1,721,010 research outputs found
Click 1,2,3-triazoles in drug discovery and development: From the flask to the clinic?
No full textAfter 20 years since its conception, click chemistry has come of age and we believe the time has come to evaluate if the copper-catalyzed azide alkyne cycloaddition (CuCAAC) reaction deserves to be considered the perfect transformation in medicinal chemistry campaigns and to weigh up the concrete results that have been produced in terms of drugs approved and clinical candidates in development. After a description of the properties of the triazole nucleus in terms of both pharmacokinetic and pharmacodynamic profile, a practical guide for the best approaches to be used for the synthesis of triazoles is provided, capitalizing on our 20-year hands-on experience in this chemistry. Finally, we describe those molecules displaying the 1,2,3-triazole nucleus that have entered the market or are, at least, in clinical trials. Only four 1,2,3-triazole-bearing drugs have been launched so far. Among them the recently approved antibody drug conjugate sacituzumab govitecan was discovered thanks to click chemistry. Nevertheless, to the best of our knowledge, there are a dozen 1,2,3-triazoles in clinical development and it is likely that we will witness the launch on the market of at least some of them, encouraging medicinal chemists to further use this approach, not only as a route to early-stage discoveries, but also as a means to developing successful drugs
Recent advances in the synthesis of polyamine derivatives and their applications
No full textBiogenic polyamines (PAs) are involved in the growth and development of normal cells, and their intracellular concentration is stable. The concentration of PAs in cancer cells is significantly increased to promote and sustain their rapid proliferation. Over the years, synthetic PAs, which differ in their structure, have demonstrated high antitumor activity and are involved in clinical trials. The chemical synthesis of PAs and their conjugates require the correct choice of synthetic pathways-methods for constructing conjugates and the orthogonal protection of amino groups. The most common methods of synthesis of PA conjugates are acylation of regioselectively protected PAs or their alkylation under the conditions of the Fukuyama reaction. One of the most promising methods of PA synthesis is the use of a multicomponent Ugi reaction, which allows various PAs to be obtained in high yields. In this review, we describe and analyze various approaches that are used in the synthesis of polyamines and their conjugates
Each Interruption is an Opportunity: Novel Synthetic Strategies Explored Through Interrupted Click Reactions
No full text: The particular and unique mechanism of the copper-catalyzed reaction between azides and alkynes (CuAAC) has not only allowed for the efficient synthesis of 1,2,3-trisubstituted 1,4-triazoles in excellent yields and under mild conditions, becoming the quintessential click reaction, but it has also enabled the straightforward formation of a metallocycle intermediate, the copper triazolyl. This, under suitable reaction conditions able to suppress its protonolysis, can be used either for the creation of new bicyclic triazolyl structures or for the generation of novel three or four-component reactions. The aim of this review is to rationalize and unify all these transformations, which are collectively referred to as "interrupted click reactions"
Exploiting the Different Nucleophilicity of the Isocyano Group: A Strategy for the Isocyanide Functionalization
No full text: By exploiting the different nucleophilicity of aromatic and aliphatic isocyanides, we selectively react aliphatic isocyano groups while preserving aromatic ones in Passerini and Ugi multicomponent reactions. This simple approach allows the synthesis of α-acyloxy carboxamides or α-acylamino carboxamides possessing one or two isocyanide groups, which are challenging to achieve through traditional formylation and dehydration protocols. These analogues have the potential to serve as valuable building blocks with diverse applications
The Dark Side of Isocyanides: Visible-Light Photocatalytic Activity in the Oxidative Functionalization of C(sp3)–H Bonds
