharmacological effects [6], including anticancer activity [7]. Relevant examples include (−)-ketorolac (6) [8], which has reached the market as a

• nonsteroidal anti-inflammatory drug [6], and licofelone (7) [9][10], a promising co-drug for anticancer combination chemotherapy [7]. Related 5,6,7,8-tetrahydroindolizines such as CMV423 (8) [11], a lead compound for treating infections by human cytomegalovirus, and the natural products polygonatine A (9) [12

Efficient synthesis of polyfunctionalized carbazoles and pyrrolo[3,4-c]carbazoles via domino Diels–Alder reaction

• Ren-Jie Fang,
• Chen Yan,
• Jing Sun,
• Ying Han and
• Chao-Guo Yan

Beilstein J. Org. Chem. 2021, 17, 2425–2432, doi:10.3762/bjoc.17.159

• alkaloids and pharmacologically active compounds representing a broad spectrum of important bioactivities such as anticancer, antituberculosis, anti-protein kinase C, antipsychotic, and antioxidative activities [1][2][3][4][5]. For some examples, carprofen is a nonsteroidal anti-inflammatory pharmaceutical

Strategies for the synthesis of brevipolides

• Yudhi D. Kurniawan and
• A'liyatur Rosyidah

Beilstein J. Org. Chem. 2021, 17, 2399–2416, doi:10.3762/bjoc.17.157

• , entries 1–7). A very low ED50 value of 8.5 nM was obtained for brevipolide C (3) (Table 2, entry 3) [4], making it a very potent lead compound for anticancer candidates related to mitochondrial dysfunction effect. A reduction in the mitochondrial membrane potential (MMP) could also indicate apoptosis [20

Post-functionalization of drug-loaded nanoparticles prepared by polymerization-induced self-assembly (PISA) with mitochondria targeting ligands

• Janina-Miriam Noy,
• Fan Chen and
• Martina Stenzel

Beilstein J. Org. Chem. 2021, 17, 2302–2314, doi:10.3762/bjoc.17.148

• methacrylate) (pPEGMA) and the anticancer drug PENAO (4-(N-(S-penicillaminylacetyl)amino)phenylarsenonous acid) or zwitterionic 2-methacryloyloxyethyl phosphorylcholine (MPC) and PENAO were reported. Both PISA particles were reacted with triphenylphosphonium (TPP) as mitochondria targeting units in order to

• more structural investigations are required to elucidate this. Keywords: micelle; mitochondria; phosphorylcholine; PISA; polymerization-induced self-assembly; Introduction Targeting mitochondria is a promising strategy for the development of new anticancer drugs [1]. Among them, organoarsenical drugs

• TPP to zwitterionic particles accelerated its anticancer performance in terms of spheroid uptake and tumour growth inhibition, while no anticancer enhancement was detected when the PEGylated micelle was conjugated with a mitochondrial agent. In conclusion, the conjugation of TPP to MPM-NP2 gave the

Constrained thermoresponsive polymers – new insights into fundamentals and applications

• Patricia Flemming,
• Alexander S. Münch,
• Andreas Fery and
• Petra Uhlmann

Beilstein J. Org. Chem. 2021, 17, 2123–2163, doi:10.3762/bjoc.17.138

Catalyzed and uncatalyzed procedures for the syntheses of isomeric covalent multi-indolyl hetero non-metallides: an account

• Ranadeep Talukdar

Beilstein J. Org. Chem. 2021, 17, 2102–2122, doi:10.3762/bjoc.17.137

• engaging but also constitute a class of important pharmacophores. Although the body of such multi-indolyl non-metallide molecules are largely shared to the anticancer agent bis(indolyl)methane, other heteroatomic analogs also possess similar medicinal properties. This concise review will discuss various

• in the spotlight of anticancer research recently. In line with this high importance associated with the molecules of current topic, i.e., more than one indole molecule flanked by a central atom, conglomeration of the available synthetic methods will have a high scientific value. This review will give

