Synthesis of Biologically Active Molecules through Multicomponent Reactions
TL;DR: The present review explores the highly significant role that multicomponent reactions (MCRs) have played as a very important tool for expedite synthesis of a vast number of organic molecules, but also highlights the fact that many of such molecules are biologically active or at least have been submitted to any biological screen.
Abstract: Focusing on the literature progress since 2002, the present review explores the highly significant role that multicomponent reactions (MCRs) have played as a very important tool for expedite synthesis of a vast number of organic molecules, but also, highlights the fact that many of such molecules are biologically active or at least have been submitted to any biological screen. The selected papers covered in this review must meet two mandatory requirements: (1) the reported products should be obtained via a multicomponent reaction; (2) the reported products should be biologically actives or at least tested for any biological property. Given the diversity of synthetic approaches utilized in MCRs, the highly diverse nature of the biological activities evaluated for the synthesized compounds, and considering their huge structural variability, much of the reported data are organized into concise schemes and tables to facilitate comparison, and to underscore the key points of this review.
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TL;DR: Copper-catalyzed transformations of enynes, such as boro- and hydrofunctionalizations, copper-mediated radical difunctionalizations, and cyclizations are reviewed, with particular attention to the regiodivergent functionalization of 1,3-enynes.
Abstract: The copper-catalyzed functionalization of enyne derivatives has recently emerged as a powerful approach in contemporary synthesis. Enynes are versatile and readily accessible substrates that can undergo a variety of reactions to yield densely functionalized, enantioenriched products. In this perspective, we review copper-catalyzed transformations of enynes, such as boro- and hydrofunctionalizations, copper-mediated radical difunctionalizations, and cyclizations. Particular attention is given to the regiodivergent functionalization of 1,3-enynes, and the current mechanistic understanding of such processes.
64 citations
39 citations
TL;DR: This Minireview survey surveys the borylative union of allenes, dienes, styrenes and other olefins, with imines, nitriles and related C−N electrophiles with copper‐catalyzed MCRs.
Abstract: Copper-catalyzed borylative multicomponent reactions (MCRs) involving olefins and C-N electrophiles are a powerful tool to rapidly build up molecular complexity. The products from these reactions contain multiple functionalities, such as amino, cyano and boronate groups, that are ubiquitous in medicinal and process chemistry programs. Copper-catalyzed MCRs are particularly attractive because they use a relatively abundant and non-toxic catalyst to selectively deliver high-value products from simple feedstocks such as olefins. In this Minireview, we explore this rapidly emerging field and survey the borylative union of allenes, dienes, styrenes and other olefins, with imines, nitriles and related C-N electrophiles.
34 citations
TL;DR: This review presents several illustrative applications of the use of sustainable protocols in the synthesis of organic compounds under solvent-free reaction conditions.
Abstract: One central challenge for XXI century chemists is the development of sustainable processes that do not represent a risk either to humanity or to the environment. In this regard, the search for more efficient and clean alternatives to achieve the chemical activation of molecules involved in chemical transformations has played a prominent role in recent years. The use of microwave or UV-Vis light irradiation, and mechanochemical activation is already widespread in many laboratories. Nevertheless, an additional condition to achieve “green” processes comes from the point of view of so-called atom economy. The removal of solvents from chemical reactions generally leads to cleaner, more efficient and more economical processes. This review presents several illustrative applications of the use of sustainable protocols in the synthesis of organic compounds under solvent-free reaction conditions.
31 citations
TL;DR: The present review provides a much-needed update on the biological potential of THIQ analogs, their structural–activity relationship (SAR), and their mechanism of action.
Abstract: Isoquinoline alkaloids are a large group of natural products in which 1,2,3,4-tetrahydroisoquinolines (THIQ) form an important class. THIQ based natural and synthetic compounds exert diverse biological activities against various infective pathogens and neurodegenerative disorders. Due to these reasons, the THIQ heterocyclic scaffold has garnered a lot of attention in the scientific community which has resulted in the development of novel THIQ analogs with potent biological activity. The present review provides a much-needed update on the biological potential of THIQ analogs, their structural–activity relationship (SAR), and their mechanism of action. In addition, a note on commonly used synthetic strategies for constructing the core scaffold has also been discussed.
