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A series of eight new conjugates of salinomycin or monensin and Cinchona alkaloids were obtained by the Cu(I)-catalysed 1,3-dipolar Huisgen cycloaddition (click chemistry) of respective N-propargyl amides of salinomycin or monensin with four different Cinchona alkaloid derived azides. In vitro antiproliferative activity of these conjugates evaluated against three cancer cell lines (LoVo, LoVo/DX, HepG2) showed that four of the compounds exhibited high antiproliferative activity (IC50 below 3.00 μm) and appeared to be less toxic and more selective against normal cells than two standard anticancer drugs.

The synthetic routes to 25-hydroxy derivatives of 4-methylcholest-4-ene and 4,4-dimethylcholest-5-ene from methyl lithocholate and methyl 3β-acetoxy-24-homochol-5-en-25-oate (6) have been investigated. The cholest-5-ene-3β,25-diol (7), readily available from 6, was transformed in a few steps into the title compounds. It was also found that bromination of 24-acetoxy-5β-cholan-3-one (1) and of its enol acetate followed by dehydrobromination is not a regioselective reaction. Formation of mixtures of 2β-bromo-3-oxo and 4β-bromo-3-oxo compounds, which gave mixtures of 24-acetoxychol-4-en-3-one (4) and 24-acetoxy-5β-chol-1-en-3-one (5) of similar polarity was observed. 4-Methyl-25-hydroxycholest-4-en-3-one (14) and 4-methyl-25-hydroxycholesta-1,4-dien-3-one (16) are potential substrates for the preparation of 4-methyl analogs of vitamin D3.

Proclaimed by Sharpless in 2001, the manifesto of click chemistry philosophy shifted the focus from target-oriented to drug-like-oriented synthesis, and has enormously accelerated the drug-discovery process over the last two decades. Copper(I)-catalyzed and metal-free versions of the Huisgen 1,3-dipolar cycloaddition of azides and alkynes have become the reference click chemistry synthetic tools. These processes are adaptable to various drug-design modes such as kinetic target guided synthesis (in situ click chemistry assembling; KTGS), combinatorial chemistry/high-throughput-screening approaches, or structure-based rational projecting. Moreover, the facile click chemistry derivatization of natural or synthetic products, linking molecules or improving the stability of leads by installation of 1,2,3-triazoles, is another important stream of bioactivities. This review is intended to provide a general overview of click-chemistry-powered drug design, with dozens of successful examples resulting in the discovery of nanomolar-active 1,2,3-triazoles in every stage of drug development.