Friedel-Crafts reactions for biomolecular chemistry.

Chemical tools and principles have become central to biological and medical research/applications by leveraging a range of classical organic chemistry reactions. Friedel-Crafts alkylation and acylation are arguably some of the most well-known and used synthetic methods for the preparation of small molecules but their use in biological and medical fields is relatively less frequent than the other reactions, possibly owing to the notion of their plausible incompatibility with biological systems. This review demonstrates advances in Friedel-Crafts alkylation and acylation reactions in a variety of biomolecular chemistry fields. With the discoveries and applications of numerous biomolecule-catalyzed or -assisted processes, these reactions have garnered considerable interest in biochemistry, enzymology, and biocatalysis. Despite the challenges of reactivity and selectivity of biomolecular reactions, the alkylation and acylation reactions demonstrated their utility for the construction and functionalization of all the four major biomolecules (i.e., nucleosides, carbohydrates/saccharides, lipids/fatty acids, and amino acids/peptides/proteins), and their diverse applications in biological, medical, and material fields are discussed. As the alkylation and acylation reactions are often fundamental educational components of organic chemistry courses, this review is intended for both experts and nonexperts by discussing their basic reaction patterns (with the depiction of each reaction mechanism in the ESI) and relevant real-world impacts in order to enrich chemical research and education. The significant growth of biomolecular Friedel-Crafts reactions described here is a testament to their broad importance and utility, and further development and investigations of the reactions will surely be the focus in the organic biomolecular chemistry fields.

Halo-1,2,3-triazoles: Valuable Compounds to Access Biologically Relevant Molecules.

1,2,3-triazole is an important building block in organic chemistry. It is now well known as a bioisostere for various functions, such as the amide or the ester bond, positioning it as a key pharmacophore in medicinal chemistry and it has found applications in various fields including life sciences. Attention was first focused on the synthesis of 1,4-disubstituted 1,2,3-triazole molecules however 1,4,5-trisubstituted 1,2,3-triazoles have now emerged as valuable molecules due to the possibility to expand the structural modularity. In the last decade, methods mainly derived from the copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) reaction have been developed to access halo-triazole compounds and have been applied to nucleosides, carbohydrates, peptides and proteins. In addition, late-stage modification of halo-triazole derivatives by metal-mediated cross-coupling or halo-exchange reactions offer the possibility to access highly functionalized molecules that can be used as tools for chemical biology. This review summarizes the synthesis, the functionalization, and the applications of 1,4,5-trisubstituted halo-1,2,3-triazoles in biologically relevant molecules.

Carbohydrate-Based NK1R Antagonists with Broad-Spectrum Anticancer Activity.

NK1R antagonists, investigated for the treatment of several pathologies, have shown encouraging results in the treatment of several cancers. In the present study, we report on the synthesis of carbohydrate-based NK1R antagonists and their evaluation as anticancer agents against a wide range of cancer cells. All of the prepared compounds, derived from either d-galactose or l-arabinose, have shown high affinity and NK1R antagonistic activity with a broad-spectrum anticancer activity and an important selectivity, comparable to Cisplatin. This strategy has allowed us to identify the galactosyl derivative 14α, as an interesting hit exhibiting significant NK1R antagonist effect (kinact 0.209 ± 0.103 µM) and high binding affinity for NK1R (IC50 = 50.4 nM, Ki = 22.4 nM by measuring the displacement of [125I] SP from NK1R). Interestingly, this galactosyl derivative has shown marked selective cytotoxic activity against 12 different types of cancer cell lines.

Temporary ether protecting groups at the anomeric center in complex carbohydrate synthesis.

The synthesis of a carbohydrate building block usually starts with introduction of a temporary protecting group at the anomeric center and ends with its selective cleavage for further transformation. Thus, the choice of the anomeric temporary protecting group must be carefully considered because it should retain intact during the whole synthetic manipulation, and it should be chemoselectively removable without affecting other functional groups at a late stage in the synthesis. Etherate groups are the most widely used temporary protecting groups at the anomeric center, generally including allyl ethers, MP (p-methoxyphenyl) ethers, benzyl ethers, PMB (p-methoxybenzyl) eithers, and silyl ethers. This chapter provides a comprehensive review on their formation, cleavage, and applications in the synthesis of complex carbohydrates.

