# Bicyclic N,S-Acetals Containing Fused Cysteine-Amide System as New Heterocyclic Class Targeting Human Farnesyltransferase (FTase-h)

## TL;DR

This paper introduces a new class of chiral compounds that effectively inhibit human farnesyltransferase, a key enzyme in cancer-related processes.

## Contribution

The study presents a novel synthetic approach to create thiazoloisoindolinone scaffolds as potent farnesyltransferase inhibitors.

## Key findings

- The synthesized N,S-acetal systems showed nanomolar inhibitory activity against FTase-h.
- Sulfoxide 5bG exhibited the best half maximal inhibitory concentration (IC50) value of 4.03 nM.
- The compounds were derived from cost-effective and readily available L-cysteine hydrochloride.

## Abstract

We report in this contribution the synthesis and in vitro biological evaluation of a novel class of chiral thiazoloisoindolinone scaffolds as potent inhibitors against human farnesyltransferase (FTase-h). The targeted products, sulfides (4), sulfoxides (5,6), and sulfones (7), containing up to three points of diversification, were obtained in a short-step sequence starting from the available and cost-effective L-cysteine hydrochloride (1), which is the source of N and S atoms and the chiral pool, and α-carbonyl benzoic acids (2), which are isoindolinone precursors. Concisely, the key ester intermediates (1) provide (a) sulfide-amides (4) by solvent-free amidation, (b) sulfoxides (5,6) by selective S-oxidation using NaIO4, and (c) sulfones (7) by oxidation using MMPP. Finally, the obtained N,S-acetal systems have shown promising inhibitory activities on FTase-h in the nanomolar range with excellent half maximal inhibitory concentration (IC50) values up to 4.0 nanomolar (for example, 25.1 nM for sulfide 4bI, 67.3 nM for sulfone 7bG, and more interesting of 4.03 nM for sulfoxide 5bG).