No full textThe possibility to harness aromatic isocyanides as visible-light photocatalysts in the α-amino C(sp3)–H functionalization is herein presented. Actually, the three-component cross-dehydrogenative coupling of aromatic tertiary amines with isocyanides and water leads to amide products under very mild conditions in high yields and with a good substrate scope. While the reaction with aromatic isocyanides proceeds upon direct photoexcitation, aliphatic isocyanides are able to form a photoactive electron–donor–acceptor complex with aromatic amines. Moreover, the use of a catalytic loading of an aromatic isocyanide promotes the oxidative coupling of N-phenyl-1,2,3,4-tetrahydroisoquinoline with an array of different (pro)nucleophiles in good to excellent yields, thus providing the proof-of-concept for the development of a new highly tunable class of organic visible-light photocatalysts
Medicinal chemistry of nicotinamide phosphoribosyltransferase (NAMPT) inhibitors
No full text: Nicotinamide phoshophoribosyltransferase (NAMPT) plays a key role in the replenishment of the NAD pool in cells. This in turn makes this enzyme an important player in bioenergetics and in the regulation of NAD-using enzymes, such as PARPs and sirtuins. Furthermore, there is now ample evidence that NAMPT is secreted and has a role as a cytokine. An important role of either the intracellular or extracellular form of NAMPT has been shown in cancer, inflammation, and metabolic diseases. The first NAMPT inhibitors (FK866 and CHS828) have already entered clinical trials, and a surge in interest in the synthesis of novel molecules has occurred. The present review summarizes the recent progress in this field
Visible-Light Photocatalytic Ugi/Aza-Wittig Cascade towards 2-Aminomethyl-1,3,4-oxadiazole Derivatives
No full textA new visible-light photocatalytic multicomponent reaction (MCR) involving N-alkyl-N-methylanilines, N-isocyanoiminotriphenylphosphorane, and carboxylic acids leading to 1,3,4-oxadiazole derivatives is reported. The developed mild reaction conditions enable a broad substrate scope and good functional group tolerance, as further highlighted in the late-stage functionalization of amino acids and drugs. Additionally, a two-step one-pot protocol for the synthesis of non-symmetrical diacylhydrazines is also reported
Data on metabolic stability, aqueous solubility and CYP inhibition of novel triazole-based nicotinamide phosphoribosyltransferase (NAMPT) inhibitors
No full textIn the related research article, entitled “Identification of novel triazole-based nicotinamide phosphoribosyltransferase (NAMPT) inhibitors endowed with antiproliferative and antiinflammatory activity” [1], we reported the in vitro hepatic metabolism data for compounds 30c, 48b, and 31b (here named as E5, A6, and T1), in comparison with the reference compounds GPP78 and FK866 [1–3]. In this article, we retrieved the available data about the hepatic microsomal stability and metabolites structural characterization of the entire library of triazole-based NAMPT inhibitors, also implementing the given information with data regarding aqueous solubility and CYP inhibition. Compounds are divided in subclasses based on the hydrolytic resistant groups replacing the amide function of GPP78 [1, 2]
Expanding the Chemical Space of Drug-like Passerini Compounds: Can α-Acyloxy Carboxamides Be Considered Hard Drugs?
No full textWith their three points of diversity, α-acyloxy carboxamides, which are accessible with the Passerini reaction, provide heterogeneity for the preparation of libraries of putative active agents or intermediates used for the formation of more complex structures. If on the one hand the presence of a hydrolyzable ester function has been exploited to design both prodrugs and soft drugs, on the other hand medicinal chemists are reluctant to use this skeleton to prepare hard drugs. Herein we investigated whether the stability of the ester could be controlled, leading to the formation of hydrolytically stable α-acyloxy carboxamides. When the group directly attached to the ester moiety (R3) is an ortho-substituted or ortho,ortho′-disubstituted aromatic ring, α-acyloxy carboxamides are stable. In human liver but not in rodents, due to the different expression of esterases, the ester function is also stable toward hydrolysis when the R1group is a bulky substituent regardless of the nature of the R3substituent
Visible-light photocatalytic functionalization of isocyanides for the synthesis of secondary amides and ketene aminals
No full textA new visible light-induced photocatalytic protocol enabling the formation of secondary amides from electron-poor organic bromides and isocyanides was developed. In addition, the in situ interception of ketenimine intermediates with nitrogen nucleophiles such as amines, hydrazines, and TMSN3 afforded, in a one-pot two-step procedure, valuable scaffolds such as ketene aminals, pyrazolones, and tetrazoles. Mechanistic evidence confirmed a radical pathway where isocyanides acted as radical geminal acceptors generating key imidoyl radical species
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