Design, synthesis and biological evaluation of novel carbohydrate-based sulfonamide derivatives as antitumor agents.

A series of novel carbohydrate-based sulfonamides were designed and synthesized by the sugar-tail approach. The classical aromatic sulfonamide pharmacophore (ArSO2NH2) was directly linked to a hydrophilic sugar-tail moiety through a rigid 1, 2, 3-triazole linker by the click chemistry reaction. The inhibitory activity against three carbonic anhydrase (CA, EC 4.2.1.1) isozymes (hCA I, hCA II and hCA IX) of all new compounds so designed were investigated in vitro and efficient inhibition against all three CA isoforms, especially the tumor-associated hCA IX, were observed. These glycoconjugate sulfonamide derivatives displayed better inhibitory efficacy in comparison with the starting segments (SA and p-hydroxybenzene sulfonamide). In particular, compound 12g was found to be the most effective and rather selective inhibitor of hCA IX with inhibitory constant (IC50) value of 7 nM, being four times more potent than the clinical used agent acetazolamide (AAZ) (IC50 = 30 nM). Meanwhile, almost all compounds showed moderate antiproliferative activities against two cancer cell lines (HT-29 and MDA-MB-231) in both hypoxic and normoxic conditions while compound 12g also exhibited the most prominent antitumor activity. Furthermore, evident recovery (20-35% reduction of IC50 values) of cytotoxic efficiency of doxorubicin with the combination of compounds 12d, 12g and 22d as CAIs were detected on MDA-MB-231 cell line under hypoxic environment. In addition, docking studies revealed that the sugar-tail fragment of the target compounds participated in interactions with hydrophilic subpocket at the surface of hCA IX active site and supported the CA IX inhibitory activities of carbohydrate-based sulfonamide derivatives.

Enhanced Immune Response Against the Thomsen-Friedenreich Tumor Antigen Using a Bivalent Entirely Carbohydrate Conjugate.

The Thomsen-Friedenreich (TF) antigen is a key target for the development of anticancer vaccines, and this ongoing challenge remains relevant due to the poor immunogenicity of the TF antigen. To overcome this challenge, we adopted a bivalent conjugate design which introduced both the TF antigen and the Thomsen-nouveau (Tn) antigen onto the immunologically relevant polysaccharide A1 (PS A1). The immunological results in C57BL/6 mice revealed that the bivalent, Tn-TF-PS A1 conjugate increased the immune response towards the TF antigen as compared to the monovalent TF-PS A1. This phenomenon was first observed with enzyme-linked immunosorbent assay (ELISA) where the bivalent conjugate generated high titers of IgG antibodies where the monovalent conjugate generated an exclusive IgM response. Fluorescence-activated cell sorting (FACS) analysis also revealed increased binding events to the tumor cell lines MCF-7 and OVCAR-5, which are consistent with the enhanced tumor cell lysis observed in a complement dependent cytotoxicity (CDC) assay. The cytokine profile generated by the bivalent construct revealed increased pro-inflammatory cytokines IL-17 and IFN-γ. This increase in cytokine concentration was matched with an increase in cytokine producing cells as observed by ELISpot. We hypothesized the mechanisms for this phenomenon to involve the macrophage galactose N-acetylgalactosamine specific lectin 2 (MGL2). This hypothesis was supported by using biotinylated probes and recombinant MGL2 to measure carbohydrate-protein interactions.

Constrained saccharides: a review of structure, biology, and synthesis.

Review primarily covers from 1995-2018Carbohydrate function, recognized in a multitude of biological processes, provides a precedent for developing carbohydrate surrogates that mimic the structure and function of bioactive compounds. In order to constrain highly flexible oligosaccharides, synthetic tethering techniques like those exemplified by stapled peptides are utilized to varying degrees of success. Naturally occurring constrained carbohydrates, however, exist with noteworthy cytotoxic and chemosensitizing properties. This review highlights the structure, biology, and synthesis of this intriguing class of molecules.

