H₂O‐Mediated Epoxide Ring‐Opening with Concomitant C–S Bond Formation: A One‐Pot Method to 3‐Hydroxy‐oxindolino‐dithiocarbamates as Cytotoxic Agents

Abstract

A simple and efficient one‐pot protocol for the synthesis of a library of 3‐hydroxy‐oxindolino‐dithiocarbamate hybrids has been developed and evaluated for their in vitro cytotoxicity potential against selected human cancer cell lines. This one‐pot reaction takes place via regiospecific spiro‐epoxide ring‐opening with concomitant C–S bond formation by an in situ generation of dithiocarbamate intermediate. Gratifyingly, the reaction has been accelerated efficiently in water medium without using any catalyst or base and enable higher yields, atom‐economy, greener synthesis and offers diverse substrate scope. Among the tested compounds, one of the representative compounds 4 p with a chloro substitution and N‐p‐CN‐benzyl on oxindole nucleus displayed potent in vitro cytotoxicity against MCF‐7 (breast cancer cells) with an IC50 value of 2.1 ± 0.4 μM. Moreover, the promising candidate 4 p induce G2/M phase cell cycle arrest and apoptosis on MCF‐7 cells, as determined by AO‐EB and DAPI staining as well as annexin binding studies

Synthesis of 2‐Aryl‐2‐hydroxyethyl Dithiocarbamates via Regioselective Addition of Tetraalkylthiuram Disulfides to Styrenes under Transition‐Metal‐Free Conditions

“…Organic dithiocarbamates are important molecules due to their outstanding bio-activity in natural and synthetic products, [13] potent anticancer agents [14] and antifungal agents. [15] They are likewise used as vulcanization accelerators in the rubber industry, [16] as linkers in solid-phase organic synthesis, [17] and recently used in the synthesis of ionic liquids.…”

Reliability of Click Chemistry on Drug Discovery: A Personal Account

“…In 2018, we reported a one‐pot method for the opening of the epoxide ring using dithiocarbamate as a nucleophile leading to the synthesis of 3‐hydroxy‐oxindolino‐dithiocarbamate hybrids 126 a – ax . This efficient protocol happens by an in situ formation of dithiocarbamate intermediate through a concomitant C−S bond formation in water and without any base or catalyst.…”

“…This efficient protocol happens by an in situ formation of dithiocarbamate intermediate through a concomitant C−S bond formation in water and without any base or catalyst. In the report, we described a wide substrate scope for this protocol with the synthesis of 40 molecules involving a variety of secondary amines 124 such as piperidine, pyrrolidine, morpholine, N ‐methyl/ tert ‐butyl piperazine and dimethylamine along with various N ‐alkylations and substitutions on spiro‐epoxyoxindoles 116 . Atom economy, water mediated‐greener synthesis remains a highlight of this protocol.…”