The late stage functionalization (LSF) of complex biorelevant compounds is a powerful tool to speed up the identification of structure-activity relationships (SARs) and to optimize ADME profiles. To ...this end, visible-light photocatalysis offers unique opportunities to achieve smooth and clean functionalization of drugs by unlocking site-specific reactivities under generally mild reaction conditions. This review offers a critical assessment of current literature, pointing out the recent developments in the field while emphasizing the expected future progress and potential applications. Along with paragraphs discussing the visible-light photocatalytic synthetic protocols so far available for LSF of drugs and drug candidates, useful and readily accessible synoptic tables of such transformations, divided by functional groups, will be provided, thus enabling a useful, fast, and easy reference to them.
Recent developments and future prospects of visible-light photocatalysis in the late-stage functionalization of pharmaceuticals and natural bioactive compounds.
The term functionalized isocyanides refers to all those isocyanides in which a neighbouring functional group can finely tune the reactivity of the isocyano group or can be exploited in ...post-functionalization processes. In this manuscript, we have reviewed all the isocyanides in which the pendant functional group causes either deviation from or reinforces the normal reactivity of the isocyano group and categorized them to highlight their common features and differences. An analysis of their synthetic potential and the possible unexplored directions for future research studies is also addressed.
Although the Ugi multicomponent reaction is more than 40 years old, there is still room for its application to the discovery of new multicomponent transformations, even within the constraints of its ...classic four‐reactant menu (aldehyde, amine, carboxylic acid, and isocyanide). Replacement of a primary amine with a secondary one thus allows the Mumm‐like rearrangement step to be avoided, freezing the reaction course at the stage of an imino‐anhydride intermediate susceptible to alternative nucleophilic trapping. Mainstream post‐transformation strategies can then add a further level of complexity. The potential of this approach to expedite access to molecular scaffolds of biological relevance and to create unprecedented chemical diversity is outlined.
The decade‐long development of modified Ugi reactions that use secondary rather than primary amines is summarized, highlighting the potential of this strategy to generate unprecedented chemical diversity and to provide shortcuts to various classes of nitrogen compounds (polyamines, heterocycles) of recognized value in biomedical research.
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”.
The copper‐catalyzed reaction between azides and alkynes, known as CuAAC, has allowed for the efficient synthesis of 1,2,3‐trisubstituted 1,4‐triazoles and the formation of a metallocycle intermediate. This intermediate can be used for creating new structures or generating multi‐component reactions, collectively referred to as “interrupted click reactions”
A chemistry professor explains the mechanism of the copper(I)‐catalyzed alkyne–azide cycloaddition (CuAAC) while suggesting that by interrupting the click reaction, it is possible to exploit the ...reactivity of the copper metallacycle intermediate to synthesize new products. The students who are listening are imagining novel synthetic pathways and finding ways to access products that are typically hard to obtain. More information can be found in the Review by M. Giustiniano, G. C. Tron and co‐workers (DOI: 10.1002/chem.202303844).
The possibility of harnessing the photoactivity of isocyanides in the development of metal-free Ugi-like visible light photo-triggered multicomponent transformations has been reported herein. More in ...detail, Ugi-3CR, Ugi-Tetrazole-3CR, and UgiJoulli-3CR afforded imide peptidomimetic derivatives in good yields and with a wide substrate scope, involving the late-stage editing of complex bioactive scaffolds. Furthermore, a 2-step-one-pot sequence affording linear secondary imides, and a 3-step-one-pot protocol leading to densely functionalized bis-amide derivatives have also been developed to highlight the huge potential of these mild metal-free reaction conditions to afford
complex and diverse compounds
while being in accordance with the
green chemistry principles
.
The direct photoexcitation of isocyanides is able to trigger a collection of Ugi-like multicomponent reactions under metal-free conditions and in the absence of any additives starting from both linear and cyclic tertiary aromatic amines.
In-water synthesis of isocyanides under micellar conditions Brunelli, Francesca; Aprile, Silvio; Russo, Camilla ...
Green chemistry : an international journal and green chemistry resource : GC,
09/2022, Letnik:
24, Številka:
18
Journal Article
Recenzirano
Odprti dostop
An in-water dehydration of
N
-formamides to afford isocyanides using micellar conditions at room temperature is reported. This method allows for the preparation of aliphatic isocyanides in an ...environmental friendly manner. The replacement of undesirable components such as phosphorous oxychloride, triethyl amine and dichloromethane (the classical combination used for the dehydration of
N
-formamides), by
p
-toluen sulphonyl chloride, sodium hydrogen carbonate and water makes this transformation really sustainable and safe.
Dehydration of
N
-formamides to isocyanides using
p
-toluen sulphonyl chloride, sodium hydrogen carbonate in aqueous micelles is reported.
Biogenic 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.
Sulfur‐centered radicals have a key role in a plethora of synthetic organic transformations, whose scope has been further expanded thanks to the possibility to generate such species under visible ...light photocatalytic conditions. This review focuses on those transformations involving isocyanides and sulfur‐centered radicals with the aim to highlight the chemical space accessible, both in terms of complexity and diversity, and the mechanistic rational underpinning the current and future development of such chemical methodologies.
Sulfur‐centered radicals have a key role in a plethora of synthetic transformations, whose scope is ever‐expanding thanks to visible light photocatalysis. The current review focuses on those transformations involving isocyanides and S‐centered radicals and aims to highlight the chemical space accessible and the mechanistic rational underpinning current and future developments.
Nicotinamide adenine dinucleotide (NAD) is a cofactor of many enzymatic reactions as well as being a substrate for a number of NAD-consuming enzymes (e.g., PARPS, sirtuins, etc). NAD can be ...synthesized
de novo
starting from tryptophan, nicotinamide, nicotinic acid, or nicotinamide riboside from the diet. On the other hand, the nicotinamide that is liberated by NAD-consuming enzymes can be salvaged to re-form NAD. In this former instance, nicotinamide phosphoribosyltransferase (NAMPT) is the bottleneck enzyme. In the many cells in which the salvage pathway is predominant, NAMPT, therefore, represents an important controller of intracellular NAD concentrations, and as a consequence of energy metabolism. It is, therefore, not surprising that NAMPT is over expressed by tumoral cells, which take advantage from this to sustain growth rate and tumor progression. This has led to the initiation of numerous medicinal chemistry programs to develop NAMPT inhibitors in the context of oncology. More recently, however, it has been shown that NAMPT inhibitors do not solely target the tumor but also have an effect on the immune system. To add complexity, this enzyme can also be secreted by cells, and in the extracellular space it acts as a cytokine mainly through the activation of Toll like Receptor 4 (TLR4), although it has not been clarified yet if this is the only receptor responsible for its actions. While specific small molecules have been developed only against the intracellular form of NAMPT, growing evidences sustain the possibility to target the extracellular form. In this contribution, the most recent evidences on the medicinal chemistry of NAMPT will be reviewed, together with the key elements that sustain the hypothesis of NAMPT targeting and the drawbacks so far encountered.
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