Synthesis of carbohydrate conjugated 6A,6D-bifunctionalized ß cyclodextrin derivatives as potential liver cancer drug carriers.

Galactosyl and lactosyl conjugated 6A,6D-bifunctionlized ß cyclodextrin derivatives were designed and synthesized as the potential liver cancer drug carriers through SN2 replacement and click reactions in order to increase liver cancer drug's targeting ability, solubility and stability. The synthetic methods and strategies to obtain the designed compounds were discussed.

The Synthesis and Biological Characterization of Acetal-Free Mimics of the Tumor-Associated Carbohydrate Antigens.

Carcinomas express unique carbohydrates, known as tumor-associated carbohydrate antigens (TACAs), on their surface. These are potential targets for anticancer vaccines; however, to date, no such vaccine has reached the clinic. One factor that may complicate the success of this effort is the lability of the glycosidic bond. Acetal-free carbohydrates are analogues that lack the glycosidic linkage by replacing either the endo or exo oxygen with a methylene. This chapter summarizes the seminal syntheses of the mucin TACAs, provides an overview of common techniques for the synthesis of carbasugars and C-glycosides, reviews the syntheses published to date of acetal-free TACA analogues, and provides an overview of their observed biological activity. We conclude by offering a summation of the challenges remaining to the field biologically and the potential that acetal-free TACAs have of answering several basic questions in carbohydrate immunology.

Selective in vivo metabolic cell-labeling-mediated cancer targeting.

Distinguishing cancer cells from normal cells through surface receptors is vital for cancer diagnosis and targeted therapy. Metabolic glycoengineering of unnatural sugars provides a powerful tool to manually introduce chemical receptors onto the cell surface; however, cancer-selective labeling still remains a great challenge. Herein we report the design of sugars that can selectively label cancer cells both in vitro and in vivo. Specifically, we inhibit the cell-labeling activity of tetraacetyl-N-azidoacetylmannosamine (Ac4ManAz) by converting its anomeric acetyl group to a caged ether bond that can be selectively cleaved by cancer-overexpressed enzymes and thus enables the overexpression of azido groups on the surface of cancer cells. Histone deacetylase and cathepsin L-responsive acetylated azidomannosamine, one such enzymatically activatable Ac4ManAz analog developed, mediated cancer-selective labeling in vivo, which enhanced tumor accumulation of a dibenzocyclooctyne-doxorubicin conjugate via click chemistry and enabled targeted therapy against LS174T colon cancer, MDA-MB-231 triple-negative breast cancer and 4T1 metastatic breast cancer in mice.

Sugar Based Biopolymers in Nanomedicine; New Emerging Era for Cancer Imaging and Therapy.

Since last decade, sugar based biopolymers are recognized in nanomedicine as promising materials for cancer imaging and therapy. Their durable, biocompatible and adhesive properties enable the fine tuning of their molecular weights (MW) and their miscellaneous nature makes the molecules acquire various conformations. These in turn provide effective endocytosis by cancer cell membranes that have already been programmed for internalization of different kinds of sugars. Therefore, biocompatible sugar based nanoparticles (SBNPs) are suitable for both cell-selective delivery of drugs and imaging through the human body. Recently, well known sugar-based markers have displayed superior performance to overcome tumor metastasis. Thereby, targeting strategies for cancer cells have been broadened to sugar-based markers as noticed in various clinic phases. In these studies, biopolymers such as chitosan, hyaluronic acid, mannan, dextran, levan, pectin, cyclodextrin, chondroitin sulphate, alginates, amylose and heparin are chemically functionalized and structurally designed as new biocompatible nanoparticles (NPs). The future cancer treatment strategies will mainly comprise of these multifunctional sugar based nanoparticles which combine the therapeutic agents with imaging technologies with the aim of rapid monitoring response to therapies. While each individual imaging and treatment step requires a long time period in effective treatment of diseases, these multifunctional sugar based nanoparticles will have the advantage of rapid detection, right drug efficiency evaluation and immediate interfere opportunity to some important diseases, especially rapidly progressing cancers. In this article, we evaluated synthesis, characterization and applications of main sugar based biopolymers and discussed their great promise in nano-formulations for cancer imaging and therapy. However much should be done and optimized prior to clinical applications of these nano-formulations for an efficient drug treatment without overall toxicity for getting most effective clinical results.