• )methanes (anticancer substances), these products are important potential pharmaceutically active ingredients as well. As a result, they have gathered much attention in the current decade as suggested by the number of contemporary publications associated. The described schemes involve both simple and

Asymmetric organocatalyzed synthesis of coumarin derivatives

• Natália M. Moreira,
• Lorena S. R. Martelli and
• Arlene G. Corrêa

Beilstein J. Org. Chem. 2021, 17, 1952–1980, doi:10.3762/bjoc.17.128

• and synthetic chemistry. Compounds of this class have shown important activities, such as anticancer and antiparasitic, besides the commercially available drugs. These properties led to the development of efficient and greener synthetic methods to achieve the 2H-chromen-2-one core. In this context

• plant constituents and display a wide range of pharmacological and biological activities, such as anticancer [1], antibacterial [2], and antifungal [3]. Moreover, coumarin derivatives have shown activity against neglected diseases as leishmaniasis [4], tuberculosis [5][6] and Chagas’ disease [7

On the application of 3d metals for C–H activation toward bioactive compounds: The key step for the synthesis of silver bullets

• Renato L. Carvalho,
• Amanda S. de Miranda,
• Mateus P. Nunes,
• Roberto S. Gomes,
• Guilherme A. M. Jardim and
• Eufrânio N. da Silva Júnior

Beilstein J. Org. Chem. 2021, 17, 1849–1938, doi:10.3762/bjoc.17.126

• authors used a bulky titanium catalyst, by which a desirable regioselectivity could be achieved (Scheme 7B and C). The obtained N-substituted anilines resemble some important compounds already known for their biological activities, such as antimalarial (17) [69] and anticancer (18) [70][71] properties

• (Scheme 13B and C) [100]. Binols have been reported to present bactericidal (34) [101] and anticancer activities (35) [102] (Scheme 13A). In this work, the use of a dinuclear catalyst was found to strikingly increase the reaction rate, presumably by reducing entropic costs associated with bringing two

• -epoxynaphthalene as electrophiles. Several 2-alkynylbenzamide products were achieved in good yields, including a derivate of moclobemide (42), a drug used to treat depression and anxiety (Scheme 15C) [122]. It is worth mentioning here that this class of molecules can be used as effective anticancer drug carriers

Sustainable manganese catalysis for late-stage C–H functionalization of bioactive structural motifs

• Jongwoo Son

Beilstein J. Org. Chem. 2021, 17, 1733–1751, doi:10.3762/bjoc.17.122

• process facilitated the fluorination of sclareolide (1) and complex steroid 3. Sclareolide (1) is a naturally available terpenoid with antifungal and anticancer activities [23]. Under the optimized reaction conditions, sclareolide (1) is fluorinated at the C2 and C3 positions in 42% (see 2a) and 16% yield

• ® (antiplatelet), Gleevec® (anticancer), and augmentin (antibiotic), also contain the benzylic amine motif. Therefore, C–H amination is synthetically important for the diversification of biologically active molecules. Transition metal catalysis has set the stage for C–H amination processes in organic syntheses

• constitute an important structural modality in small-molecule drugs, such as levonorgestrel (birth control drug), efavirenz (HIV/AIDS treatment), and erlotinib (anticancer). Although step-economical C–H alkynylations have been investigated with 4d and 5d transition metals, 3d metal-catalyzed late-stage C–H

Chemical approaches to discover the full potential of peptide nucleic acids in biomedical applications

• Nikita Brodyagin,
• Martins Katkevics,
• Venubabu Kotikam,
• Christopher A. Ryan and
• Eriks Rozners

Beilstein J. Org. Chem. 2021, 17, 1641–1688, doi:10.3762/bjoc.17.116

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

• screened for the synthesis of these rings [16][17]. Notably, triazole rings exhibit various medicinal applications, such as usages as anticancer [18] anti-HIV [19], antimalarial [20], antiplasmodial [21], and antibacterial agents [1][22]. Some significant triazole derivatives in this context are shown in

Iodine-catalyzed electrophilic substitution of indoles: Synthesis of (un)symmetrical diindolylmethanes with a quaternary carbon center

