Recent Advances in Small Molecule-Based Intracellular pH Probes.

Intracellular pH plays an important role in many biological and pathological processes. Small-molecule based pH probes are found to be the most effective for pH sensing because of ease of preparation, high sensitivity, and quick response. They have many advantages such as small perturbation to the functions of the target, functional adaptability, cellular component-specific localization, etc. The present review highlights the flurry of recent activity in the development of such probes. The probes are categorized based on the type of fluorophore used like quinoline, coumarin, BODIPY, rhodamine, indolium, naphthalimide, etc., and their analytical performance is discussed.

Recent advances in the synthesis of pyrrolo[1,2-a]indoles and their derivatives.

The pyrrolo[1,2-a]indole unit is a privileged heterocycle found in numerous natural products and has been shown to exhibit diverse pharmacological properties. Thus, recent years have witnessed immense interest from the synthesis community on the synthesis of this scaffold. In light of the ever-increasing demand for pyrrolo[1,2-a]indoles in drug discovery, this review provides an overview of recent synthesis methods for the preparation of pyrrolo[1,2-a]indoles and their derivatives. The mechanistic pathway and stereo-electronic factors affecting the yield and selectivity of the product are briefly explained. Furthermore, we have attempted to demonstrate the utility of the developed methods in the synthesis of bioactive molecules and natural products, wherever offered.

Design, Synthesis, and Biological Investigation of Epothilone B Analogues Featuring Lactone, Lactam, and Carbocyclic Macrocycles, Epoxide, Aziridine, and 1,1-Difluorocyclopropane and Other Fluorine Residues.

Despite previous studies within the epothilone field, only one member of this compound family, ixabepilone, made it to approval for clinical use. Recent advances in organic synthesis and medicinal chemistry allow further optimization of lead epothilone analogues aiming to improve their potencies and other pharmacological properties as part of the quest for discovery and development of new anticancer drugs, including antibody-drug conjugates as potential targeted cancer therapies. Herein, we report the design, synthesis, and biological evaluation of a series of new epothilone B analogues equipped with novel structural motifs, including fluorine-containing residues, 12,13-difluorocyclopropyl moieties, mono- and dimethylated macrolactones, and 1-keto macrocyclic systems, as well as two N-substituted ixabepilone analogues in which the 12,13-epoxide and macrolactam NH moieties were replaced, the former with a substituted aziridine moiety and the latter with an NCO-alkyl residue (imide or carbamate). Biological evaluation of these analogues revealed a number of exceptionally potent epothilone B analogues, demonstrating the potency enhancing effects of the fluorine residues and the aziridinyl moiety within the structure of the epothilone molecule and providing new and useful structure-activity relationships within this class of compounds.

Metal-free Hydroalkoxylation-Formal [4+2] Cycloaddition Cascade for the Synthesis of Ketals.

A transition metal free, acid promoted cascade hydroalkoxylation-formal [4+2] cycloaddition of various alkynols with salicylaldehyde is demonstrated for the synthesis of tetrahydrofurano/pyrano-chromenes and spiroketals. In general, alkynols underwent hydroalkoxylations in an endo-dig manner when internal alkynes were used to furnish the heteroannular ketals, whereas terminal alkynes proceeded in an exo-dig fashion leading to spiroketals. The study revealed that intramolecular hydroalkoxylation of alkynols is a preferred path over a generation of oxonium ions when coupling partner is salicylaldehyde. This metal-free transformation provides a new avenue for the stereoselective synthesis of tetrahydrofurano- and pyrano-chromenes in an expeditious manner.

Lewis Acid Promoted Oxonium Ion Driven Carboamination of Alkynes for the Synthesis of 4-Alkoxy Quinolines.

Lewis acid mediated multisegment coupling cascade is designed for the synthesis of densely substituted 4-alkoxy quinolines via an oxonium ion triggered alkyne carboamination sequence involving C-C and C-N bond formations. Cyclic ether fused-quinolines could also be accessed using this fast, operationally simple, high yielding, chemoselective and functional group tolerant method. Versatility and utility of this methodology is demonstrated by postfunctionalization of products obtained and its use in synthesis of potent drug molecules.

Cascade Radical Cyclization on Alkynyl Vinylogous Carbonates for the Divergent Synthesis of Tetrasubstituted Furans and Dihydrofurans.

A single alkynyl vinylogous carbonate was elaborated to tetrasubstituted furan or dihydrofuran via a cascade inter-intramolecular radical reaction by changing the radical being added. The strategy could be used in the synthesis of polycyclic heterocycles as well as bis-furan exhibiting atropisomerism. Installation of a new furan motif on the existing one was feasible by iteration. Stannyl dihydrofuran derivative was used in Stille coupling, whereas intramolecular Friedel-Crafts acylation on the furan gave furanonaphthol.

Homogeneous Catalysis: A Powerful Technology for the Modification of Important Biomolecules.

Homogeneous catalysis plays an important and ubiquitous role in the synthesis of simple and complex molecules, including drug compounds, natural products, and agrochemicals. In recent years, the wide-reaching importance of homogeneous catalysis has made it an indispensable tool for the modification of biomolecules, such as carbohydrates (sugars), amino acids, peptides, nucleosides, nucleotides, and steroids. Such a synthetic strategy offers several advantages, which have led to the development of new molecules of biological relevance at a rapid rate relative to the number of available synthetic methods. Given the powerful nature of homogeneous catalysis in effecting these synthetic transformations, this Focus Review has been compiled to highlight these important developments.

Cascade Radical Cyclization of N-Propargylindoles: Substituents Dictate Stereoselective Formation of N-Fused Indolines versus Indoles.

An efficient protocol for the synthesis of pyrrolo[1,2-a]indole derivatives having sulfide functionality using cascade radical cyclization on propargylindole is described. The nature of the substituents at the propargylic carbon bearing nitrogen of the indole has a profound effect on the rate, yield, and nature of the product obtained by the cascade radical cyclization. An expeditious one-pot route for cascade radical cyclization-desulfurization is also presented. Products obtained were elaborated to the core of the putative structure of the yuremamine and indoline derivative with five contiguous stereocenters.

Lewis Acid Mediated Cascade Friedel-Craft/Alkyne Indol-2-yl Cation Cyclization/Vinyl Cation Trapping for the Synthesis of N-Fused Indole Derivatives.

A Lewis acid promoted cascade Friedel-Craft/alkyne indol-2-yl cation cyclization/vinyl cation trapping for an efficient and divergent synthesis of N-fused indoles is developed. The present study illustrates the first example of an alkyne as a nucleophile on the less explored indol-2-yl cation. The method efficiently affords pharmaceutically important pyrrolizino-quinolines and complex fused indole derivatives in high yields.

Counter-ion-dependent alkyne iminium ion cyclization for divergent synthesis of N-fused indolylidine, indole, and indoline derivatives promoted by the Lewis/Bronsted acid.

Divergent synthesis of N-fused indolylidine, indole, and indoline derivatives using alkyne iminium ion cyclization is described. Trapping of vinyl cation intermediate generated after alkyne iminium ion cyclization was found to be dependent on the Lewis/Bronsted acid and solvent used. N-Fused indolylidine triflate could be used in the divergent synthesis of N-fused indole derivatives.