29 citations
References
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TL;DR: Recent advances that have been made by research into the role of TLR biology in host defense and disease are described.
Abstract: The discovery of Toll-like receptors (TLRs) as components that recognize conserved structures in pathogens has greatly advanced understanding of how the body senses pathogen invasion, triggers innate immune responses and primes antigen-specific adaptive immunity. Although TLRs are critical for host defense, it has become apparent that loss of negative regulation of TLR signaling, as well as recognition of self molecules by TLRs, are strongly associated with the pathogenesis of inflammatory and autoimmune diseases. Furthermore, it is now clear that the interaction between TLRs and recently identified cytosolic innate immune sensors is crucial for mounting effective immune responses. Here we describe the recent advances that have been made by research into the role of TLR biology in host defense and disease.
7,494 citations
"Synthesis of Biologically Active Mo..." refers background in this paper
...The transmembrane PRRs include the toll-like receptors (TLRs) [39], which are expressed either on the plasma membrane or in the endolysosomal compartments [38]....
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TL;DR: This unit discusses mammalian Toll receptors (TLR1‐10) that have an essential role in the innate immune recognition of microorganisms and are discussed are TLR‐mediated signaling pathways and antibodies that are available to detect specific TLRs.
Abstract: The innate immune system in drosophila and mammals senses the invasion of microorganisms using the family of Toll receptors, stimulation of which initiates a range of host defense mechanisms. In drosophila antimicrobial responses rely on two signaling pathways: the Toll pathway and the IMD pathway. In mammals there are at least 10 members of the Toll-like receptor (TLR) family that recognize specific components conserved among microorganisms. Activation of the TLRs leads not only to the induction of inflammatory responses but also to the development of antigen-specific adaptive immunity. The TLR-induced inflammatory response is dependent on a common signaling pathway that is mediated by the adaptor molecule MyD88. However, there is evidence for additional pathways that mediate TLR ligand-specific biological responses.
5,915 citations
TL;DR: MCRs and especially MCRs with isocyanides offer many opportunities to attain new reactions and basic structures, however, this requires that the chemist learns the "language" of M CRs, something that this review wishes to stimulate.
Abstract: Multicomponent reactions (MCRs) are fundamentally different from two-component reactions in several aspects. Among the MCRs, those with isocyanides have developed into popular organic-chemical reactions in the pharmaceutical industry for the preparation of compound libraries of low-molecular druglike compounds. With a small set of starting materials, very large libraries can be built up within a short time, which can then be used for research on medicinal substances. Due to the intensive research of the last few years, many new backbone types have become accessible. MCRs are also increasingly being employed in the total synthesis of natural products. MCRs and especially MCRs with isocyanides offer many opportunities to attain new reactions and basic structures. However, this requires that the chemist learns the “language” of MCRs, something that this review wishes to stimulate.
3,619 citations
"Synthesis of Biologically Active Mo..." refers background or methods in this paper
...Groebke-Blackburn-Bienaymé three-component reaction for the preparation of imidazo[2,1-c][1,2,4]triazole derivatives 60 for antibacterial assays....
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...[bmim][PF6]-Mediated three-component synthesis of spiro[indole-3,2′[1,3]-thiazine]-2,4-diones 93 of antitubercular interest....
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...In 2017, an elegant microwave-assisted synthesis of pyrrolo[1,10]phenanthrolines 62 was achieved through a four-component reaction between 1,10-phenanthroline (61), aromatic aldehydes 1, malononitrile (12) and isocyanides 18, leading to the corresponding products 62 in excellent yields at 60 ◦C (Scheme 25) [68]....