Isoxazolidine: A Privileged Scaffold for Organic and Medicinal Chemistry.

The isoxazolidine ring represents one of the privileged structures in medicinal chemistry, and there have been an increasing number of studies on isoxazolidine and isoxazolidine-containing compounds. Optimization of the 1,3-dipolar cycloaddition (1,3-DC), original methods including electrophilic or palladium-mediated cyclization of unsaturated hydroxylamine, has been developed to obtain isoxazolidines. Novel reactions involving the isoxazolidine ring have been highlighted to accomplish total synthesis or to obtain bioactive compounds, one of the most significant examples being probably the thermic ring contraction applied to the total synthesis of (±)-Gelsemoxonine. The unique isoxazolidine scaffold also exhibits an impressive potential as a mimic of nucleosides, carbohydrates, PNA, amino acids, and steroid analogs. This review aims to be a comprehensive and general summary of the different isoxazolidine syntheses, their use as starting building blocks for the preparation of natural compounds, and their main biological activities.

Regioselective synthesis of naphthoquinone/naphthoquinol-carbohydrate hybrids by [4 + 2] anionic annulations and studies on their cytotoxicity.

An efficient and regioselective synthetic route to naphthoquinone/naphthoquinol-carbohydrate hybrids has been developed. It is based upon anionic annulation of 3-nucleofugalphthalides with an acrylate appended sugar moiety. In each of the annulations studied, the arene-carbohydrate hybrids were obtained in good to excellent yields. The in vitro cytotoxic activity of the synthetic naphthoquinone/naphthonol-carbohydrate hybrids were evaluated against the human cervical cancer cell line (HeLa), and a few of them were found to exhibit potent anticancer activity against the cell line.

Carbohydrate-based peptidomimetics targeting neuropilin-1: Synthesis, molecular docking study and in vitro biological activities.

Neuropilin-1 (NRP-1), a transmembrane glycoprotein acting as a co-receptor of VEGF-A, is expressed by cancer and angiogenic endothelial cells and is involved in the angiogenesis process. Taking advantage of functionalities and stereodiversities of sugar derivatives, the design and the synthesis of carbohydrate based peptidomimetics are here described. One of these compounds (56) demonstrated inhibition of VEGF-A165 binding to NRP-1 (IC50=39µM) and specificity for NRP-1 over VEGF-R2. Biological evaluations were performed on human umbilical vein endothelial cells (HUVECs) through activation of downstream proteins (AKT and ERK phosphorylation), viability/proliferation assays and in vitro measurements of anti-angiogenic abilities.

A Carbohydrate-Derived Splice Modulator.

Small-molecule splice modulators have recently been recognized for their clinical potential for diverse cancers. This, combined with their use as tools to study the importance of splice-regulated events and their association with disease, continues to fuel the discovery of new splice modulators. One of the key challenges found in the current class of materials arises from their instability, where rapid metabolic degradation can lead to off-target responses. We now describe the preparation of bench-stable splice modulators by adapting carbohydrate motifs as a central scaffold to provide rapid access to potent splice modulators.

Carbohydrate CuAAC click chemistry for therapy and diagnosis.