• Thanigaimalai Pillaiyar,
• Masoud Sedaghati,
• Andhika B. Mahardhika,
• Lukas L. Wendt and
• Christa E. Müller

Beilstein J. Org. Chem. 2021, 17, 1464–1475, doi:10.3762/bjoc.17.102

• biological activities (Figure 1) [10]. Unsubstituted DIM (I), for example, exhibits antimicrobial [5], anticancer [11][12][13], and anti-inflammatory effects (Figure 1) [14]. There is preclinical evidence for activity against several types of cancer [15], and DIM has been clinically evaluated for the

• treatment of prostate cancer [16] and showed promise for the treatment of cervical dysplasia [17]. The related trisindoline (II) was reported to possess antibiotic activity [18], while DIM derivatives III and IV also showed anticancer activities (Figure 1). Owing to their exciting biological activities, DIM

Synthesis of 1-indolyl-3,5,8-substituted γ-carbolines: one-pot solvent-free protocol and biological evaluation

• Premansh Dudhe,
• Mena Asha Krishnan,
• Kratika Yadav,
• Diptendu Roy,
• Krishnan Venkatasubbaiah,
• Biswarup Pathak and
• Venkatesh Chelvam

Beilstein J. Org. Chem. 2021, 17, 1453–1463, doi:10.3762/bjoc.17.101

• –c are shown to undergo a novel cascade imination-heterocylization in the presence of the organic base DIPEA to provide 1-indolyl-3,5,8-substituted γ-carbolines 3aa–ea in good yields. The γ-carbolines are fluorescent and exhibit anticancer activities against cervical, lung, breast, skin, and kidney

• single-photon counting (TCSPC) experiments. The average fluorescence lifetime of compound 3ac was found to be 8.35 ns and 4.73 ns in DMSO and DCM, respectively (Table 2, Figure 4). Biological evaluation of γ-carbolines as anticancer agents A panel of carboline derivatives 3ac, 3bc, 3ca, and 3ga, along

• -free method provides direct access to complex molecular structures in good yield from inexpensive substrates. The optical and biological evaluations carried out for representative γ-carbolines revealed promising photophysical and anticancer properties of the core framework for developing novel

Double-headed nucleosides: Synthesis and applications

• Vineet Verma,
• Jyotirmoy Maity,
• Vipin K. Maikhuri,
• Ritika Sharma,
• Himal K. Ganguly and
• Ashok K. Prasad

Beilstein J. Org. Chem. 2021, 17, 1392–1439, doi:10.3762/bjoc.17.98

A comprehensive review of flow chemistry techniques tailored to the flavours and fragrances industries

• Guido Gambacorta,
• James S. Sharley and
• Ian R. Baxendale

Beilstein J. Org. Chem. 2021, 17, 1181–1312, doi:10.3762/bjoc.17.90

Synthesis of functionalized imidazo[4,5-e]thiazolo[3,2-b]triazines by condensation of imidazo[4,5-e]triazinethiones with DMAD or DEAD and rearrangement to imidazo[4,5-e]thiazolo[2,3-c]triazines

• Alexei N. Izmest’ev,
• Dmitry B. Vinogradov,
• Natalya G. Kolotyrkina,
• Angelina N. Kravchenko and
• Galina A. Gazieva

Beilstein J. Org. Chem. 2021, 17, 1141–1148, doi:10.3762/bjoc.17.87

• ], antituberculosis [2], anti-inflammatory [3][4], anticancer [5], antidiabetic [6][7], and antiviral activities [8]. A significant number of biologically active thiazolidines amount to their heteroannelated derivatives, namely, condensed thiazolo[3,2-a]pyrimidines [9] and thiazolo[3,2-b]-1,2,4-triazoles [10], as

• well as related thiazolo[3,2-b]-1,2,4-triazines and thiazolo[2,3-c]-1,2,4-triazines possessing antimicrobial, antidepressant, anti-HIV, and anticancer activities [10][11][12][13][14][15]. Modifications of the position 5 of the thiazolidine cycle often lead to an enhancement of the pharmacological