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...Unlike the usual stepwise formation of individual bonds in the target molecule via a multi-step synthetic approach, the defining attribute of MCRs is the inherent formation of several bonds in one operation without isolating the intermediates (referred to as the bond-forming efficiency, BFE) [1,11,12], nor changing the reaction conditions or adding further reagents....
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..., described the synthesis of fully substituted imidazo[2,1-c][1,2,4]triazoles 60 by a Groebke-Blackburn-Bienaymé reaction between 5-amino-1,2,4-triazoles 2, aromatic aldehydes 1 and isocyanides 18 using scandium triflate as a Lewis acid catalyst (Scheme 24)....
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TL;DR: A cell-permeable small molecule (JQ1) that binds competitively to acetyl-lysine recognition motifs, or bromodomains is reported, establishing proof-of-concept for targeting protein–protein interactions of epigenetic ‘readers’, and providing a versatile chemical scaffold for the development of chemical probes more broadly throughout the b romodomain family.
Abstract: Epigenetic proteins are intently pursued targets in ligand discovery. So far, successful efforts have been limited to chromatin modifying enzymes, or so-called epigenetic 'writers' and 'erasers'. Potent inhibitors of histone binding modules have not yet been described. Here we report a cell-permeable small molecule (JQ1) that binds competitively to acetyl-lysine recognition motifs, or bromodomains. High potency and specificity towards a subset of human bromodomains is explained by co-crystal structures with bromodomain and extra-terminal (BET) family member BRD4, revealing excellent shape complementarity with the acetyl-lysine binding cavity. Recurrent translocation of BRD4 is observed in a genetically-defined, incurable subtype of human squamous carcinoma. Competitive binding by JQ1 displaces the BRD4 fusion oncoprotein from chromatin, prompting squamous differentiation and specific antiproliferative effects in BRD4-dependent cell lines and patient-derived xenograft models. These data establish proof-of-concept for targeting protein-protein interactions of epigenetic 'readers', and provide a versatile chemical scaffold for the development of chemical probes more broadly throughout the bromodomain family.
3,489 citations
"Synthesis of Biologically Active Mo..." refers background in this paper
...The inhibition of the bromodomain and extra-terminal (BET) domain subfamily of human bromodomains from chromatin [34], has contributed new insights into gene regulation and emerged as a promising therapeutic strategy in cancer....
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TL;DR: Research for leishmaniasis has been more and more focusing on the development of new tools such as diagnostic tests, drugs and vaccines, and the newly available control tools should allow a scaling up of control activities in priority areas.
Abstract: Leishmaniasis represents a complex of diseases with an important clinical and epidemiological diversity. Visceral leishmaniasis (VL) is of higher priority than cutaneous leishmaniasis (CL) as it is a fatal disease in the absence of treatment. Anthroponotic VL foci are of special concern as they are at the origin of frequent and deathly epidemics (e.g. Sudan). Leishmaniasis burden remains important: 88 countries, 350 million people at risk, 500,000 new cases of VL per year, 1-1.5 million for CL and DALYs: 2.4 millions. Most of the burden is concentrated on few countries which allows clear geographic priorities. Leishmaniasis is still an important public health problem due to not only environmental risk factors such as massive migrations, urbanisation, deforestation, new irrigation schemes, but also to individual risk factors: HIV, malnutrition, genetic, etc em leader Leishmaniasis is part of those diseases which still requires improved control tools. Consequently WHO/TDR research for leishmaniasis has been more and more focusing on the development of new tools such as diagnostic tests, drugs and vaccines. The ongoing effort has already produced significant results. The newly available control tools should allow a scaling up of control activities in priority areas. In anthroponotic foci, the feasibility of getting a strong impact on mortality, morbidity and transmission, is high.
2,150 citations
"Synthesis of Biologically Active Mo..." refers background in this paper
...The existing chemotherapies are not effective enough as these have various drawbacks such as significant toxicity, variable efficacy, lack of oral bioavailability, and high cost involved during the treatment [20]....
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