Carbohydrates are important as signaling molecules and for cellular recognition events, therefore offering scope for the development of carbohydrate-mimetic diagnostics and drug candidates. As a consequence, the construction of carbohydrate-based bioactive compounds and sensors has become an active research area. While the advent of click chemistry has greatly accelerated the progress of medicinal chemistry and chemical biology, recent literature has seen an extensive use of such approaches to construct functionally diverse carbohydrate derivatives. Here we summarize some of the progress, covering the period 2010 to mid-2015, in Cu(I)-catalyzed azide-alkyne 1,3-dipolar cycloaddition CuAAC "click chemistry" of carbohydrate derivatives, in the context of potential therapeutic and diagnostic tool development.

TiO2-catalyzed synthesis of sugars from formaldehyde in extraterrestrial impacts on the early Earth.

Recent synthetic efforts aimed at reconstructing the beginning of life on our planet point at the plausibility of scenarios fueled by extraterrestrial energy sources. In the current work we show that beyond nucleobases the sugar components of the first informational polymers can be synthesized in this way. We demonstrate that a laser-induced high-energy chemistry combined with TiO2 catalysis readily produces a mixture of pentoses, among them ribose, arabinose and xylose. This chemistry might be highly relevant to the Late Heavy Bombardment period of Earth's history about 4-3.85 billion years ago. In addition, we present an in-depth theoretical analysis of the most challenging step of the reaction pathway, i.e., the TiO2-catalyzed dimerization of formaldehyde leading to glycolaldehyde.

Recent advances in synthetic carbohydrate-based human immunodeficiency virus vaccines.

An effective vaccine for human immunodeficiency virus (HIV) is urgently needed to prevent HIV infection and progression to acquired immune deficiency syndrome (AIDS). As glycosylation of viral proteins becomes better understood, carbohydrate-based antiviral vaccines against special viruses have attracted much attention. Significant efforts in carbohydrate synthesis and immunogenicity research have resulted in the development of multiple carbohydrate-based HIV vaccines. This review summarizes recent advances in synthetic carbohydrate-based vaccines design strategies and the applications of these vaccines in the prevention of HIV.

High-Throughput Synthesis of Diverse Compound Collections for Lead Discovery and Optimization.

Small-molecule intervention of protein function is one central dogma of drug discovery. The generation of small-molecule libraries fuels the discovery pipeline at many stages and thereby resembles a key aspect of this endeavor. High-throughput synthesis is a major source for compound libraries utilized in academia and industry, seeking new chemical modulators of pharmacological targets. Here, we discuss the crucial factors of library design strategies from the perspective of synthetic chemistry, giving a brief historic background and a summary of current approaches. Simple measures of success of a high-throughput synthesis such as quantity or diversity have long been discarded and replaced by more integrated measures. Case studies are presented and put into context to highlight the cross-connectivity of the various stages of the drug discovery process.

Synthesis, characterization, cytotoxic and antitubercular activities of new gold(I) and gold(III) complexes containing ligands derived from carbohydrates.

Novel gold(I) and gold(III) complexes containing derivatives of D-galactose, D-ribose and D-glucono-1,5-lactone as ligands were synthesized and characterized by IR, (1)H, and (13)C NMR, high resolution mass spectra and cyclic voltammetry. The compounds were evaluated in vitro for their cytotoxicity against three types of tumor cells: cervical carcinoma (HeLa) breast adenocarcinoma (MCF-7) and glioblastoma (MO59J) and one non-tumor cell line: human lung fibroblasts (GM07492A). Their antitubercular activity was evaluated as well expressed as the minimum inhibitory concentration (MIC90) in µg/mL. In general, the gold(I) complexes were more active than gold(III) complexes, for example, the gold(I) complex (1) was about 8.8 times and 7.6 times more cytotoxic than gold(III) complex (8) in MO59J and MCF-7 cells, respectively. Ribose and alkyl phosphine derivative complexes were more active than galactose and aryl phosphine complexes. The presence of a thiazolidine ring did not improve the cytotoxicity. The study of the cytotoxic activity revealed effective antitumor activities for the gold(I) complexes, being more active than cisplatin in all the tested tumor cell lines. Gold(I) compounds (1), (2), (3), (4) and (6) exhibited relevant antitubercular activity even when compared with first line drugs such as rifampicin.