Ligand based repourposing of naphtodithiophene compounds in the antitumor targeted therapy

A crucial point in Medicinal Chemistry is the discovery of promising lead compounds and their optimization, in order to obtain new molecules with a good bioavailability and a high affinity for focused biological target. In lead optimization matter, the medicinal chemists have at their disposal several approaches more or less intuitive, such as the synthesis of drug analogues, isomer and isosteres, the modification of ring systems or the rational pharmacophore identification by computer-assisted drug design. In this context, the drug repurposing is a fashionable strategy to assign new therapeutic uses to known drugs or to promising molecules halted during the clinical development process.(1) In this work we propose a series of new naphthodithiophene compounds of type 1 and 2, firstly targeted as G-quadruplex (G4) stabilizers, and now repositioned as PTP1B and BCL2 inhibitors. The naphthodithiophene prototypes resulted as output molecules of in silico virtual screening structure-based studies (molecular docking, induced fit docking, molecular dynamics) applied on an in house database, that allow to correlate, with a good affinity score, these planar heterocyclic compounds to the secondary DNA structure rich in guanine, G4. Even if the preliminary in vitro studies suggested a good antiproliferative activity of the synthetized naphthodithiophenes 1 and 2 against the HeLa human cancer cell line, the consequent binding tests with G4s isoforms were unsatisfactory. Herein, we illustrate the description of the synthetic pathway carried out for the isolation and characterization of the whole new series of naphthodithiophene compounds 1 and 2 and their biological re-tasking as potential PTP1B and BCL2 inhibitors, with the help of new and innovative chemoinformatic tools